Pesticide-Induced Diseases: Brain and Nervous System Disorders

Updates from the Daily News Blog

PACT Act Success and Reflection Ahead of Veteran's Day, Charts Pathway for Organic
November 11, 2024

National Call To Ban Weed Killer Linked to Parkinson’s Disease Gains Momentum, Stalls in California
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One of World's Largest Dementia Clusters in Young People May Be Tied to High Blood Levels of Glyphosate
September 3, 2024

Modes of Action of Persistent Pesticides Documented, with Ongoing Poisoning and Multigenerational Effects
August 20, 2024

Pesticide-Induced Gut Microbiota Composition Alterations Linked to Parkinson’s Disease Prognosis
August 15, 2024

Cross-Sectional Study Finds Connection Between Pesticide Exposure and Alzheimer’s Disease
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Parkinson’s Disease Explodes as Researchers Find Connection to Pesticide Exposure and Genes
May 3, 2024

Research Links Parkinson’s and Lewy Body Disease with Chemical Effects on Brain and Gut
April 19, 2024

ALS Risk Elevated from Toxic Petrochemical Landscape Pesticides, Study Adds to Previous Findings
April 18, 2024

California Bill Would Ban Deadly Weedkiller, Paraquat, Linked to Parkinson’s Disease in Face of EPA Inaction
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• Environmental pesticide exposure and Alzheimer's disease in southern Spain: A cross-sectional study
  The intensive cultivation under plastic in southern Spain has made the agricultural model highly productive. Although strict regulations on pesticide usage exist, exposure to pesticides in the environment has been associated with an increased appearance of neurodegenerative diseases including Alzheimer's disease (AD). A cross-sectional study was performed to examine the prevalence and risk of AD related to pesticide exposure in Andalusia (Spain). We utilized the Odds Ratio statistical test to compare the prevalence rate of AD in the exposed and unexposed areas. 40,044 cases were collected from computerized hospital records between 2000 and 2021. Districts with higher pesticide use showed significantly higher prevalence rates and increased risk of developing AD, compared to those with lower pesticide use. These findings provide further evidence supporting an increased risk of AD following environmental exposure to pesticides at the level of the general population.
  [Ruiz-González, C. et al. (2024) Environmental pesticide exposure and alzheimer’s disease in southern Spain: A cross-sectional study, Psychiatry Research. Available at: https://www.sciencedirect.com/science/article/pii/S0165178124002178?via%3Dihub. ]
• Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells
  Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment. The disruption of autophagosome-lysosome function has been linked to the pathogenesis of Alzheimer's disease. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant that has the potential to cause neuronal damage. We found that TDCIPP significantly increased the expression of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), presenilin-1 (PS1) and Aβ42. Proteomic studies with TMT labeling revealed changes in the profiles of N2a-APPswe cells after exposure to TDCIPP. Proteomic and bioinformatics analyses revealed that lysosomal proteins were dysregulated in N2a-APPswe cells after treatment with TDCIPP. The LC3, P62, CTSD, and LAMP1 levels were increased after TDCIPP exposure, and dysregulated protein expression was validated by Western blotting. The exposure to TDCIPP led to the accumulation of autophagosomes, and this phenomenon was enhanced in the presence of chloroquine (CQ). Our results revealed for the first time that TDCIPP could be a potential environmental risk factor for AD development. The inhibition of autophagosome-lysosome fusion may have a significant impact on the generation of Aβ1-42 in response to TDCIPP.
  [Zou, C. et al. (2024) Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells, Heliyon. Available at: https://www.cell.com/heliyon/fulltext/S2405-8440(24)02863-9. ]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
  Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
  [Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ]
• Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease
  Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
  [Tang, B.L., 2020. Toxics, 8(2), p.21.]
• Pesticides, cognitive functions and dementia: A review
  Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person’s quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer’s disease.
  [Aloizou, A.M., Siokas, V., Vogiatzi, C., Peristeri, E., Docea, A., Petrakis, D., Provatas, A., Folia, V., Chalkia, C., Vinceti, M. and Wilks, M., 2020. Pesticides, cognitive functions and dementia: A review. Toxicology Letters.]
• Gut microbiota in neurodegenerative disorders
  Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.

   
  [Sarkar, S. R., & Banerjee, S. (2019). Gut microbiota in neurodegenerative disorders. Journal of neuroimmunology, 328, 98-104. https://www.sciencedirect.com/science/article/pii/S0165572818304545 ]

• Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
  Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
  [Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.]
• Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
  Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.
  [Pearson, B.L., Simon, J.M., McCoy, E.S., Salazar, G., Fragola, G. and Zylka, M.J., 2016. Nature communications, 7(1), pp.1-12.]
• Organophosphate pesticide exposure and neurodegeneration
  Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
  [Sánchez-Santed, F., Colomina, M.T. and Hernández, E.H., 2016. Cortex, 74, pp.417-426.]
• Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment.
  Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.Search was conducted in PubMed and Web of Science databases and articles were selected if the following inclusion criteria were met: being a SR, published until April 2015 and without language restrictions.The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.
  [Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M. 2016. Environ Int. 92-93:657-79. ]
• Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.
  Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.
  [Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. 2015. Front Cell Neurosci. 9:124]
• Elevated serum pesticide levels and risk for Alzheimer disease.
  The aim of this study was to evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association.A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases.Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status.Levels of DDE were 3.8-fold higher in the serum of those with AD when compared with control participants. The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD and lower Mini-Mental State Examination scores. The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele. Serum levels of DDE were highly correlated with brain levels of DDE. Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein.Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.
  [Richardson JR, Roy A, Shalat SL, et al. 2014. JAMA Neurol.71(3):284-90]
• Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
  The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
  [Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
• Linking pesticide exposure and dementia: what is the evidence?
  There has been a steep increase in the prevalence of dementia in recent decades, which has roughly followed an increase in pesticide use some decades earlier, a time when it is probable that current dementia patients could have been exposed to pesticides. This raises the question whether pesticides contribute to dementia pathogenesis. Indeed, many studies have found increased prevalence of cognitive, behavioral and psychomotor dysfunction in individuals chronically exposed to pesticides. Furthermore, evidence from recent studies shows a possible association between chronic pesticide exposure and an increased prevalence of dementia, including Alzheimer's disease (AD) dementia. At the cellular and molecular level, the mechanism of action of many classes of pesticides suggests that these compounds could be, at least partly, accountable for the neurodegeneration accompanying AD and other dementias. For example, organophosphates, which inhibit acetylcholinesterase as do the drugs used in treating AD symptoms, have also been shown to lead to microtubule derangements and tau hyperphosphorylation, a hallmark of AD. This emerging association is of considerable public health importance, given the increasing dementia prevalence and pesticide use. Here we review the epidemiological links between dementia and pesticide exposure and discuss the possible pathophysiological mechanisms and clinical implications of this association.
  [Zaganas I, Kapetanaki S, et al. 2013. Toxicology. 307:3-11]
• Neurotoxicity of pesticides: its relationship with neurodegenerative diseases
  Several epidemiological studies suggest that pesticides could lead to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Among pesticides, insecticides appear more neurotoxic than others but the neurotoxic mechanisms leading to adverse health effects remain unclear. The currently used pesticides such as rotenone and paraquat could disrupt mitochondrial bioenergetic function, reactive oxygen metabolism, redox function and promote α-synuclein aggregation. In addition, recent studies demonstrate that genetic susceptibility to Parkinson's disease could monitor pesticide susceptibility, as demonstrated for polymorphisms in pesticide metabolizing enzymes that are involved in organophosphorus sensitivity.
  [Thany SH, Reynier P, Lenaers G. 2013. Med Sci (Paris). 29(3):273-8]
• Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica.
  Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. Authors conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica. Initial screens were given: mini-mental states exam (MMSE) and a modified version of a 10-item united Parkinson's disease rating motor subscale (UPDRS). Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed. The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest, and finger-tapping. Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3-4 times the expected based on international data. Among subjects who took the UPDRS, the exposed had an increased risk of PD. No excess risk was found for a diagnosis of AD or mild cognitive impairment. Authors conclude that elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure.
  [Steenland K, Wesseling C, Román N, Quirós I, Juncos JL. 2013. Environ Res.120:96-101]
• Parkinson disease and Alzheimer disease: environmental risk factors.
  The purpose of this review is to update and summarise available evidence on environmental risk factors that have been associated with risk of Parkinson disease (PD) or Alzheimer disease (AD) and discuss their potential mechanisms.Evidence consistently suggests that a higher risk of PD is associated with pesticides and that a higher risk of AD is associated with pesticides, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, smoking, traumatic brain injury and depression. There is weak evidence suggesting that higher risk of PD is associated with high iron intake, chronic anaemia and traumatic brain injury. Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use, while a lower risk of AD is associated with moderate alcohol consumption, physical exercise, perimenopausal hormone replacement therapy and good cognitive reserve. Several environmental factors contribute significantly to risk of PD and AD. Some may already be active in the early stages of life, and some may interact with other genetic factors. Population-based strategies to modify such factors could potentially result in fewer cases of PD or AD.
  [Campdelacreu J.2012. Neurologia. Epub ahead of print]
• Association between environmental exposure to pesticides and neurodegenerative diseases
  Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
  [Parrón, T., Requena, M., Hernández, A.F. and Alarcón, R., 2011. Toxicology and applied pharmacology, 256(3), pp.379-385.]
• Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2.
  Pesticide exposure is a risk factor of Alzheimer's disease (AD). However, little is known about how pesticide exposure may promote AD pathogenesis. In this study, we investigated the effects of paraquat pesticide exposure on β-amyloid (Aβ) levels and cognition using wild-type (WT) mice and β-amyloid precursor protein (APP) transgenic mice. Our results showed that wild-type mice and APP transgenic mice after paraquat exposure had increased oxidative damage specifically in mitochondria of cerebral cortex and exhibited mitochondrial dysfunction. Moreover, the elevated mitochondrial damage was directly correlated with impaired associative learning and memory and increased Aβ levels in APP transgenic mice exposed to paraquat. Furthermore, overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme important for H2O2 removal, protected against paraquat-induced mitochondrial damage and concomitantly improved cognition and decreased Aβ levels in APP transgenic mice. Therefore, our results demonstrate that mitochondrial damage is a key mechanism underlying cognitive impairment and elevated amyloidogenesis induced by paraquat and that enhanced removal of mitochondrial H2O2 could be an effective strategy to ameliorate AD pathogenesis induced by pesticide exposure.
  [Chen, L., et al. 2011. Neurobiol Aging. [Epub ahead of print]
• Alzheimer disease: Risk of dementia and Alzheimer disease increases with occupational pesticide exposure
  Occupational exposure to pesticides increases the risk of developing dementia and Alzheimer disease (AD) in later life, according to this longitudinal population-based cohort study. The results of this study provide further evidence that certain environmental factors are risk factors for these debilitating conditions.
  [Jones N.2010. Nat Rev Neurol. 6(7):353]
• Occupational exposure to pesticides increases the risk of incident AD
  Study of individuals from an agricultural community in Utah shows increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09–1.76, and for Alzheimer’s Disease (AD) (HR 1.42, 95% CI 1.06–1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05–2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99–2.24)
  [Hayden KM, et al. 2010. Neurology, May 11;74(19):1524-30]
• Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies.
  Eleven studies explored the relationship of AD with solvents, seven with EMF, six with pesticides, six with lead and three with aluminium. For pesticides, studies of greater quality and prospective design found increased and statistically significant associations.
  [Santibáñez M, et al. 2007. Occup Environ Med. Nov;64(11):723-32. Epub 2007 May 24]
• Neurodegenerative Diseases and Exposure to Pesticides in the Elderly.
  Study of 1,507 French elderly (1992–1998) shows lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson’s disease and Alzheimer’s disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively.
  [Baldi, I, et al. Am J Epidemiol 2003; 157:409-414.]
• Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada.
  Study of a longitudinal, population-based study of dementia in Manitoba, Canada shows occupational exposure to fumigants and/or defoliants was a significant risk factor for Alzheimer's disease (relative risk [RR] = 4.35; 95% CI : 1.05--17.90).
  [Tyas SL, et al. Int J Epidemiol. 2001 Jun;30(3):598-9]

• Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study
  Background: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden. Objective: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment. Methods: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome. Results: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, padjusted < 0.001), gasoline-powered equipment (OR = 1.16, padjusted < 0.001), and lawn care products (OR = 1.15, padjusted < 0.001) representing the top three risk factors sorted by padjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment. Conclusion: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.
  [Goutman, S.A. et al. (2024) ‘Residential exposure associations with ALS risk, survival, and phenotype: A Michigan-based case-control study’, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. Available at: https://www.tandfonline.com/doi/full/10.1080/21678421.2024.2336110. ]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Associations of self-reported occupational exposures and settings to ALS: a case–control study
  Background
  Environmental exposures contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal and progressive neurological disease. Identification of these exposures is important for targeted screening and risk factor modification.

  Objective
  To identify occupational exposures that are associated with a higher risk of ALS using both survey and standard occupational classification (SOC) coding procedures, and to highlight how exposure surveys can complement SOC coding.

  Methods
  ALS participants and neurologically healthy controls recruited in Michigan completed a detailed exposure assessment on their four most recent and longest held occupations. Exposure scores were generated from the exposure survey, and occupations were assigned to SOC codes by experienced exposure scientists.

  Results
  This study included 381 ALS and 272 control participants. ALS participants reported higher duration-adjusted occupational exposure to particulate matter (OR = 1.45, 95% CI 1.19–1.78, p < 0.001), volatile organic compounds (OR = 1.22, 95% CI 1.02–1.45, p = 0.029), metals (OR = 1.48, 95% CI 1.21–1.82, p < 0.001), and combustion and diesel exhaust pollutants (OR = 1.20, 95% CI 1.01–1.43, p = 0.041) prior to ALS diagnosis, when adjusted for sex, age, and military service compared to controls. In multivariable models, only occupational exposure to metals remained significant risk (OR = 1.56, 95% CI 1.11–2.20, p = 0.011), although in an adaptive elastic net model, particulate matter (OR = 1.203), pesticides (OR = 1.015), and metals (1.334) were all selected as risk factors. Work in SOC code “Production Occupations” was associated with a higher ALS risk. SOC codes “Building and Grounds Cleaning and Maintenance Occupations”, “Construction and Extraction Occupations”, “Installation, Maintenance, and Repair Occupations”, and “Production Occupations” were all associated with a higher exposure to metals as determined using survey data.

  Discussion
  Occupational exposure to particulate matter, volatile organic compounds, metals, pesticides, and combustion and diesel exhaust and employment in “Production Occupations” was associated with an increased ALS risk in this cohort.
  [Goutman, S.A. et al. (2022) Associations of self-reported occupational exposures and settings to ALS: A case–control study, Int Arch Occup Environ Health. Available at: https://link.springer.com/article/10.1007/s00420-022-01874-4#citeas. ]

• Pesticides applied to crops and amyotrophic lateral sclerosis risk in the U.S
  Environmental exposures are implicated in the etiology of amyotrophic lateral sclerosis (ALS). Application of insecticides, herbicides, and fungicides with neurotoxic properties to crops is permitted in the U.S., however reporting of the quantities is government mandated. To identify pesticides that may be associated with ALS etiology for future study. The study geospatially estimated exposure to crop-applied pesticides as risk factors for ALS in a large de-identified medical claims database, the SYMPHONY Integrated Dataverse®. We extracted residence at diagnosis of ∼26,000 nationally distributed ALS patients, and matched non-ALS controls. We mapped county-level U.S. Geological Survey data on applications of 423 pesticides to estimate local residential exposure. We randomly broke the SYMPHONY dataset into two groups to form independent discovery and validation cohorts, then confirmed top hits using residential history information from a study of NH, VT, and OH. Pesticides with the largest positive statistically significant associations in both the discovery and the validation studies and evidence of neurotoxicity in the literature were the herbicides 2,4-D (OR 1.25 95 % CI 1.17–1.34) and glyphosate (OR 1.29 95 %CI 1.19–1.39), and the insecticides carbaryl (OR 1.32 95 %CI 1.23–1.42) and chlorpyrifos (OR 1.25 95 %CI 1.17–1.33). The geospatial analysis results support potential neurotoxic pesticide exposures as risk factors for sporadic ALS. Focused studies to assess these identified potential relationships are warranted.
  [Andrew, A., Zhou, J., Gui, J., Harrison, A., Shi, X., Li, M., Guetti, B., Nathan, R., Tischbein, M., Pioro, E.P. and Stommel, E. NeuroToxicology, 87, pp.128-135.]
• Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
  Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19–5.72), electric shock (OR = 2.09, 95% CI 0.62–7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73–2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88–2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12–0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.
  [Filippini, T., Fiore, M., Tesauro, M., Malagoli, C., Consonni, M., Violi, F., Arcolin, E., Iacuzio, L., Oliveri Conti, G., Cristaldi, A. and Zuccarello, P., 2020. International journal of environmental research and public health, 17(3), p.857.]
• Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
  Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases (n = 95) and randomly selected population referents (n = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79–7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02–7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14–4.54) and paint removers (OR = 2.01, 95% CI 0.90–4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70–4.09) and 2.41 (95% CI 1.13–5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63–2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88–9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology.
  [Filippini, T., Tesauro, M., Fiore, M., Malagoli, C., Consonni, M., Violi, F., Iacuzio, L., Arcolin, E., Oliveri Conti, G., Cristaldi, A. and Zuccarello, P., 2020. International Journal of Environmental Research and Public Health, 17(8), p.2882.]
• Environmental and Occupational Exposures and Amyotrophic Lateral Sclerosis in New England
  Recent data provide support for the concept that potentially modifiable exposures are responsible for sporadic amyotrophic lateral sclerosis (ALS). To evaluate environmental and occupational exposures as risk factors for sporadic ALS. We performed a case-control study of ALS among residents of New England, USA. The analysis compared questionnaire responses from 295 patients with a confirmed ALS diagnosis to those of 225 controls without neurodegenerative illness. Self-reported job- or hobby-related exposure to one or more chemicals, such as pesticides, solvents, or heavy metals, increased the risk of ALS (adjusted OR 2.51; 95% CI 1.64-3.89). Industries with a higher toxicant exposure potential (construction, manufacturing, mechanical, military, or painting) were associated with an elevated occupational risk (adjusted OR 3.95; 95% CI 2.04-8.30). We also identified increases in the risk of ALS associated with frequent participation in water sports, particularly waterskiing (adjusted OR 3.89; 95% CI 1.97-8.44). Occupation and waterskiing both retained independent statistical significance in a composite model containing age, gender, and smoking status. Our study contributes to a growing body of literature implicating occupational- and hobby-related toxicant exposures in ALS etiology. These epidemiologic study results also provide motivation for future evaluation of water-body-related risk factors.
  [Andrew, A.S., Caller, T.A., Tandan, R., Duell, E.J., Henegan, P.L., Field, N.C., Bradley, W.G. and Stommel, E.W., 2017. Neurodegenerative Diseases, 17(2-3), pp.110-116.]
• Pesticides, polychlorinated biphenyls and polycyclic aromatic hydrocarbons in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a case-control study
  Neurotoxic chemicals including several pesticides have been suggested to play a role in the etiology of amyotrophic lateral sclerosis (ALS). We investigated the relation between organochlorine pesticides and their metabolites (OCPs), polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) in the etiology of sporadic ALS, determining for the first time their levels in cerebrospinal fluid as indicator of antecedent exposure. We recruited 38 ALS patients and 38 controls referred to an Italian clinical center for ALS care, who underwent a lumbar puncture for diagnostic purposes between 1994–2013, and had 1 mL of cerebrospinal fluid available for the determination of OCPs, PCBs and PAHs. Many chemicals were undetectable in both case and control CSF samples, and we found little evidence of any increased disease risk according to higher levels of exposure. Among males >60 years, we found a slight but statistically very unstable increased ALS risk with higher levels of the congener PCB 28 and the OCP metabolite p,p’-DDE. Overall, these results do not suggest an involvement of the neurotoxic chemicals investigated in this study in disease etiology, although small numbers limited the precision of our results
  [Vinceti, M., Violi, F., Tzatzarakis, M., Mandrioli, J., Malagoli, C., Hatch, E.E., Fini, N., Fasano, A., Rakitskii, V.N., Kalantzi, O.I. and Tsatsakis, A., 2017. Environmental research, 155, pp.261-267.]
• Amyotrophic lateral sclerosis and environmental factors
  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, β-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement.
  [Bozzoni, V., Pansarasa, O., Diamanti, L., Nosari, G., Cereda, C. and Ceroni, M., 2016. Functional neurology, 31(1), p.7.]
• Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
  Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS). To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan. Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography–mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall τ correlation coefficient. Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs. Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR] = 5.09; 95% CI, 1.85-13.99; P = .002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR = 2.31; 95% CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18; 95% CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.57; 95% CI, 1.31-5.02; P = .006; and cis-chlordane: OR = 6.51; 95% CI, 2.05-20.73; P = .002) and 1 PCB (PCB 151: OR = 1.66; 95% CI, 1.03-2.67; P = .04. There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall τ correlation coefficients ranged from −0.18 (Dacthal and “use pesticides to treat home or yard”) to 0.24 (trans-nonachlor and “store lawn care products in garage”). In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.
  [Su, F.C., Goutman, S.A., Chernyak, S., Mukherjee, B., Callaghan, B.C., Batterman, S. and Feldman, E.L., 2016. JAMA neurology, 73(7), pp.803-811.]
• Organophosphate pesticide exposure and neurodegeneration
  Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
  [Sánchez-Santed, F., Colomina, M.T. and Hernández, E.H., 2016. Cortex, 74, pp.417-426.]
• Amyotrophic Lateral Sclerosis and Agricultural Environments: A Systematic Review
  The aim of this study was to examine the relationship between the risk of amyotrophic lateral sclerosis (ALS) and exposure to rural environments. Studies were identified through OVID MEDLINE and EMBASE search up to September 2013 using as keywords rural residence, farmers, and pesticide exposure. Twenty-two studies were included for this meta-analysis. Summary odds ratios (ORs) were calculated using random effect model by type of exposure index, and subgroup analyses were conducted according to study design, gender, region, case ascertainment, and exposure assessment. The risk of ALS was significantly increased with pesticide exposure (OR, 1.44; 95% CI, 1.22-1.70) and with farmers (OR, 1.42; 95% CI, 1.17-1.73), but was not significant with rural residence (OR, 1.25; 95% CI, 0.84-1.87). The risk estimates for subgroup analysis between pesticide exposure and ALS indicated a significant positive association with men (OR, 1.96), and in studies using El Escorial criteria for ALS definition (OR, 1.63) and expert judgment for pesticide exposure (OR, 2.04) as well. No significant publication bias was observed. Our findings support the association of pesticide exposure and an increased risk for ALS, stressing that the use of more specific exposure information resulted in more significant associations.
  [Kang, H., Cha, E.S., Choi, G.J. and Lee, W.J., 2014. Journal of Korean medical science, 29(12), pp.1610-1617.]
• Environmental Risk Factors and Amyotrophic Lateral Sclerosis (ALS): A Case-Control Study of ALS in Michigan
  An interim report of a case-control study was conducted to explore the role of environmental factors in the development of amyotrophic lateral sclerosis (ALS). Sixty-six cases and 66 age- and gender-matched controls were recruited. Detailed information regarding residence history, occupational history, smoking, physical activity, and other factors was obtained using questionnaires. The association of ALS with potential risk factors, including smoking, physical activity and chemical exposure, was investigated using conditional logistic regression models. As compared to controls, a greater number of our randomly selected ALS patients reported exposure to fertilizers to treat private yards and gardens and occupational exposure to pesticides in the last 30 years than our randomly selected control cases. Smoking, occupational exposures to metals, dust/fibers/fumes/gas and radiation, and physical activity were not associated with ALS when comparing the randomly selected ALS patients to the control subjects. To further explore and confirm results, exposures over several time frames, including 0–10 and 10–30 years earlier, were considered, and analyses were stratified by age and gender. Pesticide and fertilizer exposure were both significantly associated with ALS in the randomly selected ALS patients. While study results need to be interpreted cautiously given the small sample size and the lack of direct exposure measures, these results suggest that environmental and particularly residential exposure factors warrant close attention in studies examining risk factors of ALS.
  [Yu, Y., Su, F.C., Callaghan, B.C., Goutman, S.A., Batterman, S.A. and Feldman, E.L., 2014. PloS one, 9(6).]
• Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
  The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
  [Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
• Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?
  The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.
  [Vinceti, M., Bottecchi, I., Fan, A., Finkelstein, Y. and Mandrioli, J., 2012. Reviews on environmental health, 27(1), pp.19-41.]
• Pesticide exposure and amyotrophic lateral sclerosis
  Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993–1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1–3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8–3.5), pyrethroids (1.4, 0.6–3.4), herbicides (1.6, 0.7–3.7), and fumigants (1.8, 0.8–3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8–5.1), dieldrin (2.6, 0.9–7.3), DDT (2.1, 0.9–5.0), and toxaphene (2.0, 0.8–4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations.
  [Kamel, F., Umbach, D.M., Bedlack, R.S., Richards, M., Watson, M., Alavanja, M.C., Blair, A., Hoppin, J.A., Schmidt, S. and Sandler, D.P., 2012. Neurotoxicology, 33(3), pp.457-462.]
• Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: A meta-analysis of epidemiological studies: Pesticide exposure as a risk factor for ALS
  Exposure to pesticides and agricultural chemicals has been linked to amyotrophic lateral sclerosis (ALS) although findings have been inconsistent. A meta-analysis of studies published through May, 2011 was conducted to investigate the association of pesticide exposure and risk of ALS.Six peer-reviewed studies that met criteria were included in a meta-analysis of men involving 1,517 ALS deaths from one retrospective cohort study and 589 ALS or motor neuron disease cases from five case-control studies. A random effects model was used to calculate sex-specific pooled odds ratios (ORs).Evidence was found for an association of exposure to pesticides and risk of ALS in male cases compared to controls (OR=1.88, 95% CI: 1.36–2.61), although the chemical or class of pesticide was not specified by the majority of studies.This meta-analysis supports the relationship of exposure to pesticides and development of ALS among male cases compared to controls. The weight of evidence links pesticide exposure to ALS; however, additional prospective studies with a target exposure group are necessary to better elucidate the relationship. Future research should focus on more accurate exposure assessment and the use of job exposure matrices.
  [Malek, A.M., Barchowsky, A., Bowser, R., Youk, A. and Talbott, E.O., 2012. Environmental research, 117, pp.112-119.]
• A Case of Amyotrophic Lateral Sclerosis in a Worker Treating Pesticide Wastes
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the motor neuron of the cerebrum, brain stem, and spinal cord. It has been suggested that various occupational or environmental agents could be a cause of ALS. We report upon a case of a person contracting ALS who experienced a long-time exposure to pesticides, implying that pesticides are probable causal agents of ALS.The patient has been experiencing shoulder pain and limitation of movement that started abruptly about three years ago. Over time, these symptoms have become aggravated despite ongoing therapies including medication. After two years, he was diagnosed with ALS through electromyography, nerve conduction velocity and many laboratory tests at a university hospital in Seoul. His social and medical history was non-specific.The patient had worked for about 15 years at a waste disposal site and mainly destroyed glass bottles containing pesticides. During this period, his respiratory tract and skin were exposed to various raw pesticides without appropriate personal protective equipment. He did this job one or two times a week and worked for two or more hours without a break.Through an investigation into the patient's working environment, significant levels of dichlorvos, one of the organophosphates, were detected. The study results revealed that the patient was exposed to considerable doses of pesticides as opposed to men spraying pesticides. Although controversial, pesticide exposures have been associated with ALS. However, we suggest that in this case the possibility that these pesticide exposures acted
  [Choy, S. and Kim, J.W., 2011. Korean Journal of Occupational and Environmental Medicine, 23(4), pp.480-487.]
• Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population-based case-control study
   A few epidemiologic studies have suggested an association of agricultural work and pesticides exposure with a severe degenerative disease of the motor neurons, amyotrophic lateral sclerosis (ALS), though conflicting results have also been provided. We investigated through a populationbased case-control study the possible relation between overall occupational exposure to pesticides and ALS risk in the northern Italy municipality of Reggio Emilia. By administering a questionnaire, we investigated occupational history and leisure-time habits of the 41 ALS patients diagnosed in the 1995-2006 period, and of 82 age- and sex-matched randomly sampled population controls. More cases than controls were found to have been exposed to pesticides for at least six months (31.7% vs 13.4%, respectively), in all cases within the occupational environment. In a conditional logistic regression model, we found an excess ALS risk associated with exposure to pesticides, with a relative risk of 3.6 (95% confidence interval 1.2-10.5). Such association persisted after inclusion in the statistical analysis of potential confounders. Despite the limited statistical stability of the risk estimates, these results appear to indicate that occupational exposure to pesticides is a risk factor for ALS, suggesting the need to further investigate this issue.
  [Bonvicini, F., Marcello, N., Mandrioli, J., Pietrini, V. and Vinceti, M., 2010. Annali dell'Istituto superiore di sanita, 46, pp.284-287.]
• Exposure to Chemicals and Metals and Risk of Amyotrophic Lateral Sclerosis: A Systematic Review
  Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS.
  [Sutedja, N.A., Veldink, J.H., Fischer, K., Kromhout, H., Heederik, D., Huisman, M.H., Wokke, J.H. and van den Berg, L.H., 2009. Amyotrophic Lateral Sclerosis, 10(5-6), pp.302-309.]
• The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis
  Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted at (demonstrated) in the Chamorro indigenous people of Guam. During the 1950s and 1960s these indigenous people presented an extremely high incidence of ALS which was presumed to be associated with the consumption of flying fox and cycad seeds. No other strong association between ALS and environmental toxicants has since been reported, although circumstantial epidemiological evidence has implicated exposure to heavy metals such as lead and mercury, industrial solvents and pesticides especially organophosphates and certain occupations such as playing professional soccer. Given that only ∼10% of all ALS diagnosis have a genetic basis, a gene–environmental interaction provides a plausible explanation for the other 90% of cases. This mini-review provides an overview of our current knowledge of environmental etiologies of ALS with emphasis on the effects of mercury, lead and pesticides as potential risk factors in developing ALS. Epidemiologic and experimental evidence from animal models investigating the possible association between exposure to environmental toxicant and ALS disease has proven inconclusive. Nonetheless, there are indications that there may be causal links, and a need for more research.
  [Johnson, F.O. and Atchison, W.D., 2009. Neurotoxicology, 30(5), pp.761-765.]
• A gene–environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis
  Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene–environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms −909c > g, −832g > a, −162g > a and −108c > t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele −108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene–environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.
  [Morahan, J.M., Yu, B., Trent, R.J. and Pamphlett, R., 2007. Neurotoxicology, 28(3), pp.532-540.]
• Amyotrophic Lateral Sclerosis and Exposure to Environmental Toxins: An Australian Case-Control Study
  It has been suggested that environmental toxins could be risk factors for sporadic amyotrophic lateral sclerosis (SALS). We therefore analysed epidemiological data on 179 SALS cases and 179 age-, ethnicity- and sex-matched controls in Australia using self-reporting questionnaires. SALS was associated with solvent/chemical exposure (OR = 1.92, 95% CI: 1.26–2.93), overall herbicide/pesticide exposure (OR = 1.57, 95% CI: 1.03–2.41) and industrial herbicide/pesticide exposure (OR = 5.58, 95% CI: 2.07–15.06). Exposure to herbicides/pesticides showed a dose-response effect. All positive findings were more statistically significant in males. These findings support those from northern hemisphere studies, indicating that environmental toxins can be risk factors for SALS.
  [Morahan, J.M. and Pamphlett, R., 2006. Neuroepidemiology, 27(3), pp.130-135.]
• Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS)
  We conducted case‐control and prospective longitudinal studies to examine risk factors and predictors of disease progression for ALS. Ninety‐five subjects with ALS and 106 healthy control subjects were enrolled. All subjects completed a risk factor questionnaire at enrollment. The ALS subjects were prospectively followed for one year to define factors that influence the rate of disease progression, measured by rate of change in percent predicted forced vital capacity (%FVC) and the ALS functional rating scale (ALSFRS) score. The association of each potential risk factor with ALS was determined using univariate logistic regression. A random slope model was used to determine the association of each risk factor with disease progression. The demographic characteristics of ALS subjects and controls at enrollment did not differ. Significant risk factors for ALS included reported exposure to lead (p = 0.02) and pesticides (p = 0.03). Disease progression was faster in the ALS subjects having bulbar onset and a shorter time period between onset of symptoms and diagnosis. Pertinent variables not associated with either causation or progression of ALS included physical activity, cigarette smoking and a history of physical trauma or other clinical disorders.
  [Muddasir Qureshi, M., Hayden, D., Urbinelli, L., Ferrante, K., Newhall, K., Myers, D., Hilgenberg, S., Smart, R., Brown, R.H. and Cudkowicz, M.E., 2006. Amyotrophic Lateral Sclerosis, 7(3), pp.173-182.]
• Increased Incidence of FMO1 Gene Single Nucleotide Polymorphisms in Sporadic Amyotrophic Lateral Sclerosis
  Flavin-containing monooxygenases (FMO) represent a gene family involved in the oxidative metabolism of a variety of xenobiotics, pesticides and drugs. A new function for FMO proteins has been recently uncovered: yeast FMO has been demonstrated to take part in maintaining the redox balance, catalysing the oxidation of reduced glutathione (GSH) to glutathione disulfide (GSSG). The GSSG/GSH balance is an important buffering system for reactive oxygen species and its involvement has been documented in ALS and other neurodegenerative disorders. Human FMO genes present different mutations, which may be related to ethnicity, altered metabolic activity and, in some cases, specific diseases. The human FMO1 gene presents 20 single nucleotide polymorphisms (SNPs) located in coding regions, intronic sequences and untranslated regions. The FMO1 gene has also recently been found underexpressed in spinal cord of ALS patients. Using SSCP and direct sequencing, we studied the allelic and genotypic frequency of two 3'UTR SNPs of the FMO1 gene in sporadic ALS patients compared to a healthy control population. We found a significantly higher frequency of these two polymorphisms, exclusive of the female population, in SALS patients compared to controls (p<0.01), suggesting that specific allelic variants of the FMO1 gene might be associated to susceptibility to develop ALS.
  [Cereda, C., Gabanti, E., Corato, M., De Silvestri, A., Alimonti, D., Cova, E., Malaspina, A. and Ceroni, M., 2006. Amyotrophic Lateral Sclerosis, 7(4), pp.233-240.]

• Microbiome–gut–brain dysfunction in prodromal and symptomatic Lewy body diseases
  Lewy body diseases, such as Parkinson’s disease and dementia with Lewy bodies, vary in their clinical phenotype but exhibit the same defining pathological feature, α-synuclein aggregation. Microbiome–gut–brain dysfunction may play a role in the initiation or progression of disease processes, though there are multiple potential mechanisms. We discuss the need to evaluate gastrointestinal mechanisms of pathogenesis across Lewy body diseases, as disease mechanisms likely span across diagnostic categories and a ‘body first’ clinical syndrome may better account for the heterogeneity of clinical presentations across the disorders. We discuss two primary hypotheses that suggest that either α-synuclein aggregation occurs in the gut and spreads in a prion-like fashion to the brain or systemic inflammatory processes driven by gastrointestinal dysfunction contribute to the pathophysiology of Lewy body diseases. Both of these hypotheses posit that dysbiosis and intestinal permeability are key mechanisms and potential treatment targets. Ultimately, this work can identify early interventions targeting initial disease pathogenic processes before the development of overt motor and cognitive symptoms.
  [Ryman, S., Vakhtin, A. A., Richardson, S. P., & Lin, H. C. (2023). Microbiome–gut–brain dysfunction in prodromal and symptomatic Lewy body diseases. Journal of neurology, 270(2), 746-758. https://link.springer.com/article/10.1007/s00415-022-11461-9 ]
• Pesticides, cognitive functions and dementia: A review
  Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person’s quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer’s disease.
  [Aloizou, A.M., Siokas, V., Vogiatzi, C., Peristeri, E., Docea, A., Petrakis, D., Provatas, A., Folia, V., Chalkia, C., Vinceti, M. and Wilks, M., 2020. Pesticides, cognitive functions and dementia: A review. Toxicology Letters.]
• Association between background exposure to organochlorine pesticides and the risk of cognitive impairment: A prospective study that accounts for weight change
  Background exposure to organochlorine (OC) pesticides was recently linked to cognitive impairment and dementia in cross-sectional and case–control studies. This prospective study was performed to evaluate if OC pesticides at baseline are associated with the future risk of cognitive impairment in elderly, with particular focus on weight change. Plasma concentrations of 3 OC pesticides (p,p′-DDE, trans-nonachlor, and hexachlorobenzene) were measured among 989 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Cognitive impairment was validated by reviewing medical records. During the ten year follow-up, cognitive impairment was developed in 75 subjects. When weight change from age 70 to 75 was considered in analyses, elderly with incident cases before age 75 were excluded to keep the prospective perspective, leaving 795 study subjects and 44 incident cases. The summary measure of 3 OC pesticides predicted the development of cognitive impairment after adjusting for covariates, including weight change. Compared to subjects with OC pesticides < 25th percentile, adjusted hazard ratios (HRs) in those with 25th–
  [Lee, D.H., Lind, P.M., Jacobs Jr, D.R., Salihovic, S., van Bavel, B. and Lind, L., 2016. Association between background exposure to organochlorine pesticides and the risk of cognitive impairment: a prospective study that accounts for weight change. Environment international, 89, pp.179-184.]
• Neurobehavioral effects of long-term exposure to pesticides: results from the 4-year follow-up of the PHYTONER Study
  The aim of the PHYTONER study is to investigate the role of pesticides on neurobehavioral performances in French vineyard workers. 929 workers affiliated to the health insurance system for farmers in the Bordeaux area of south-western France were enrolled in the study in 1997–1998. They were contacted for a first follow-up in 2001–2003. Participants completed a questionnaire and nine neurobehavioral tests. They were classified according to their life-long pesticide exposure, as directly exposed, indirectly exposed or non-exposed. Educational level, age, sex, alcohol consumption, smoking, psychotropic drug use and depressive symptoms were taken into account in the analysis. 614 subjects were available for investigation at follow-up. Follow-up analysis confirmed that the risk of obtaining a low performance on the tests was higher in exposed subjects, with ORs ranging from 1.35 to 5.60. Evolution of performances over the follow-up period demonstrated that exposed subjects had the worst decreases in performance. The risk of having a two-point lower score on the Mini-Mental State Examination was 2.15 (95% CI 1.18 to 3.94) in exposed subjects. These results suggest long-term cognitive effects of chronic exposure to pesticides and raise the issue of the risk of evolution towards dementia. The PHYTONER study is the first to provide prospective data on the natural history of neurological disorders associated with pesticide exposure.
  [Baldi, I., Gruber, A., Rondeau, V., Lebailly, P., Brochard, P. and Fabrigoule, C., 2011. Neurobehavioral effects of long-term exposure to pesticides: results from the 4-year follow-up of the PHYTONER study. Occupational and environmental medicine, 68(2), pp.108-115.]
• Alzheimer disease: Risk of dementia and Alzheimer disease increases with occupational pesticide exposure
  Occupational exposure to pesticides increases the risk of developing dementia and Alzheimer disease (AD) in later life, according to this longitudinal population-based cohort study. The results of this study provide further evidence that certain environmental factors are risk factors for these debilitating conditions.
  [Jones N.2010. Nat Rev Neurol. 6(7):353]

• Occupational exposure to pesticides as a potential risk factor for epilepsy
  Epilepsy is a chronic neurological disorder in which brain activity becomes abnormal, causing seizures. In a previous study we found that environmental exposure to pesticides was associated with a greater risk of epilepsy. The present study examined possible occupational risk factors that may contribute to the occurrence of epilepsy in farmers and pesticide applicators (sprayers). A case-referent study was conducted on 19,704 individuals over a 17-year study period (2000–2016). Epilepsy cases (n = 5091) were collected from Hospital records and referents (non-epilepsy cases, n = 14.613) from the Centre for Prevention of Occupational Risks, both from Almería (South-Eastern Spain). A significant increased risk of having epilepsy was found in farmers working in intensive agriculture (high-yield greenhouse crops) compared to extensive agriculture (open-air crops). The risk was greater for farmers residing in rural areas with high pesticide use (intensive farming crops in plastic greenhouses) and for those not wearing protective gloves. As for sprayers, the greatest risk of epilepsy was observed in those not wearing face mask, and in those living in areas with high pesticide use (greenhouse intensive agriculture). Overall, this study supports previous findings on the association between epilepsy and pesticide exposure in the general population, and extends the risk to farmers occupationally exposed to pesticides, mainly those engaged in intensive agriculture.
  [Alarcón, R., Giménez, B., Hernández, A.F., López-Villén, A., Parrón, T., García-González, J. and Requena, M., 2023. Neurotoxicology, 96, pp.166-173.]
• Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus
  Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.
  [Bernardino, P.N., Hobson, B.A., Huddleston, S.L., Andrew, P.M., MacMahon, J.A., Saito, N.H., Porter, V.A., Bruun, D.A., Harvey, D.J., Garbow, J.R. and Gelli, A., 2023. Neurobiology of Disease, 187, p.106316.]
• Association between environmental exposure to pesticides and epilepsy
  There is increasing evidence of an association between long-term environmental exposure to pesticides and neurodegenerative disorders; however, the relationship with epilepsy has not been addressed thus far. This study was aimed at determining the prevalence and risk of developing epilepsy among people from South-East Spain living in areas of high vs. low exposure to pesticides based on agronomic data. The study population consisted of 4007 subjects with a diagnosis of epilepsy and 580,077 control subjects adjusted for age, sex and geographical area. Data were collected from hospital records of the Spanish health care system (basic minimum dataset) between the years 1998 and 2010. The prevalence of epilepsy was significantly higher in areas of greater pesticide use relative to areas of lesser use. Overall, an increased risk of epilepsy was observed in the population living in areas of high vs. low use of pesticides (OR: 1.65; p < 0.001). Although this study was exploratory in nature, the results suggest that environmental exposure to pesticides might increase the risk of having epilepsy.
  [Requena, M., Parrón, T., Navarro, A., García, J., Ventura, M.I., Hernández, A.F. and Alarcón, R., 2018. Neurotoxicology, 68, pp.13-18.]
• Pesticide poisoning as a factor of seizure and epilepsy development.
  [M]any pesticides which are used today can lead either to the formation of single seizures or to epilepsy due to chronic poisoning. Taking into considerarion the active processes of neurogenesis in young brain, such poisonings are dangerous especially for children.
  [Shavalda, E., Melik-Kasumov, T., Batyan, A. and Subbota, E., 2016.]
• Role of Organochlorine Pesticides in Children with Idiopathic Seizures
  Organochlorine pesticides (OCP) are persistent organic pollutants that have been implicated in causing several deleterious effects in humans. These are known neurotoxins in high doses, but the role of environmentally acquired OCPs in the body to induce seizures in children has not been investigated yet. To assess the serum levels of OCPs in children aged 2–12 with idiopathic seizure and to find out any association between the two are our objectives. It was a cross-sectional pilot study. Twenty developmentally normal children aged 2–12, presenting with idiopathic generalized seizures, were recruited. Twenty age-matched controls without any history of seizures were also taken. Their serum levels of alpha, beta, and gamma hexachlorocyclohexane (HCH); and aldrin; dieldrin; p,p-dichlorodiphenyltrichloroethane (DDT), o,p-DDT, and p,p dichlorodiphenyldichloroethylene (DDE); and alpha and beta endosulfan were analysed using gas chromatography (GC). Mann-Whitney U test was used to compare OCP levels between the groups. Spearman correlation was used to find the correlation between individual pesticide levels with age and seizure duration. Results. Levels of beta, gamma, and total HCH were significantly higher among cases as compared to the control group (P less than or equal to 0.05). There exists a possible association between idiopathic seizures and high serum levels of OCPs, especially HCH.
  [Arora, S.K., Batra, P., Sharma, T., Banerjee, B.D. and Gupta, S., 2013. International Scholarly Research Notices, 2013.]
• Chemical toxins that cause seizures
  Seizurogenic chemicals include a variety of toxic agents, including chemical warfare agents, toxic industrial chemicals, and natural toxins. Chemical weapons such as sarin and VX, and pesticides such as parathion and carbaryl cause hyperstimulation of cholinergic receptors and an increase in excitatory neurotransmission. Glutamatergic hyperstimulation can occur after exposure to excitatory amino acid toxins such as the marine toxin domoic acid. Other pesticides such as lindane and strychnine do not affect excitatory neurotransmission directly, but rather, they block the inhibitory regulation of neurotransmission by antagonism of inhibitory GABA and glycine synapses. In this paper, chemicals that cause seizures by a variety of molecular mechanisms and pathways are discussed.
  [Jett, D.A., 2012. Neurotoxicology, 33(6), pp.1473-1475.]
• Seizure activity post organophosphate exposure
  Electrographic seizures are a feature of organophosphate anticholinesterase intoxication. Clinical studies of pesticide poisonings suggest that seizures are more common in children than in adults. Since flaccid paralysis, a characteristic sign of organophosphate poisoning, can mask convulsions, the most reliable indicator of seizures is the electroencephalogram, but this has not been widely used in clinical studies. Seizures can rapidly progress to status epilepticus, contributing to mortality and, in survivors, to neuronal damage and neurological impairment. Anticonvulsant drugs can significantly reduce the lethal and toxic effects of these compounds. A benzodiazepine, usually diazepam, is the treatment currently indicated for control of seizures. Animal studies have indicated that the early phase of seizure activity (0-5 min after seizure onset) is purely cholinergic, predominantly involving muscarinic mechanisms. Seizure activity subsequently progresses through mixed cholinergic and noncholinergic modulation (5-40 min) into a final noncholinergic phase. Neuropathology caused by seizures is most likely associated with glutamatergic excitotoxicity. Future prospects for improved treatments include new benzodiazepines, glutamate receptor antagonists, antimuscarinics with additional antiglutamatergic activity and adenosine receptor antagonists.
  [Tattersall, J., 2009. Frontiers in bioscience (Landmark edition), 14, p.3688.]
• Seizures after eating a snack food contaminated with the pesticide endrin. The tale of the toxic taquitos.
  In September 1988 we investigated reports of seizures in persons who had eaten taquitos, a commercially prepared snack food. We identified and interviewed 5 persons with new-onset seizures within 12 hours of eating taquitos, all purchased during a 1-week period from a single store. Leftover taquitos were found to contain endrin, a highly toxic chlorinated hydrocarbon pesticide. Although tissue confirmation of exposure to endrin was not possible and the level of contamination in the tested taquitos was below that previously thought to be capable of inducing seizures, the pattern of symptoms and the common time and place of purchase strongly suggested that the seizures were due to endrin-contaminated taquitos. The source of endrin contamination could not be determined. This episode is the first report of illness associated with endrin-contaminated food products in the United States.
  [Waller, K., Prendergast, T.J., Slagle, A. and Jackson, R.J., 1992. Western journal of medicine, 157(6), p.648.]

• Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
  Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
  [Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ]
• Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation
  Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.
  [Wheeler, M.A., Jaronen, M., Covacu, R., Zandee, S.E., Scalisi, G., Rothhammer, V., Tjon, E.C., Chao, C.C., Kenison, J.E., Blain, M. and Rao, V.T., 2019. Cell, 176(3), pp.581-596.]
• Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
  Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.
  [Mostafalou, S. and Abdollahi, M., 2013. Toxicology and applied pharmacology, 268(2), pp.157-177.]
• Association between environmental exposure to pesticides and neurodegenerative diseases
  Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
  [Parrón, T., Requena, M., Hernández, A.F. and Alarcón, R., 2011. Toxicology and applied pharmacology, 256(3), pp.379-385.]

• Cost-effectiveness analysis of insecticide ban aimed at preventing Parkinson's disease in Central California
  

  Abstract

  Background

  Our study assessed whether banning specific insecticides to reduce the PD burden in three Central California (CA) counties is cost-effective.

  Method

  We applied a cost-effectiveness analysis using a cohort-based Markov model to estimate the impact and costs of banning seven insecticides that were previously associated with PD in these counties as well as mixture exposures to some of these pesticides. We relied for our estimations on the cohort of 65- and 66-year-olds living in these counties who were unaffected by PD at baseline in 2020 and projected their incidence, costs, and reduction in quality-adjusted-life-years (QALY) loss due to developing PD over a 20-year period. We included a shiny app for modeling different scenarios (https://sherlockli.shinyapps.io/pesticide_pd_economics_part_2/).

  Results

  According to our scenarios, banning insecticides to reduce the occurrence of PD in three Central CA counties was cost-effective relative to not banning insecticides. In the worst-case scenario of exposure to a single pesticide, methomyl, versus none would result in an estimated 205 (95 % CI: 75, 348) additional PD cases or 12 % (95 % CI: 4 %, 20 %) increase in PD cases over a 20-year period based on residential proximity to pesticide applications. The increase in PD cases due to methomyl would increase health-related costs by $72.0 million (95 % CI: $5.5 million, $187.4 million). Each additional PD patient due to methomyl exposure would incur $109,327 (95 % CI, $5554, $347,757) in costs per QALY loss due to PD. Exposure to methomyl based on workplace proximity to pesticide applications generated similar estimates. The highest PD burden and associated costs would be incurred from exposure to multiple pesticides simultaneously.

  Conclusion

  Our study provides an assessment of the cost-effectiveness of banning specific insecticides to reduce PD burden in terms of health-related QALYs and related costs. This information may help policymakers and stakeholders to make decisions concerning the regulation of pesticides.

  
  [Li, S. et al. (2024) ‘Cost-effectiveness analysis of insecticide ban aimed at preventing parkinson’s disease in Central California’, Science of The Total Environment, 912, p. 168913. doi:10.1016/j.scitotenv.2023.168913. ]
• Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use
  Parkinson’s disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.
  [Ngo, K.J. et al. (2024) Lysosomal genes contribute to parkinson’s disease near agriculture with high intensity pesticide use, Nature News. Available at: https://www.nature.com/articles/s41531-024-00703-4. ]
• Parkinson’s Disease Is Predominantly an Environmental Disease
  Abstract

  Parkinson’s disease is the world’s fastest growing brain disorder, and exposure to environmental toxicants is the principal reason. In this paper, we consider alternative, but unsatisfactory, explanations for its rise, including improved diagnostic skills, aging populations, and genetic causes. We then detail three environmental toxicants that are likely among the main causes of Parkinson’s disease— certain pesticides, the solvent trichloroethylene, and air pollution. All three environmental toxicants are ubiquitous, many affect mitochondrial functioning, and all can access humans via various routes, including inhalation and ingestion. We reach the hopeful conclusion that most of Parkinson’s disease is thus preventable and that we can help to create a world where Parkinson’s disease is increasingly rare.
  [Dorsey, E.R. and Bloem, B.R. (2024) ‘Parkinson’s disease is predominantly an environmental disease’, Journal of Parkinson’s Disease, pp. 1–15. doi:10.3233/jpd-230357. ]

• Pesticides and the Gut Microbiota: Implications for Parkinson’s Disease
  Parkinson’s disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in daily habits. The disease develops in a complex way, with movement problems caused by Lewy bodies and the loss of dopamine-producing neurons. Some research suggests Lewy bodies might start in the gut, hinting at a connection between these structures and gut health in PD patients. These patients often have different gut bacteria and metabolites. Pesticides are known to increase the risk of PD, with evidence showing they harm more than just dopamine neurons. Long-term exposure to pesticides in food might affect the gut barrier, gut bacteria, and the blood–brain barrier, but the exact link is still unknown. This review looks at how pesticides and gut bacteria separately influence PD development and progression, highlighting the harmful effects of pesticides and changes in gut bacteria. We have examined the interaction between pesticides and gut bacteria in PD patients, summarizing how pesticides cause imbalances in gut bacteria, the resulting changes, and their overall effects on the PD prognosis.
  [Ghosh, N., Sinha, K., & Sil, P. C. (2024). Pesticides and the Gut Microbiota: Implications for Parkinson’s Disease. Chemical Research in Toxicology. https://pubs.acs.org/doi/abs/10.1021/acs.chemrestox.4c00057]
• A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides
  Parkinson’s disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson’s-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.
  [Paul, K.C., Krolewski, R.C., Lucumi Moreno, E., Blank, J., Holton, K.M., Ahfeldt, T., Furlong, M., Yu, Y., Cockburn, M., Thompson, L.K. and Kreymerman, A., 2023. Nature Communications, 14(1), p.2803.]
• Developmental origins of Parkinson disease: Improving the rodent models
  Numerous pesticides are inhibitors of the oxidative phosphorylation system. Oxidative phosphorylation dysfunction adversely affects neurogenesis and often accompanies Parkinson disease. Since brain development occurs mainly in the prenatal period, early exposure to pesticides could alter the development of the nervous system and increase the risk of Parkinson disease. Different rodent models have been used to confirm this hypothesis. However, more precise considerations of the selected strain, the xenobiotic, its mode of administration, and the timing of animal analysis, are necessary to resemble the model to the human clinical condition and obtain more reliable results.
  [Jiménez-Salvador, I., Meade, P., Iglesias, E., Bayona-Bafaluy, P. and Ruiz-Pesini, E., 2023. Ageing Research Reviews, 86, p.101880.]
• Gut bacterial profiles in Parkinson's disease: A systematic review
  Introduction
  Recent advances have highlighted the relationships between gut dysbiosis and Parkinson's disease (PD). Microbiota transplantation from PD patients to mice can induce increased alpha-synuclein-mediated motor deficits. Human studies have identified differences in the gut microbiota of PD patients compared to healthy controls. We undertook a systematic review to evaluate the available evidence for the involvement of gut bacteria in the etiology of PD.

  Methods
  The PubMed databank, the China National Knowledge Infrastructure databank, and Wanfang Data were searched from inception until June 2021 to identify human case–control studies that investigated relationships between PD and microbiota quantified from feces. We evaluated the resulting studies focusing on bacterial taxa that were different between PD patients and healthy controls.

  Results
  Twenty-six studies were found in which 53 microbial families and 98 genera exhibited differences between patients with PD and healthy controls. The genera identified by more than two studies as increased in PD were Bifidobacterium, Alistipes, Christensenella, Enterococcus, Oscillospira, Bilophila, Desulfovibrio, Escherichia/Shigella, and Akkermansia, while Prevotella, Blautia, Faecalibacterium, Fusicatenibacter, and Haemophilus had three or more reports of being lower in PD patients. More than one report demonstrated that Bacteroides, Odoribacter, Parabacteroides, Butyricicoccus, Butyrivibrio, Clostridium, Coprococcus, Lachnospira, Lactobacillus, Megasphaera, Phascolarctobacterium, Roseburia, Ruminococcus, Streptococcus, and Klebsiella were altered in both directions.

  Conclusion
  Our review shows that the involvement of the gut microbiome in the etiology of PD may involve alterations of short-chain fatty acids (SCFAs)-producing bacteria and an increase in putative gut pathobionts. SCFAs-producing bacteria may vary above or below an “optimal range,” causing imbalances. Considering that Bifidobacterium, Lactobacillus, and Akkermansia are beneficial for human health, increased Bifidobacterium and Lactobacillus in the PD gut microbiome may be associated with PD medications, especially COMT inhibitors, while a high level of Akkermansia may be associated with aging.
  [Li, Z., Liang, H., Hu, Y., Lu, L., Zheng, C., Fan, Y., … & Xu, P. (2023). Gut bacterial profiles in Parkinson’s disease: A systematic review. CNS neuroscience & therapeutics, 29(1), 140-157. https://onlinelibrary.wiley.com/doi/full/10.1111/cns.13990 ]

• History of high household pesticide use and Parkinson's disease in Brazil
  

  Abstract

  The prevalence of Parkinson's disease (PD) is growing worldwide and household pesticides exposure may be related to this phenomenon. We showed that individuals with high exposure to household pesticides have two times more risk of developing PD. Household pesticide exposure did not impact age at PD onset.

  
  [Moura, D.D. et al. (2023) ‘History of high household pesticide use and parkinson’s disease in Brazil’, Parkinsonism & Related Disorders, 113, p. 105493. doi:10.1016/j.parkreldis.2023.105493. ]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.
  Parkinson’s disease is a severe neurodegenerative disease. Several environmental contaminants such as pesticides have been suspected to favor the appearance of this pathology. The protein DJ-1 (or Park7) protects against the development of Parkinson’s disease. Thus, the possible inhibitory effects of about a hundred pesticides on human DJ-1 have been studied. We identified fifteen of them as strong inhibitors of DJ-1 with IC50 values between 0.02 and 30 µM. Thiocarbamates are particularly good inhibitors, as shown by thiram that acts as an irreversible inhibitor of an esterase activity of DJ-1 with an IC50 value of 0.02 µM. Thiram was also found as a good inhibitor of the protective activity of DJ-1 against glycation. Such inhibitory effects could be one of the various biological effects of these pesticides that may explain their involvement in the development of Parkinson’s disease.
  [Mathas, N., Poncet, G., Laurent, C., Larigot, L., Le-Grand, B., Gonis, E., Birman, S., Galardon, E., Sari, M.A., Tiouaini, M. and Nioche, P., 2023. Toxicology, 487, p.153467.]
• Microbiome–gut–brain dysfunction in prodromal and symptomatic Lewy body diseases
  Lewy body diseases, such as Parkinson’s disease and dementia with Lewy bodies, vary in their clinical phenotype but exhibit the same defining pathological feature, α-synuclein aggregation. Microbiome–gut–brain dysfunction may play a role in the initiation or progression of disease processes, though there are multiple potential mechanisms. We discuss the need to evaluate gastrointestinal mechanisms of pathogenesis across Lewy body diseases, as disease mechanisms likely span across diagnostic categories and a ‘body first’ clinical syndrome may better account for the heterogeneity of clinical presentations across the disorders. We discuss two primary hypotheses that suggest that either α-synuclein aggregation occurs in the gut and spreads in a prion-like fashion to the brain or systemic inflammatory processes driven by gastrointestinal dysfunction contribute to the pathophysiology of Lewy body diseases. Both of these hypotheses posit that dysbiosis and intestinal permeability are key mechanisms and potential treatment targets. Ultimately, this work can identify early interventions targeting initial disease pathogenic processes before the development of overt motor and cognitive symptoms.
  [Ryman, S., Vakhtin, A. A., Richardson, S. P., & Lin, H. C. (2023). Microbiome–gut–brain dysfunction in prodromal and symptomatic Lewy body diseases. Journal of neurology, 270(2), 746-758. https://link.springer.com/article/10.1007/s00415-022-11461-9 ]
• Paraquat and Parkinson’s Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis
  Parkinson’s disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways.
  [WZ, C.S., Naidu, R. and Tang, K.S., 2023. Current Neuropharmacology.]
• Analysis of serum levels of organochlorine pesticides and related factors in Parkinson’s disease
  There is evidence that environmental factors contribute to the onset and progression of Parkinson’s disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of developing PD. However, few studies have investigated the association between specific pesticides and PD, especially in China, which was one of the first countries to adopt the use of pesticides. In this study, serum levels of 19 pesticides were measured in 90 patients with PD and 90 healthy spouse controls. We also analyzed the interaction between specific pesticides and PD. In addition, the association between pesticides and clinical features of PD was also investigated. Finally, we investigated the underlying mechanism of the association between pesticides and PD. Serum levels of organochlorine pesticides, which included α-hexachlorocyclohexane (HCH), β-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p’-dichlorodiphenyltrichloroethane and o,p’-dichloro-diphenyl-trichloroethane were higher in PD patients than controls. Moreover, α-HCH and propanil levels were associated with PD. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. In SH-SY5Y cells, α-HCH and propanil increased level of reactive oxygen species and decreased mitochondrial membrane potential. Furthermore, propanil, but not α-HCH, induced the aggregation of α-synuclein. This study revealed that elevated serum levels of α-HCH and propanil were associated with PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. Moreover, propanil, but not α-HCH, induced the aggregation of α-synuclein. Further research is needed to fully elucidate the effects of pesticides on PD.
  [Xu, S., Yang, X., Qian, Y., Luo, Q., Song, Y. and Xiao, Q. Neurotoxicology, 88, pp.216-223.]
• Environmental Neurotoxic Pesticide Exposure Induces Gut Inflammation and Enteric Neuronal Degeneration by Impairing Enteric Glial Mitochondrial Function in Pesticide Models of Parkinson’s Disease: Potential Relevance to Gut-Brain Axis Inflammation in Parki
  Despite the growing recognition that gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD) and occurs as a major prodromal symptom of PD, its cellular and molecular mechanisms remain largely unknown. Among the various types of GI cells, enteric glial cells (EGCs), which resemble astrocytes in structure and function, play a critical role in the pathophysiology of many GI diseases including PD. Thus, we investigated how EGCs respond to the environmental pesticides rotenone (Rot) and tebufenpyrad (Tebu) in cell and animal models to better understand the mechanism underlying GI abnormalities. Both Rot and Tebu induce dopaminergic neuronal cell death through complex 1 inhibition of the mitochondrial respiratory chain. We report that exposing a rat enteric glial cell model (CRL-2690 cells) to these pesticides increased mitochondrial fission and reduced mitochondrial fusion by impairing MFN2 function. Furthermore, they also increased mitochondrial superoxide generation and impaired mitochondrial ATP levels and basal respiratory rate. Measurement of LC3, p62 and lysosomal assays revealed impaired autolysosomal function in ECGs during mitochondrial stress. Consistent with our recent findings that mitochondrial dysfunction augments inflammation in astrocytes and microglia, we found that neurotoxic pesticide exposure also enhanced the production of pro-inflammatory factors in EGCs in direct correlation with the loss in mitochondrial mass. Finally, we show that pesticide-induced mitochondrial defects functionally impaired smooth muscle velocity, acceleration, and total kinetic energy in a mixed primary culture of the enteric nervous system (ENS). Collectively, our studies demonstrate for the first time that exposure to environmental neurotoxic pesticides impairs mitochondrial bioenergetics and activates inflammatory pathways in EGCs, further augmenting mitochondrial dysfunction and pro-inflammatory events to induce gut dysfunction. Our findings have major implications in understanding the GI-related pathogenesis and progression of environmentally linked PD.
  [Palanisamy, B.N., Sarkar, S., Malovic, E., Samidurai, M., Charli, A., Zenitsky, G., Jin, H., Anantharam, V., Kanthasamy, A. and Kanthasamy, A. The International Journal of Biochemistry & Cell Biology, p.106225.]
• Proximity to residential and workplace pesticides application and the risk of progression of Parkinson's diseases in Central California
  Background
  Pesticide exposure has consistently been associated with Parkinson's disease (PD) onset. Yet, fewer epidemiologic studies have examined whether pesticides influence PD motor and non-motor symptom progression.

  Objectives
  Using a geographic information system tool that integrates agricultural pesticide use reports and land use records to derive ambient exposures at residences and workplaces, we assessed associations between specific pesticides previously related to PD onset with PD symptom progression in two PD patient cohorts living in agricultural regions of California.

  Methods
  We calculated the pounds of pesticide applied agriculturally near each participant's residential or occupational addresses from 1974 to the year of PD diagnosis, using a geographic information system tool that links the California Pesticide Use Reports database to land use data. We examined 53 pesticides selected a priori as they have previously been associated with PD onset. We longitudinally followed two PD patient cohorts (PEG1 N = 242, PEG2 N = 259) for an average of 5.0 years (SD ± 3.5) and 2.7 years (SD ± 1.6) respectively and assessed PD symptoms using the movement disorder specialist-administered Unified Parkinson's disease Rating Scale part III (UPDRS), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Weighted time-to-event regression models were implemented to estimate effects.

  Results
  Ten agricultural pesticides, including copper sulfate (pentahydrate), 2-methyl-4-chlorophenoxyacetic acid (MCPA) dimethylamine salt, tribufos, sodium cacodylate, methamidophos, ethephon, propargite, bromoxynil octanoate, monosodium methanearsonate (MSMA), and dicamba, were associated with faster symptom progression. Among these pesticides, residential or workplace proximity to higher amounts of copper sulfate (pentahydrate) and MCPA (dimethylamine salt) was associated with all three progression endpoints (copper sulfate: HRs = 1.22–1.36, 95 % CIs = 1.03–1.73; MCPA: HRs = 1.27–1.35, 95 % CIs = 1.02–1.70).

  Conclusions
  Our findings suggest that pesticide exposure may not only be relevant for PD onset but also PD progression phenotypes. We have implicated ten specific pesticide active ingredients in faster PD motor and non-motor decline.
  [Li, S. et al. (2022) Proximity to residential and workplace pesticides application and the risk of progression of parkinson’s diseases in Central California, Science of The Total Environment. Available at: https://www.sciencedirect.com/science/article/pii/S0048969722079542. ]

• Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
  Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
  [Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ]
• Pesticides expenditures by farming type and incidence of Parkinson disease in farmers: A French nationwide study
  Professional pesticides exposure is associated with PD risk, but it remains unclear whether specific products, which strongly depend on farming type, are specifically involved. We performed a nationwide ecological study to examine the association of pesticides expenditures for the main farming types with PD incidence in French farmers. We used the French National Health Insurance database to identify incident PD cases in farmers (2010–2015). We combined data on pesticides expenditures with the agricultural census to compute pesticides expenditures for nine farming types in 2000 in 3571 French cantons. The association between pesticides expenditures and PD age/sex standardized incidence was examined using multilevel Poisson regression, adjusted for smoking, neurologists’ density, and deprivation index. 10,282 incident PD cases were identified. Cantons with the highest pesticides expenditures for vineyards without designation of origin were characterized by 16% (95% CI = 6–28%) higher PD incidence (p-trend corrected for multiple testing = 0.006). This association was significant in men and older farmers. There was no association with pesticides expenditures for other farming types, including vineyards with designation of origin. PD incidence increased significantly with pesticides expenditures in vineyards without designation of origin characterized by high fungicide use. This result suggests that agricultural practices and pesticides used in these vineyards may play a role in PD and that farmers in these farms should benefit from preventive measures aiming at reducing exposure. Our study highlights the importance of considering farming type in studies on pesticides and PD and the usefulness of pesticides expenditures for exposure assessment.

   
  [Perrin, L., Spinosi, J., Chaperon, L., Kab, S., Moisan, F. and Ebaz, A. Environmental Research, 197, p.111161.]

• Pre-differentiation exposure to low-dose of atrazine results in persistent phenotypic changes in human neuronal cell lines
  Exposures to organic pesticides, particularly during a developmental window, have been associated with various neurodegenerative diseases later in life. Atrazine (ATZ), one of the most used pesticides in the U.S., is suspected to be associated with increased neurodegeneration later in life but few studies assessed the neurotoxicity of developmental ATZ exposure using human neuronal cells. Here, we exposed human SH-SY5Y cells to 0.3, 3, and 30 ppb of ATZ prior to differentiating them into dopaminergic-like neurons in ATZ-free medium to mimic developmental exposure. The differentiated neurons exhibit altered neurite outgrowth and SNCA pathology depending on the ATZ treatment doses. Epigenome changes, such as decreases in 5mC (for 0.3 ppb only), H3K9me3, and H3K27me3 were observed immediately after exposure. These alterations persist in a compensatory manner in differentiated neurons. Specifically, we observed significant reductions in 5mC and H3K9me3, as well as, an increase in H3K27me3 in ATZ-exposed cells after differentiation, suggesting substantial chromatin rearrangements after developmental ATZ exposure. Transcriptional changes of relevant epigenetic enzymes were also quantified but found to only partially explain the observed epigenome alteration. Our results thus collectively suggest that exposure to low-dose of ATZ prior to differentiation can result in long-lasting changes in epigenome and increase risks of SNCA-related Parkinson's Disease.
  [Xie, J., Lin, L., Sánchez, O.F., Bryan, C., Freeman, J.L. and Yuan, C., 2021. Environmental Pollution, 271, p.116379.]
• Gene Variants May Affect PD Risk After Pesticide Exposure
  

  The likelihood of developing Parkinson's disease (PD) is associated with prior exposure to occupational pesticides, both with regard to sporadic cases of PD and among patients who have a GBA genetic risk variant for PD, a new study suggests. This association was not as strong for the LRRK2 risk variant for PD. Pesticide exposure was also associated with cognitive decline, especially for carriers of the GBA variant, the researchers noted.

   

  
  [Keller., D. 2020. Medscape Conference News]
• Glyphosate exposure exacerbates the dopaminergic neurotoxicity in the mouse brain after repeated administration of MPTP
  Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. Epidemiological studies suggest that the exposure of the herbicide glyphosate may influence the development of PD in humans. In this study, we examined whether the exposure of glyphosate can affect the reduction of dopamine transporter (DAT) in the striatum and tyrosine hydroxylase (TH) in the substantial nigra (SNr) of mouse brain after repeated administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Repeated injections of MPTP (10 mg/kg × 3, 2-h interval) significantly decreased the density of DAT-immunoreactivity in the striatum and the number of TH-immunoreactivity in the SNr. Glyphosate exposure for 14 days significantly potentiated MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of mouse brain. This study suggests that glyphosate exposure might exacerbate MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of adult mice. It is likely that exposure of glyphosate may be an environmental risk factor for PD since glyphosate has been used widely in the world.
  [Pu, Y., Chang, L., Qu, Y., Wang, S., Tan, Y., Wang, X., Zhang, J. and Hashimoto, K., 2020. Neuroscience Letters, p.135032.]
• Interaction Between Genetic Variants and Serum Levels of Organochlorine Pesticides Contributes to Parkinson’s Disease.
  There is evidence that genetic and environmental factors contribute to the onset and progression of Parkinson’s disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of PD. However, few studies have investigated the interaction between specific pesticides and genetic variants related to PD in the Chinese population. In this cross-sectional study, 19 serum levels of pesticides were measured. In addition, we also analyzed the interaction between specific pesticides and candidate genetic variants for PD. Finally, we investigated the mechanistic basis for the association between pesticides and increased risk of PD. Serum levels of organochlorine pesticides including α-hexachlorocyclohexane (α-HCH), β-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p’-dichlorodiphenyltrichloroethane (p,p’-DDE) and o,p’-dichloro-diphenyl-trichloroethane (o,p’-DDT) were higher in PD patients than in controls. α-HCH and propanil levels were associated with increased PD risk. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. Interactions between high pesticide levels and polymorphisms in rs11931074 and rs16940758 (α-HCH or β-HCH interacted with TT genotype in rs11931074 and δ-HCH interacted with TT genotype in rs16940758) were associated with the risk of PD. In cell model, α-HCH and propanil increased the level of reactive oxygen species and decreased the mitochondrial membrane potential. Propanil but not α-HCH induced the aggregation of α-synuclein. Elevated serum levels of α-HCH and propanil are associated with increased risk of PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. The interaction between genetic variants and pesticides also increased the risk of PD. Effects of genetic variants and pesticides on the risk of PD should be studied in more detail with a larger sample size to further understand the mechanisms involved.
  [Xu, S., Yang, X., Qian, Y., Wan, D., Sun, F., Luo, Q., Song, Y. and Xiao, Q., 2020. Interaction Between Genetic Variants and Serum Levels of Organochlorine Pesticides Contributes to Parkinson’s Disease. Research Square.]
• Organochlorine pesticide levels in Greek patients with Parkinson’s Disease
  Parkinson’s disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data. To examine the relationship between OC blood concentrations and PD risk. In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p’-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls. All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p’-DDE (n = 214, 100% of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5%, controls 53.5%). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders [Odds Ratio, OR (95% confidence interval, C.I.)]: 2.592,(1.29-5.21)], whilst lower levels of HCB were detect among PD patients [OR,95%CI:0.176(0.09-0.35)]. Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.
  [Dardiotis, E., Aloizou, A.M., Sakalakis, E., Siokas, V., Koureas, M., Xiromerisiou, G., Petinaki, E., Wilks, M., Tsatsakis, A., Hadjichristodoulou, C. and Stefanis, L., 2020. Toxicology Reports.]
• Parkinson’s Disease in Louisiana, 1999–2012: Based on Hospital Primary Discharge Diagnoses, Incidence, and Risk in Relation to Local Agricultural Crops, Pesticides, and Aquifer Recharge
  The two major causes of Parkinson’s disease (PD) are genetic susceptibility and exposure to agricultural pesticides. Access to 23,224 individuals’ hospital primary discharge diagnoses of PD allowed the mapping of cases against known crop distributions and pesticides. Our main objective was to map PD risks (cases per 10,000 people) against crops and their pesticides. The ZIP Code address locations, and the 2000 and 2010 census data, were used to map the risks of PD throughout Louisiana and in relation to United States Department of Agriculture (USDA)-recorded crops. The introduction of glyphosate-resistant crops appears to have initiated the PD disappearance from northeastern parishes on the west bank of the Mississippi river. Rice and sugar cane are seemingly unassociated with PD, as is the Mississippi itself, except for Jefferson and St. Charles Parishes, which are essentially urban or industrial. The present major PD-affected areas are associated with commercial forests, woodlands, and pastures, and thus with certain arbor-pastoral pesticides, 2,4-D, chlorpyrifos, and paraquat. Human populations at maximum risk are those living in areas of moderate and high aquifer-recharge potential. The levels of estimated pesticide exposure in these recharge areas we were able to access were of variable use, but significant amounts of 2,4-D were being used.
  [Hugh-Jones, M.E., Peele, R.H. and Wilson, V.L., 2020. International Journal of Environmental Research and Public Health, 17(5), p.1584.]
• Pesticide use and incident Parkinson’s disease in a cohort of farmers and their spouses
  Background:
  Extensive literature suggests an association between general pesticide use and Parkinson’s disease (PD). However, with few exceptions, little is known about associations between specific pesticides and PD.

  Objective:
  We evaluated use of pesticides and incident PD in 38,274 pesticide applicators and 27,836 of their spouses in the Agricultural Health Study cohort, followed over 20 years.

  Methods:
  We used self-reported information on ever-use of 50 specific pesticides as of enrollment for both applicators and spouses, and considered intensity-weighted lifetime days (IWLD) reported at enrollment and through the first 5-year follow-up among applicators. We estimated covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression. We also examined heterogeneity in associations by history of head injury and chemical resistant glove use.

  Results:
  A total of 373 applicators and 118 spouses self-reported incident doctor-diagnosed PD. Ever-use of the insecticide terbufos (HR:1.31, 95%CI:1.02-1.68) and the herbicides trifluralin (HR:1.29, 95%CI: 0.99-1.70) and 2,4,5-T (HR:1.57, 95%CI:1.21-2.04) was associated with elevated PD risk. On the other hand, diazinon (HR:0.73, 95%CI: 0.58-0.94) and 2,4,5-TP (HR:0.39, 95%CI:0.25-0.62) were associated with reduced risk. We observed heterogeneity in ever-use associations by head injury and chemical-resistant glove use for some pesticides, with higher risk among those who reported a history of head injury, or who did not use gloves. PD risk was also elevated for applicators in the highest category of IWLD for dichlorvos, permethrin (animal use), and benomyl.

  Conclusions:
  We found evidence of increased PD risk for some pesticides. Our results also suggest higher susceptibility for pesticide-associated PD among individuals with head injury as well as protection with use of chemical resistant gloves, although further research is needed to understand the impact of head injury. Research on current and newer pesticides, including mechanisms relevant to PD, is important given widespread pesticide use.
  [Shrestha, S. et al. (2020) Pesticide use and incident parkinson’s disease in a cohort of farmers and their spouses, Environmental research. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822498/. ]

• Environment, lifestyle, and Parkinson's disease: Implications for prevention in the next decade
  There is evidence from observational studies for a role of a number of environmental exposures and lifestyle habits in modulating the risk for Parkinson's disease. Environmental and lifestyle associations, if causal, represent opportunities for Parkinson's disease prevention or disease modification at individual and population levels. In the past decade, additional evidence has been published that improves causal inference and/or enhances our understanding of the complexity of these associations. A number of gene–environment interactions have been elucidated, and our understanding of the roles of physical activity, pesticide and other chemical exposures, dietary habits, emotional stress, head injury, and smoking has been refined. In the next decade, better techniques will help us to close the gaps in our knowledge, including taking into account Parkinson's disease heterogeneity and gene and risk factor interactions in observational studies. To do this, larger datasets, global consortia, genomewide environment interaction studies, prospective studies throughout the lifespan, and improvements in the methodology of clinical trials of physical activity will be key. Despite the caveats of observational studies, a number of low-risk and potentially high-yield recommendations for lifestyle modification could be made to minimize the individual and societal burdens of Parkinson's disease, including dietary modifications, increasing physical activity, and head injury avoidance. Furthermore, a reduction in pesticide use could have a major impact on global health related to and beyond Parkinson's disease. Given the increasing prevalence of this disorder, formulating and promoting these recommendations should be a high priority.
  [Marras, C., Canning, C. G., & Goldman, S. M. (2019). Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade. Movement Disorders, 34(6), 801-811. https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.27720 ]
• Gut Inflammation in Association With Pathogenesis of Parkinson’s Disease
  Parkinson’s disease (PD) is a neurodegenerative disease that is generally thought to be caused by multiple factors, including environmental and genetic factors. Emerging evidence suggests that intestinal disturbances, such as constipation, are common non-motor symptoms of PD. Gut inflammation may be closely associated with pathogenesis in PD. This review aims to discuss the cross-talk between gut inflammation and PD pathology initiation and progression. Firstly, we will highlight the studies demonstrating how gut inflammation is related to PD. Secondly, we will analyze how gut inflammation spreads from the gastro-intestine to the brain. Here, we will mainly discuss the neural pathway of pathologic α-syn and the systemic inflammatory routes. Thereafter, we will address how alterations in the brain subsequently lead to dopaminergic neuron degeneration, in which oxidative stress, glutamate excitotoxicity, T cell driven inflammation and cyclooxygenase-2 (COX-2) are involved. We conclude a model of PD triggered by gut inflammation, which provides a new angle to understand the mechanisms of the disease.
  [Chen, Q. Q., Haikal, C., Li, W., & Li, J. Y. (2019). Gut inflammation in association with pathogenesis of Parkinson’s disease. Frontiers in molecular neuroscience, 12, 218. https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00218/full ]
• Gut microbiota in neurodegenerative disorders
  Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.

   
  [Sarkar, S. R., & Banerjee, S. (2019). Gut microbiota in neurodegenerative disorders. Journal of neuroimmunology, 328, 98-104. https://www.sciencedirect.com/science/article/pii/S0165572818304545 ]

• Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies
  

  Abstract

  This investigation aimed to conduct a systematic review of the literature and meta-analysis to determine whether exposure to the herbicide paraquat was associated with the development of Parkinson’s disease (PD). Observational studies that enrolled adults exposed to paraquat with PD as the outcome of interest were searched in the PubMed, Embase, LILACS, TOXNET, and Web of Science databases up to May 2019. Two authors independently selected relevant studies, extracted data, and assessed methodological quality. The evidence certainty was assessed by the GRADE approach, which served as basis for a tentative causality assessment, supplemented by the Bradford Hill criteria when necessary. Results from nine case–control studies indicated that PD occurrence was 25% higher in participants exposed to paraquat. The only cohort investigation included demonstrated a non-significant OR of 1.08. Results from subgroup analyses also indicated higher PD frequency in participants that were exposed to paraquat for longer periods or individuals co-exposed with paraquat and any other dithiocarbamate. Data indicate apositive association between exposure to paraquat and PD occurrence, but the weight-of-evidence does not enable one to assume an indisputable cause–effect relationship between these two conditions. Better designed studies are needed to increase confidence in results.
  [Vaccari, C. et al. (2019) ‘Paraquat and parkinson’s disease: A systematic review and meta-analysis of observational studies’, Journal of Toxicology and Environmental Health, Part B, 22(5–6), pp. 172–202. doi:10.1080/10937404.2019.1659197. ]

• Paraquat exposure and Parkinson’s disease: A systematic review and meta-analysis
  To reconcile and unify available results regarding paraquat exposure and Parkinson’s disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27–2.13; I2 = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson’s disease are warranted.
  [Tangamornsuksan, W., Lohitnavy, O., Sruamsiri, R., Chaiyakunapruk, N., Norman Scholfield, C., Reisfeld, B., & Lohitnavy, M. (2019). Paraquat exposure and Parkinson’s disease: A systematic review and meta-analysis. Archives of Environmental & Occupational Health, 74(5), 225-238. https://www.tandfonline.com/doi/abs/10.1080/19338244.2018.1492894 ]
• Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson’s Disease: A Critical Review
  Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson’s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson’s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson’s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson’s disease patients.
  [Nair, A. T., Ramachandran, V., Joghee, N. M., Antony, S., & Ramalingam, G. (2018). Gut microbiota dysfunction as reliable non-invasive early diagnostic biomarkers in the pathophysiology of Parkinson’s disease: a critical review. Journal of Neurogastroenterology and Motility, 24(1), 30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753901/ ]
• The Emerging Evidence of the Parkinson Pandemic
  

  Abstract

  Neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson disease. From 1990 to 2015, the number of people with Parkinson disease doubled to over 6 million. Driven principally by aging, this number is projected to double again to over 12 million by 2040. Additional factors, including increasing longevity, declining smoking rates, and increasing industrialization, could raise the burden to over 17 million. For most of human history, Parkinson has been a rare disorder. However, demography and the by-products of industrialization have now created a Parkinson pandemic that will require heightened activism, focused planning, and novel approaches.

  
  [Dorsey, E.R. et al. (2018) ‘The emerging evidence of the parkinson pandemic’, Journal of Parkinson’s Disease, 8(s1). doi:10.3233/jpd-181474. ]
• Cerebellar neurochemical and histopathological changes in rat model of Parkinson's disease induced by intrastriatal injection of rotenone.
  The aim of the present work was to investigate the neurochemical changes induced in the cerebellum of rat model of Parkinson's disease (PD). Rats were divided into two groups; control and rat model of PD induced by the intrastriatal injection of rotenone. As compared to control, a significant increase in the excitatory amino acid neurotransmitters; glutamate and aspartate together with a significant decrease in the inhibitory amino acids, GABA, glycine and taurine were observed in the cerebellum of rat model of PD. This was associated with a significant increase in lipid peroxidation, nitric oxide and tumor necrosis factor-α and a significant decrease in reduced glutathione. A significant decrease in acetylcholinesterase and a significant increase in Na+,K+-ATPase were recorded in the cerebellum of rat model of PD. In addition the cerebellar sections from rat model of PD showed marked necrosis of Purkinje cells, irregular damaged cells, cytoplasmic shrinkage, necrosis and perineuronal vacuolation. The present results indicate that the disturbance in the balance between the excitatory and inhibitory amino acids may have a role in the pathogenesis of PD. According to the present neurochemical and histopathological changes, the cerebellum should be taken into consideration during the treatment of PD.
  [Khadrawy YA, Mourad IM, Mohammed HS, et al. 2017. Gen Physiol Biophys. 36(1):99-108. ]
• Environmental exposure to pesticides and the risk of Parkinson's disease in the Netherlands.
  Exposure to pesticides has been linked to Parkinson's disease (PD), although associations between specific pesticides and PD have not been well studied. Residents of rural areas can be exposed through environmental drift and volatilization of agricultural pesticides. Our aim was to investigate the association between lifetime environmental exposure to individual pesticides and the risk of PD, in a national case-control study. Environmental exposure to pesticides was estimated using a spatio-temporal model, based on agricultural crops around the residential address. Distance up to 100m from the residence was considered most relevant, considering pesticide drift potential of application methods used in the Netherlands. Exposure estimates were generated for 157 pesticides, used during the study period, of which four (i.e. paraquat, maneb, lindane, benomyl) were considered a priori relevant for PD. A total of 352 PD cases and 607 hospital-based controls were included. No significant associations with PD were found for the a priori pesticides. In a hypothesis generating analysis, including 153 pesticides, increased risk of PD was found for 21 pesticides, mainly used on cereals and potatoes. Results were suggestive for an association between bulb cultivation and PD. For paraquat, risk estimates for the highest cumulative exposure tertile were in line with previously reported elevated risks. Increased risk of PD was observed for exposure to (a cluster of) pesticides used on rotating crops. High correlations limited our ability to identify individual pesticides responsible for this association. This study provides some evidence for an association between environmental exposure to specific pesticides and the risk of PD, and generates new leads for further epidemiological and mechanistic research.
  [Brouwer M, Huss A, van der Mark M, Nijssen PCG, et al. 2017. Environ Int. 107:100-110.]
• Epidemiology, environmental risk factors and genetics of Parkinson's disease.
  Parkinson's disease (PD) is a frequent neurodegenerative disease with a premotor phase that lasts several years. Risk factors that have been linked to PD are tobacco, caffeine, black tea, pesticides and calcium channel blockers. Some risk factors may be due to inverse causality (e.g. changes in personality during the premotor phase). The genetics of PD are complex with a contribution of Mendelian (e.g. SNCA, LRRK2, Parkin, Pink1,…) and non-Mendelian factors (e.g. single nucleotide polymorphisms). Glucocerebrosidase gene mutations (Gaucher disease) are currently the strongest genetic risk factor for PD. Studying risk factors will help to better understand the pathogenesis of PD.
  [Delamarre A, Meissner WG. 2017. Presse Med. 46(2 Pt 1):175-181.]
• Neurological Deficits After Long-term Pyrethroid Exposure.
  Pyrethroid pesticides have been suggested to be a cause of Parkinson's disease and other neurodegenerative diseases. To investigate this, a cross-sectional study was conducted among 120 Bolivian public health vector program spray men, primarily exposed to pyrethroids. Pesticide exposure and central nervous system (CNS) symptoms were determined by a structured interview, whereas neuromotor and neurocognitive performance was assessed using the computerized Behavioral Assessment and Research System and CATSYS system. Individuals exposed to higher levels reported significantly more CNS symptoms (adjusted odds ratio per quintile of cumulative exposure = 2.01 [1.22-3.31]). There was no association seen between pyrethroid exposure and neuromotor performance. Higher spraying intensity was associated with significantly worse neurocognitive performance in structural equation models (adjusted β per quintile = -0.405 [-0.660 to -0.150]), and workers only exposed to pyrethroids performed worse than workers also exposed to other pesticides (adjusted β = -1.344 [-2.224 to -0.464]). Chronic pyrethroid exposure may cause deterioration in neurocognitive performance, and exposure control is recommended.
  [Hansen MRH, Jørs E, Lander F, Condarco G, et al. 2017. Environ Health Insights. 11:1178630217700628.]
• Occupational pesticide use and Parkinson's disease in the Parkinson Environment Gene (PEG) study
  

  Highlights

  • Occupational pesticide use increases Parkinson's risk in central California.
  • Carbamate, organochlorine, and organophosphorus pesticide use increase PD risk.
  • Home/garden or ambient exposures affected occupational use associations minimally.
  • Some PPE types may not adequately protect pesticide applicators.

  Abstract

  Objective

  To study the influence of occupational pesticide use on Parkinson's disease (PD) in a population with information on various occupational, residential, and household sources of pesticide exposure.

  Methods

  In a population-based case control study in Central California, we used structured interviews to collect occupational history details including pesticide use in jobs, duration of use, product names, and personal protective equipment use from 360 PD cases and 827 controls. We linked reported products to California's pesticide product label database and identified pesticide active ingredients and occupational use by chemical class including fungicides, insecticides, and herbicides. Employing unconditional logistic regression, we estimated odds ratios and 95% confidence intervals for PD and occupational pesticide use.

  Results

  Ever occupational use of carbamates increased risk of PD by 455%, while organophosphorus (OP) and organochlorine (OC) pesticide use doubled risk. PD risk increased 110–211% with ever occupational use of fungicides, herbicides, and insecticides. Using any pesticide occupationally for > 10 years doubled the risk of PD compared with no occupational pesticide use. Surprisingly, we estimated higher risks among those reporting use of personal protective equipment (PPE).

  Conclusions

  Our findings provide additional evidence that occupational pesticide exposures increase PD risk. This was the case even after controlling for other sources of pesticide exposure. Specifically, risk increased with occupational use of carbamates, OPs, and OCs, as well as of fungicides, herbicides, or insecticides. Interestingly, some types of PPE use may not provide adequate protection during pesticide applications.

  
  [Narayan, S. et al. (2017) ‘Occupational pesticide use and parkinson’s disease in the parkinson environment gene (PEG) study’, Environment International, 107, pp. 266–273. doi:10.1016/j.envint.2017.04.010. ]
• Organophosphate pesticides and PON1 L55M in Parkinson's disease progression.
  To investigate whether ambient agricultural OP exposure and PON1 L55M influence the rate of motor, cognitive, and mood-related symptom progression in PD.We followed a longitudinal cohort of 246 incident PD patients on average over 5years (7.5years after diagnosis), repeatedly measuring symptom progression with the Mini-Mental State Exam (MMSE), Unified Parkinson's Disease Rating Scale (UPDRS), and Geriatric Depressive Scale (GDS). OP exposures were generated with a geographic information system (GIS) based exposure assessment tool.High OP exposures were associated with faster progression of motor (UPDRS β=0.24, 95% CI=-0.01, 0.49) and cognitive scores (MMSE β=-0.06, 95% CI=-0.11, -0.01). PON1 55MM was associated with faster progression of motor (UPDRS β=0.28, 95% CI=0.08, 0.48) and depressive symptoms (GDS β=0.07; 95% CI=0.01, 0.13). We also found the PON1 L55M variant to interact with OP exposures in influencing MMSE cognitive scores (β=-1.26, 95% CI=-2.43, -0.09). Study provides preliminary support for the involvement of OP pesticides and PON1 in PD-related motor, cognitive, or depressive symptom progression. Future studies are needed to replicate findings and examine whether elderly populations generally are similarly impacted by pesticides or PON1 55M genotypes.
  [Paul KC, Sinsheimer JS, Cockburn M, Bronstein JM, et al. 2017. Environ Int. 107:75-81.]
• Paraquat and maneb co-exposure induces noradrenergic locus coeruleus neurodegeneration through NADPH oxidase-mediated microglial activation.
  Co-exposure to paraquat (PQ) and maneb (Mb) has been shown to increase the risk of Parkinson's disease (PD) and dopaminergic (DA) neurodegeneration in the substantia nigra pars compacta (SNpc) is observed in PQ and Mb-treated experimental animals. The loss of noradrenergic locus coeruleus (LC/NE) neurons in brainstem is a common feature shared by multiple neurodegenerative diseases, including PD. However, whether PQ and Mb is able to damage LC/NE neurons remains undefined. In this study, mice treated with combined PQ and Mb displayed progressive LC/NE neurodegeneration. Time course studies revealed that the activation of microglia preceded LC/NE neurodegeneration. Mechanistically, the activation of NADPH oxidase contributed to microglial activation and subsequent LC/NE neurodegeneration. We found that PQ and Mb co-exposure induced activation of NADPH oxidase as shown by increased superoxide production and membrane translocation of p47phox, a cytosolic subunit of NADPH oxidase. Inhibition of NADPH oxidase by apocynin, a widely used NADPH oxidase inhibitor, suppressed microglial activation and gene expressions of proinflammatory factors. Furthermore, reduced activation of nuclear factor-κB (NF-κB) pathway was observed in apocynin-treated mice. More importantly, inhibition of NADPH oxidase by apocynin afforded LC/NE neuroprotection against PQ and Mb-induced neurotoxicity. Thus, our findings revealed the critical role NADPH oxidase-mediated microglial activation in driving LC/NE neurodegeneration induced by PQ and Mb, providing new insights into the pathogenesis of environmental toxins-induced PD.
  [Hou L, Zhang C, Wang K, Liu X, et al. 2017. Toxicology. 380:1-10. ]
• Parkinson's Disease: From Pathogenesis to Pharmacogenomics.
  Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson's disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin-proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the "wearing-off phenomenon", with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.
  [Cacabelos R. 2017. Int J Mol Sci. 18(3)]
• Pesticides: an update of human exposure and toxicity.
  Pesticides are a family of compounds which have brought many benefits to mankind in the agricultural, industrial, and health areas, but their toxicities in both humans and animals have always been a concern. Regardless of acute poisonings which are common for some classes of pesticides like organophosphoruses, the association of chronic and sub-lethal exposure to pesticides with a prevalence of some persistent diseases is going to be a phenomenon to which global attention has been attracted. In this review, incidence of various malignant, neurodegenerative, respiratory, reproductive, developmental, and metabolic diseases in relation to different routes of human exposure to pesticides such as occupational, environmental, residential, parental, maternal, and paternal has been systematically criticized in different categories of pesticide toxicities like carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. A huge body of evidence exists on the possible role of pesticide exposures in the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity. Most of the disorders are induced by insecticides and herbicides most notably organophosphorus, organochlorines, phenoxyacetic acids, and triazine compounds.
  [Mostafalou S and Abdollahi M.2017. Arch Toxicol. 91(2):549-599]
• A Review of the Association Between Parkinson Disease and Malignant Melanoma
  An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma.The objective was to research possible etiological links to explain the connection between PD and melanoma. Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy. Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors.
  [Disse M, Reich H, Lee PK, Schram SS. 2016. Dermatol Surg. 42(2):141-6.]
• Association between Parkinson's Disease and Cigarette Smoking, Rural Living, Well-Water Consumption, Farming and Pesticide Use: Systematic Review and Meta-Analysis.
  Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson's disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a "positive control" because a strong inverse association has been described consistently in the literature. PubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson's disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides, or paraquat. There was a consistent inverse (negative) association between current cigarette smoking and PD risk. In contrast, associations between PD and rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat were less consistent when assessed quantitatively or qualitatively. The weight of the evidence and meta-analysis support the conclusion that there is a causal relationship between PD risk and cigarette smoking, or some unknown factor correlated with cigarette smoking. There may be risk factors associated with rural living, farming, pesticide use or well-water consumption that are causally related to PD, but the studies to date have not identified such factors. To overcome the limitations of research in this area, future studies will have to better characterize the onset of PD and its relationship to rural living, farming and exposure to pesticides.
  [Breckenridge CB, Berry C, Chang ET, et al. 2016. PLoS One.11(4):e0151841]
• Deguelin and Its Role in Chronic Diseases.
  Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson's disease (PD). PD is a neurodegenerative disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra, as well the manifestation of symptoms such as bradykinesia, rigidity, and rest tremor. While exploring the genetic impact of PD is imperative, environmental factors, such as exposure to pesticides, herbicides, and insecticides, have also been connected to the development of PD. The etiology and pathogenesis of PD are yet to be fully understood and elucidated, but mitochondrial dysfunction is gaining recognition as a molecular hallmark of PD. In fact, deguelin has been reported to elicit PD-like symptoms (degeneration of the dopaminergic pathway) in rats administered with deguelin (6 mg/kg/day for 6 days), possibly through the inhibition of mitochondrial complex I. Further research investigating the mechanisms by which deguelin inhibits central cellular processes is essential in order to advance any prospective research addressing potential applications and risks of deguelin.
  [Boyd J, Han A. 2016. Adv Exp Med Biol. 929:363-375.]
• Early life exposure to permethrin: a progressive animal model of Parkinson's disease.
  Oxidative stress, alpha-synuclein changes, mitochondrial complex I defects and dopamine loss, observed in the striatum of rats exposed to the pesticide permethrin in early life, could represent neuropathological hallmarks of Parkinson's disease (PD). Nevertheless, an animal model of PD should also fulfill criteria of face and predictive validities. This study was designed to: 1) verify dopaminergic status in the striatum and substantia nigra pars compacta; 2) recognize non-motor symptoms; 3) investigate the time-course development of motor disabilities; 4) assess L-Dopa effectiveness on motor symptoms in rats previously exposed to permethrin in early life. The permethrin-treated group received 34mg/kg daily of permethrin from postnatal day 6 to 21, whereas the age-matched control group was administered with the vehicle only. At adolescent age, the permethrin-treated group showed decreased levels of dopamine in the striatum, loss of dopaminergic neurons in the substantia nigra pars compacta and cognitive impairments. Motor coordination defects appeared at adult age (150days old) in permethrin-treated rats on rotarod and beam walking tasks, whereas no differences between the treated and control groups were detected on the foot print task. Predictive validity was evaluated by testing the ability of L-Dopa (5, 10 or 15mg/kg, os) to restore the postural instability in permethrin-treated rats (150days old) tested in a beam walking task. The results revealed full reversal of motor deficits starting from 10mg/kg of L-Dopa. The overall results indicate that this animal model replicates the progressive, time-dependent nature of the neurodegenerative process in Parkinson's disease.
  [Nasuti C, Brunori G, Eusepi P, Marinelli L, et al. 2016. J Pharmacol Toxicol Methods. 83:80-86.]
• Environmental Exposures and Parkinson's Disease.
  Parkinson's disease (PD) affects millions around the world. The Braak hypothesis proposes that in PD a pathologic agent may penetrate the nervous system via the olfactory bulb, gut, or both and spreads throughout the nervous system. The agent is unknown, but several environmental exposures have been associated with PD. Here, we summarize and examine the evidence for such environmental exposures. We completed a comprehensive review of human epidemiologic studies of pesticides, selected industrial compounds, and metals and their association with PD in PubMed and Google Scholar until April 2016. Most studies show that rotenone and paraquat are linked to increased PD risk and PD-like neuropathology. Organochlorines have also been linked to PD in human and laboratory studies. Organophosphates and pyrethroids have limited but suggestive human and animal data linked to PD. Iron has been found to be elevated in PD brain tissue but the pathophysiological link is unclear. PD due to manganese has not been demonstrated, though a parkinsonian syndrome associated with manganese is well-documented. Overall, the evidence linking paraquat, rotenone, and organochlorines with PD appears strong; however, organophosphates, pyrethroids, and polychlorinated biphenyls require further study. The studies related to metals do not support an association with PD.
  [Nandipati S, Litvan I. 2016. Int J Environ Res Public Health. 13(9).]
• Genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease.
  Genetic factors and environmental exposures, including pesticides, contribute to the risk of Parkinson's disease (PD). There have been few studies of gene and pesticide exposure interactions in PD, and all of the prior studies used a candidate gene approach. We performed the first genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease. Analyses were performed using data on >700,000 single nucleotide polymorphisms (SNPs) in 364 discordant sibling pairs. In addition to testing for SNP-pesticide interaction effects, we also performed exploratory analyses of gene-pesticide interactions at the gene level. None of the gene-environment interaction results were significant after genome-wide correction for multiple testing (α = 1.5E-07 for SNP-level tests; α = 2.1E-06 for gene-level tests). Top results in the SNP-level tests provided suggestive evidence (P < 5.0E-06) that the effect of pesticide exposure on PD risk may be modified by SNPs in the ERCC6L2 gene (P = 2.4E-06), which was also supported by suggestive evidence in the gene-level analysis (P = 4.7E-05). None of the candidate genes assessed in prior studies of gene-pesticide interactions reached statistical support in this genome-wide screen. Although no significant interactions were identified, several of the genes with suggestive evidence of gene-environment interaction effects have biological plausibility for PD risk. Further investigation of the role of those genes in PD risk, particularly in the context of pesticide exposure, in large and carefully recruited samples is warranted.
  [Biernacka JM, Chung SJ, Armasu SM, Anderson KS, et al. 2016. Parkinsonism Relat Disord. 32:25-30]
• Of Pesticides and Men: a California Story of Genes and Environment in Parkinson's Disease
  At the start of the postgenomics era, most Parkinson's disease (PD) etiology cannot be explained by our knowledge of genetic or environmental factors alone. For more than a decade, we have explored gene-environment (GxE) interactions possibly responsible for the heterogeneity of genetic as well as environmental results across populations. We developed three pesticide exposure measures (ambient due to agricultural applications, home and garden use, and occupational use) in a large population-based case-control study of incident PD in central California. Specifically, we assessed interactions with genes responsible for pesticide metabolism (PON1); transport across the blood-brain barrier (ABCB1); pesticides interfering with or depending on dopamine transporter activity (DAT/SLC6A3) and dopamine metabolism (ALDH2); impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1); and contributing to immune dysregulation (HLA-DR). These studies established some specificity for pesticides' neurodegenerative actions, contributed biologic plausibility to epidemiologic findings, and identified genetically susceptible populations.
  [Ritz BR, Paul KC, Bronstein JM. 2016. Curr Environ Health Rep. 3(1):40-52.]
• Organophosphate pesticide exposure and neurodegeneration
  Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
  [Sánchez-Santed, F., Colomina, M.T. and Hernández, E.H., 2016. Cortex, 74, pp.417-426.]
• Parkinson's Disease and Pesticides Exposure: New Findings From a Comprehensive Study in Nebraska, USA
  The association between exposure to agricultural pesticides and Parkinson's Disease (PD) has long been a topic of study in the field of environmental health. This research takes advantage of the unique Nebraska PD registry and state-level crop classification data to investigate the PD-pesticides exposure relationship.First, Geographic Information System and satellite remote sensing data were adopted to calculate exposure to different pesticides for Nebraska residents. An integrated spatial exploratory framework was then adopted to explore the association between PD incidence and exposure to specific pesticide ingredients at the county level.Our results reveal similarities in geographic patterns of pesticide exposure and PD incidence. The regression analyses indicate that, for most Nebraska counties, PD incidence was significantly associated with exposure to certain pesticide ingredients such as alachlor and broxomy. However, the results also suggest that factors other than pesticide exposure may help further explain the risk of PD at the county level.We found significant associations between PD incidence and exposure to different pesticide ingredients. These results have useful implications for PD prevention in Nebraska and other agricultural states in the United States.
  [Wan N, Lin G. 2016. J Rural Health. 32(3):303-13.]
• Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
  Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
  [Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64]
• Subcutaneous rotenone rat model of Parkinson's disease: Dose exploration study
  Subcutaneous administration of rotenone has recently attracted attention because of its convenience, simplicity and efficacy in replicating features of Parkinson's disease (PD) in animal models. However, the wide range of doses reported in the literature makes it difficult to evaluate the effectiveness of this technique objectively. The aim of the present study was to identify the optimum dose of subcutaneous rotenone for establishing a model of PD. We injected male Wistar rats subcutaneously with one of three doses of rotenone (1.5, 2, or 2.5mg/kg) daily for 5 weeks. Rotenone caused a dose-dependent increase in α-synuclein in the substantia nigra. Furthermore, at 2 and 2.5mg/kg, rotenone caused a significant decrease in the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra, and dopamine in the striatum. However, mortality at 2.5mg/kg was 46.7%, compared with just 6.7% at 2mg/kg; the high mortality observed at 2.5mg/kg would limit its application. The 2mg/kg dose showed no detrimental effect on body weight after 5 weeks of daily injections. Furthermore, rats in the 2mg/kg group showed a longer latency to descend from a horizontal bar and a grid wall, decreased rearing, and shorter latency to fall from a rotarod than rats that received vehicle or saline. Mitochondrial damage, observed by transmission electron microscopy, was also evident at this dose. Together, our data indicate that daily subcutaneous injection of 2mg/kg rotenone in rats facilitates the formation of α-synuclein and reproduces the typical features of PD, while maintaining low mortality.
  [Zhang ZN, Zhang JS, Xiang J, Yu ZH, et al. 2016. Brain Res. 1655:104-113.]
• Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment.
  Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.Search was conducted in PubMed and Web of Science databases and articles were selected if the following inclusion criteria were met: being a SR, published until April 2015 and without language restrictions.The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.
  [Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M. 2016. Environ Int. 92-93:657-79. ]
• The epidemiology of Parkinson's disease: risk factors and prevention.
  Since 2006, several longitudinal studies have assessed environmental or behavioural factors that seem to modify the risk of developing Parkinson's disease. Increased risk of Parkinson's disease has been associated with exposure to pesticides, consumption of dairy products, history of melanoma, and traumatic brain injury, whereas a reduced risk has been reported in association with smoking, caffeine consumption, higher serum urate concentrations, physical activity, and use of ibuprofen and other common medications. Randomised trials are investigating the possibility that some of the negative risk factors might be neuroprotective and thus beneficial in individuals with early Parkinson's disease, particularly with respect to smoking (nicotine), caffeine, and urate. In the future, it might be possible to identify Parkinson's disease in its prodromal phase and to promote neuroprotective interventions before the onset of motor symptoms. At this time, however, the only intervention that seems justifiable for the primary prevention of Parkinson's disease is the promotion of physical activity, which is likely to be beneficial for the prevention of several chronic diseases.
  [Ascherio A, Schwarzschild MA. 2016. Lancet Neurol. 15(12):1257-1272. ]
• Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France.
  Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes. This study examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Authors examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant). There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models and a synergistic interaction between duration and intensity. High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly, for tremor dominant than for non-tremor dominant PD. This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor dominant PD in men, the most typical PD presentation.
  [Moisan F1, Spinosi J, Delabre L, et al. 2015. Environ Health Perspec. DOI:10.1289/ehp.1307970]
• Blood α-synuclein in agricultural pesticide handlers in central Washington State.
  Epidemiologic studies suggest that occupational exposure to pesticides might increase Parkinson disease risk. Some pesticides, such as the organophosphorus insecticide chlorpyrifos, appear to increase the expression of α-synuclein, a protein critically involved in Parkinson disease. Therefore, study assessed total blood cell α-synuclein in 90 specimens from 63 agricultural pesticide handlers, mainly Hispanic men from central Washington State, who participated in the state's cholinesterase monitoring program in 2007-2010. Additionally, authors assessed whether α-synuclein levels were associated with butyrylcholinesterase-chlorpyrifos adducts or cholinesterase inhibition measured in peripheral blood, or with self-reported pesticide exposure or paraoxonase (PON1) genotype. There was no evidence by any of those indicators that exposure to chlorpyrifos was associated with greater blood α-synuclein. Authors observed somewhat greater α-synuclein with the PON1-108T (lower paraoxonase enzyme) allele, and with ≥ 10 h of exposure to cholinesterase inhibiting insecticides in the preceding 30 days, but neither of these associations followed a clear dose-response pattern. Results suggest that selected genetic and environmental factors may affect α-synuclein blood levels. However, longitudinal studies with larger numbers of pesticide handlers will be required to confirm and elucidate the possible associations observed in this exploratory cross-sectional study.
  [Searles Nielsen S, Checkoway H, Zhang J, et al. 2015. Environ Res.136:75-81.]
• Environment-contact administration of rotenone: A new rodent model of Parkinson's disease.
  Authors describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. Results showed significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of α-synuclein in the substantia nigra and striatum (α-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Results provide new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies.
  [Liu Y, Sun JD, Song LK, et al. 2015. Behav Brain Res.294:149-161]
• Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.
  Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.
  [Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. 2015. Front Cell Neurosci. 9:124]
• Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson's disease
  Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk. To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk. In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD. For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions. This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.
  [Narayan S, Sinsheimer JS, Paul KC, et al. 2015. Environ Res. 143(Pt A):98-106.]
• Groundwater pesticide levels and the association with Parkinson disease.
  It is unclear whether exposure to environmentally relevant levels of pesticides in groundwater is associated with an increased risk of Parkinson disease (PD). The purpose of this study was to examine the relationship between PD and pesticide levels in groundwater. This cross-sectional study included 332 971 Medicare beneficiaries, including 4207 prevalent cases of PD from the 2007 Colorado Medicare Beneficiary Database. Residential pesticide levels were estimated from a spatial model based on 286 well water samples with atrazine, simazine, alachlor, and metolachlor measurements. A logistic regression model with known PD risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. Results found that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% while adjusting for age, race/ethnicity, and gender suggesting that higher age-standardized PD prevalence ratios are associated with increasing levels of pesticides in groundwater.
  [James KA, Hall DA. 2015. Int J Toxicol.34(3):266-73.]
• Occupational exposures and Parkinson's disease mortality in a prospective Dutch cohort.
  Study investigated the association between six occupational exposures (ie, pesticides, solvents, metals, diesel motor emissions (DME), extremely low frequency magnetic fields (ELF-MF) and electric shocks) and Parkinson's disease (PD) mortality in a large population-based prospective cohort study. The Netherlands Cohort Study on diet and cancer enrolled 58,279 men and 62,573 women aged 55-69 years in 1986. Following a case-cohort design, a subcohort of 5,000 participants was randomly sampled from the complete cohort. Information on occupational history and potential confounders was collected at baseline. Job-exposure matrices were applied to assign occupational exposures. Associations with PD mortality were evaluated using Cox regression. Among men, elevated HRs were observed for exposure to pesticides and ever high exposed to ELF-MF. No association with exposure duration or trend in cumulative exposure was observed for any of the occupational exposures. Associations with PD mortality were observed for occupational exposure to pesticides and ELF-MF. However, the weight given to these findings is limited by the absence of a monotonic trend with either duration or cumulative exposure.
  [Brouwer M, Koeman T, van den Brandt PA, et al. 2015. Occup Environ Med. 72(6):448-55.]
• Occupational exposures and parkinsonism
  In recent years, the contribution of exposure to environmental toxicants has been recognized as a significant contributor to the etiopathogenesis of parkinsonism. Of these toxicants, exposure to pesticides, metals, solvents used in manufacturing processes, as well as flame-retardant chemicals used in consumer and commercial products, has received the greatest attention as possible risk factors. Related to this, individuals who are exposed to these compounds at high concentrations or for prolonged periods of time in an occupational setting appear to be one of the more vulnerable populations to these effects. Our understanding of which compounds are involved and the potential molecular pathways that are susceptible to these chemicals and may underlie the pathogenesis has greatly improved. However, there are still hundreds of chemicals that we are exposed to in the environment for which we do not have any information on their potential neurotoxicity on the nigrostriatal dopamine system. Thus, using our past accomplishments as a blueprint, future endeavors should focus on elaborating upon these initial findings in order to identify specific and relevant chemical toxicants in our environment that can impact the risk of parkinsonism and work towards a means to attenuate or abolish their effects on the human population.
  [Caudle WM. 2015. Handb Clin Neurol. 131:225-39.]
• Oxidative stress and Parkinson's disease
  Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
  [Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. 2015. Front Neuroanat. 9:91.]
• Oxidative stress and Parkinson's disease.
  Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, authors give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
  [Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. 2015. Front Neuroanat. 8(9):91]
• Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.
  Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson's disease (PD). Mechanisms of relatively selective rotenone-induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. Authors tested whether rotenone interferes with vesicular uptake and intracellular ALDH activity. Rotenone dose dependently increased DOPAL, F-DOPAL, and 3,4-dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the sum of its deaminated metabolites. In test tubes, rotenone did not affect conversion of DOPAL to DOPAC by ALDH when NAD(+) was supplied, whereas the direct-acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC concentrations in the reaction mixtures. Study proposes that rotenone builds up intracellular DOPAL by decreasing ALDH activity and attenuating vesicular sequestration of cytoplasmic catecholamines. The results provide a novel mechanism for selective rotenone-induced toxicity in dopaminergic neurons.
  [Goldstein DS, Sullivan P, et al. 2015. J Neurochem.133(1):14-25.]
• Rotenone exerts similar stimulatory effects on H2O2 production by isolated brain mitochondria from young-adult and old rats.
  The aim of the present study was to evaluate whether brain mitochondria from old rats (24 months old) would be more susceptible to rotenone-induced inhibition of oxygen consumption and increased generation of H2O2 than mitochondria from young-adult rats (3-4 months old). Isolated brain mitochondria were incubated in the presence of different rotenone concentrations (5, 10, and 100nM), and oxygen consumption and H2O2 production were measured during respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration). Respiratory state 3 and citrate synthase activity were significantly lower in mitochondria from old rats. Mitochondria from young-adult and old rats showed similar sensitivity to rotenone-induced inhibition of oxygen consumption. Similarly, H2O2 production rates by both types of mitochondria were dose-dependently stimulated to the same extent by increasing concentrations of rotenone. We conclude that rotenone exerts similar effects on oxygen consumption and H2O2 production by isolated brain mitochondria from young-adult and old rats. Therefore, aging does not increase the mitochondrial H2O2 generation in response to complex I inhibition.
  [Michelini LG, Figueira TR, et al. 2015. Neurosci Lett. 589:25-30.]
• The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings.
  The study aims at providing new and more specific evidence for the validity of the rotenone rat model of Parkinson's disease (PD) by examining whether neuronal activity in the subthalamic nucleus (STN) is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group, accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region. Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate, more bursts per minute and a higher oscillatory activity in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. Study also found found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. The rotenone-induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features.
  [von Wrangel C1, Schwabe K, et al. 2015. Behav Brain Res. 279:52-61.]
• A variety of pesticides trigger in vitro α-synuclein accumulation, a key event in Parkinson's disease.
  Whereas epidemiological studies largely failed to identify pesticides specifically involved in Parkinson's disease (PD), it is of critical importance to set up in vitro toxicity studies of pesticides. Study measured changes of αS levels following pesticide exposures of human cell lines in vitro, using either ELISA detection of endogenous αS or flow cytometry after overexpression using recombinant adenoviruses. We showed that three pesticides (paraquat, rotenone and maneb), which have frequently been associated with PD, produced a dose-dependent increase in cellular αS levels, but also of αS released into the culture medium. Examining an additional series of 20 pesticides from different families and chemical structures, study found that beside some insecticides, including an organophosphate and three pyrethroids, a majority of the 12 studied fungicides were also producing an αS accumulation, three of them (thiophanate-methyl, fenhexamid and cyprodinil) having similar or more pronounced effects than paraquat. A variety of pesticides can disrupt αS homeostasis in vitro; our data illustrate an experimental strategy that could help in the identification of chemicals that could be specifically involved in PD etiology.
  [Chorfa A, Lazizzera C, Bétemps D, et al. 2014. Arch Toxicol. doi:10.1007/s00204-014-1388-2]
• Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease.
  The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson's disease (PD) risk in an epidemiologic study. A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals.
  [Fitzmaurice AG, Rhodes SL, et al. 2014. Neurology.82(5):419-26.]
• Cypermethrin alters the status of oxidative stress in the peripheral blood: relevance to Parkinsonism.
  While oxidative stress is implicated in Parkinson's disease (PD), prolonged exposure to moderate dose of cypermethrin induces Parkinsonism. The study aimed to investigate the status of oxidative stress indicators and antioxidant defence system of the polymorphonuclear leukocytes (PMNs), platelets and plasma to delineate the effect of Parkinsonian dose of cypermethrin in the peripheral blood of rats and its subsequent relevance to Parkinsonism. The striatal dopamine was measured to assess the degree of neurodegeneration/neuroprotection. Cypermethrin increased nitrite and LPO in the plasma, platelets and PMNs while it reduced the striatal dopamine content. Catalase and glutathione-S-transferase (GST) activity were increased in the PMNs and platelets; however, it was reduced in the plasma. Conversely, SOD and GR activities were reduced in the PMNs and platelets but increased in the plasma. Minocycline or syndopa reduced the cypermethrin-mediated changes towards normalcy. The results demonstrate that cypermethrin alters the status of oxidative stress indicators and impairs antioxidant defence system of the peripheral blood, which could be effectively salvaged by minocycline or syndopa. The results could be of value for predicting the nigrostriatal toxicity relevant to Parkinsonism.
  [Tripathi P, Singh A, Agrawal S, et al. 2014. J Physiol Biochem. 70(4):915-24.]
• Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring.
  Recent epidemiological evidence has found exposure to the organochlorine insecticide endosulfan to be a risk factor for Parkinson's disease (PD). However, the specific dopaminergic targets or vulnerable developmental time points related to endosulfan exposure have not been investigated. Study sought to investigate dopaminergic neurotoxicity following developmental exposure to endosulfan as well as following an additional challenge with MPTP. In vitro findings demonstrate a reduction in SK-N-SH cells and ventral mesencephalic primary cultures after endosulfan treatment. Using an in vivo developmental model, exposure to endosulfan during gestation and lactation caused a reduction in DAT and TH in the striatum of male offspring. These alterations were exacerbated following subsequent treatment with MPTP. In contrast, exposure of adult mice to endosulfan did not elicit dopaminergic damage and did not appear to increase the vulnerability of the dopamine neurons to MPTP. These findings suggest that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system. Furthermore, these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.
  [Wilson WW, Shapiro LP, et al. 2014. Neurotoxicology. 44:279-87]
• Dietary fat intake, pesticide use, and Parkinson's disease.
  Dietary fat intake may modify Parkinson's disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides.Researchers conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses. They evaluated diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls.
  In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 in individuals with PUFA intake below the median but 1.2 in those with higher intake. The OR for rotenone was 5.8 in those with saturated fat intake above the median but 1.5 in those with lower intake.PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.
  [Kamel F, Goldman SM, Umbach DM, et al. 2014. Parkinsonism Relat Disord. 20(1):82-7.]
• Environmental toxins and Parkinson's disease.
  Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis.
  [Goldman SM. 2014. Annu Rev Pharmacol Toxicol.54:141-64]
• In vitro dopaminergic neurotoxicity of pesticides: a link with neurodegeneration?
  From epidemiological studies, it is known that there is a link between exposure to certain chemical classes of these so-called pesticides and the prevalence of neurodegenerative disorders such as Parkinson's disease in humans. However, which particular compound(s) account for this link or what underlying mechanisms are involved is still largely unresolved. The degenerative process in Parkinson's disease is largely limited to the dopaminergic neurons in the basal ganglia. Cellular mechanisms that are implicated in parkinsonian neurodegeneration include mitochondrial dysfunction, oxidative stress, disturbance of intracellular calcium homeostasis and endoplasmic reticulum (ER) stress. A major characteristic that distinguishes the dopaminergic neurons in the basal ganglia from other dopaminergic neurons is a particular reliance on intracellular calcium for spontaneous activity. Considering the energy consuming nature of maintenance of the intracellular calcium homeostasis and its involvement in life and death of a neuron, this may explain the specific vulnerability of this neuronal population. Despite a large variation in primary mechanism of action it has been demonstrated that pesticides from different classes disturb intracellular calcium homeostasis, thus interfering with intracellular calcium signalling. This relates to altered dopaminergic signalling, disturbed protein homeostasis and increased oxidative stress. Therefore, effects of (mixtures of) pesticides on the intracellular calcium homeostasis may play a role in the development of Parkinson's disease in humans. Although human exposure to pesticides via e.g. food often occurs in complex mixtures, (human) risk assessment is largely based on the assessment of single compounds. The discovery of common modes of action across different classes of pesticides therefore underpins the urgency of development of new models and approaches in risk assessment.
  [Heusinkveld HJ, van den Berg M, Westerink RH. 2014. Veterinary Quarterly. 34(3):120-31.]
• Microstructural changes in the substantia nigra of asymptomatic agricultural workers.
  Epidemiological studies suggest that pesticide exposure is linked to higher Parkinson's disease (PD) risk, but there are no studies demonstrating substantia nigra (SN) changes with chronic pesticide exposure in human subjects. Thus, high resolution T2-weighted magnetic resonance imaging (MRI) and diffusion tensor (DTI) images were obtained from 12 agricultural workers with chronic pesticide exposure, 12 controls, and 12 PD subjects. Neither controls nor pesticide-exposed subjects, had any parkinsonian symptoms. Exposure history to pesticides was assessed by a structured questionnaire. DTI measures in the SN, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were obtained for all subjects and compared among groups. Compared to controls, PD patients showed the expected significant changes in all DTI measurements in the SN. The pesticide-exposed subjects, compared to controls, had significantly lower FA values, but no significant differences in RD, MD, or AD measures. The study is the first to demonstrate microstructural changes in the SN of human subjects with chronic pesticide exposure. The changes detected by MRI may mark "one of the hits" leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD.
  [Du G, Lewis MM, Sterling NW, et al. 2014. Neurotoxicol Teratol. 41:60-4.]
• Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.
  Authors studied the associations of Parkinson disease (PD) with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use.The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl.This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.
  [van der Mark M, Vermeulen R, Nijssen PC. 2014. Occup Environ Med. 71(11):757-64.]
• Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
  The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
  [Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
• Rotenone and paraquat perturb dopamine metabolism: A computational analysis of pesticide toxicity.
  Pesticides, such as rotenone and paraquat, are suspected in the pathogenesis of Parkinson's disease (PD), whose hallmark is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Thus, compounds expected to play a role in the pathogenesis of PD will likely impact the function of dopaminergic neurons. To explore the relationship between pesticide exposure and dopaminergic toxicity, the authors developed a custom-tailored mathematical model of dopamine metabolism and utilized it to infer potential mechanisms underlying the toxicity of rotenone and paraquat, asking how these pesticides perturb specific processes. They performed two types of analyses, which are conceptually different and complement each other. The first analysis, a purely algebraic reverse engineering approach, analytically and deterministically computes the altered profile of enzyme activities that characterize the effects of a pesticide. The second method consists of large-scale Monte Carlo simulations that statistically reveal possible mechanisms of pesticides. The results from the reverse engineering approach show that rotenone and paraquat exposures lead to distinctly different flux perturbations. Rotenone seems to affect all fluxes associated with dopamine compartmentalization, whereas paraquat exposure perturbs fluxes associated with dopamine and its breakdown metabolites. The statistical results of the Monte-Carlo analysis suggest several specific mechanisms. The findings are interesting, because no a priori assumptions are made regarding specific pesticide actions, and all parameters characterizing the processes in the dopamine model are treated in an unbiased manner. The results show how approaches from computational systems biology can help identify mechanisms underlying the toxicity of pesticide exposure.
  [Qi Z, Miller GW, Voit EO. 2014. Toxicology.315:92-101]
• The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk.
  Alzheimer's disease, Parkinson's disease, and motor neuron disease, the most common of the late-life neurodegenerative disorders, are in most cases thought to have complex etiologies. Common features among these disorders include insidious onset, pathological findings of protein aggregates and selected neuronal degeneration, and resulting characteristic clinical syndromes. The number of elders in the US, including aging veterans, is increasing. Investigation of causes and preventive interventions for neurodegenerative disorders is increasingly relevant. Recent epidemiological and laboratory studies suggest that exposures years or decades before diagnosis can trigger the processes that ultimately result in a neurodegenerative disease. If this is correct, preventive measures may be needed in midlife or earlier. This article focuses on putative risk factors relevant to military service.
  [Tanner CM, Goldman SM, Ross GW, Grate SJ. 2014. Alzheimers Dement.10(3 Suppl):S213-25]
• Younger age at onset of sporadic Parkinson's disease among subjects occupationally exposed to metals and pesticides.
  An earlier age at onset of Parkinson's disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides were significantly younger than unexposed controls. These subjects were then divided into three groups to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect.
  [Ratner MH1, Farb DH, et al. 2014. Interdiscip Toxicol. 7(3):123-33.]
• Chronic exposure to rotenone, a dopaminergic toxin, results in peripheral neuropathy associated with dopaminergic damage.
  Rotenone, a widely used pesticide, causes a syndrome in rats that replicates, both pathologically and behaviorally, the symptoms of Parkinson's disease (PD). In the present study, authors sought to determine if a chronic exposure to rotenone, resulting in dopaminergic loss, could also lead to peripheral neuronal damage related to motor dysfunction. Adult male Sprague-Dawley rats were treated with rotenone. The motor nerve conduction velocity (MCV) was assessed using action potentials detected from the tail muscle through surface receiver electrodes installed around the distal portion of the tail. Rats exposed to rotenone often developed hind limb paresis with a significant decrease in MCV as detected in tail nerves. Time-dependent rotenone-induced striatal depletion of DA (60% after 7 days and 80% after 27 days) was observed. Furthermore, Neurofilament-neurofilament B, Flouro-Jade C and myelin basic protein analyses suggested a time-dependent rotenone-induced neurodegeneration in sciatic nerves. These data, for the first time, indicate an association between dopaminergic damage and peripheral motor nerve degeneration in an animal model of dopaminergic toxicity. Peripheral motor nerve dysfunction in rats following a chronic exposure to rotenone may serve not only as a relevant experimental model of motor neuropathy but also as a peripheral marker of dopaminergic neuronal damage to the central nervous system.
  [Binienda ZK, Sarkar S, et al. 2013. Neurosci Lett. 541:233-7]
• Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.
  Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of this study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Results showed that after paraquat/maneb treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease.
  [Bastías-Candia S, Di Benedetto M, D'Addario C, Candeletti S, Romualdi P. 2013. Environ Toxicol. doi: 10.1002/tox.21943]
• Exposure to pesticides or solvents and risk of Parkinson disease.
  Study investigated the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies. A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant. The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. Future studies should also focus on specific chemical agents.
  [Pezzoli G, Cereda E. 2013. Neurology. 80(22):2035-41]
• Household organophosphorus pesticide use and Parkinson's disease.
  Parkinson's disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. The study investigates whether long-term use of household pesticides, especially those containing organophosphates (OPs), increases the odds of PD. In a population-based case-control study, authors assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Frequent use of any household pesticide increased the odds of PD by 47%; frequent use of products containing OPs increased the odds of PD more strongly by 71% and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. Study provides evidence that household use of OP pesticides is associated with an increased risk of developing PD.
  [Narayan S, Liew Z, Paul K, et al. 2013. Int J Epidemiol. 42(5):1476-85.]
• Neurotoxicity of pesticides: its relationship with neurodegenerative diseases
  Several epidemiological studies suggest that pesticides could lead to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Among pesticides, insecticides appear more neurotoxic than others but the neurotoxic mechanisms leading to adverse health effects remain unclear. The currently used pesticides such as rotenone and paraquat could disrupt mitochondrial bioenergetic function, reactive oxygen metabolism, redox function and promote α-synuclein aggregation. In addition, recent studies demonstrate that genetic susceptibility to Parkinson's disease could monitor pesticide susceptibility, as demonstrated for polymorphisms in pesticide metabolizing enzymes that are involved in organophosphorus sensitivity.
  [Thany SH, Reynier P, Lenaers G. 2013. Med Sci (Paris). 29(3):273-8]
• Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease.
  Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. 254 patients with PD and 169 controls were studied. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls. This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.
  [Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, et al. 2013. Arq Neuropsiquiatr. 71(8):527-32]
• Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica.
  Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. Authors conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica. Initial screens were given: mini-mental states exam (MMSE) and a modified version of a 10-item united Parkinson's disease rating motor subscale (UPDRS). Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed. The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest, and finger-tapping. Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3-4 times the expected based on international data. Among subjects who took the UPDRS, the exposed had an increased risk of PD. No excess risk was found for a diagnosis of AD or mild cognitive impairment. Authors conclude that elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure.
  [Steenland K, Wesseling C, Román N, Quirós I, Juncos JL. 2013. Environ Res.120:96-101]
• Parkinson's disease and pesticide exposure--a new assessment.
  Some commonly used pesticides possess neurotoxicity, and exposure to such compounds may trigger mechanisms similar to those in the development of idiopathic Parkinson's disease (PD). Authors conducted a systematic review of epidemiological studies, aiming at a critical evaluation of the association between the development of PD and pesticide exposure. Reported effect sizes (ES) in the relevant studies were pooled into the meta-analysis to derive summary ES. The summary ES suggested a significantly positive association between PD and overall pesticide use (non-occupational and/or occupational pesticide use), as well as between PD and occupational pesticide exposure. Both occupational herbicide and occupational insecticide exposure showed a significant association with PD. The results of the meta-analysis reported in this study suggest the existence of a statistically positive association between PD and pesticide exposure. The majority of the studies that were pooled in the meta-analysis were case-control design with very few cohort studies and most with poor exposure characterization thus, any further case-control studies using similar methodologies are unlikely to have a significant impact or understanding on the currently-reported association between pesticide exposure and the development of idiopathic PD. Therefore, authors believe that if further epidemiological studies are going to be conducted in the area, they should be prospective cohort studies that will include accurate exposure assessment.
  [Allen MT, Levy LS. 2013. Crit Rev Toxicol. 43(6):515-34]
• Parkinson's disease: evidence for environmental risk factors.
  Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions.
  [Kieburtz K, Wunderle KB. 2013. Mov Disord. 28(1):8-13]
• Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis.
  Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes.
  [Liu X, Ma T, Qu B, et al. 2013. Genet Test Mol Biomarkers. 17(11):826-32]
• Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.
  Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. The goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. Study assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases and population-based controls from three counties in California with considerable commercial agriculture. Study determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. Study limited effect measure modification assessment to Caucasians. Eleven of 28 pesticides screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. Authors estimated an odds ratio of 2.14 for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene. Results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.
  [Rhodes SL, Fitzmaurice AG, Cockburn M, et al. 2013. Environ Res. 126:1-8]
• The interplay between environmental and genetic factors in Parkinson's disease susceptibility: the evidence for pesticides.
  Several genetic and environmental factors have been implicated in the pathogenesis of PD. Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD. In the present review authors summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD. A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk. They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides. These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD.
  [Dardiotis E, Xiromerisiou G, et al. 2013. Toxicology. 307:17-23]
• The role of pesticide exposure in the genesis of Parkinson's disease: epidemiological studies and experimental data.
  The aim of this study is to address the uncertainties provided by epidemiological studies on the role of pesticide exposures in the development of Parkinson's disease (PD), with the help of experimental toxicological data. Animal models that reproduce all clinical and pathological features of human PD are not available. In addition, the fundamental questions relate to the extrapolation from experimental to actual human exposure, taking also into account the role of genetic factors. Available measurements or estimates of human exposure levels that are significantly lower than those used in animal experimentation provide little support for a causal correlation between pesticide exposure and development of PD in humans. A possible role of acute poisonings or episodes of excessive exposure, and/or of combined exposures especially at early age and/or in the presence of certain genetic variants can be hypothesised. Follow up of survivors of acute poisonings by pesticides would provide information useful in this respect. According to the available data, from a public health point of view, prevention of "high" exposures, even asymptomatic ones, especially in utero and during early age is a priority.
  [Moretto A, Colosio C. et al. 2013. Toxicology. 307:24-34]
• Genetic modification of the association of paraquat and Parkinson's disease
  Authors investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5; in men with GSTT1*0, the OR was 11.1. Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.
  [Goldman, S, Kamel, F, Webster Ross, G, et al. 2012. Movement Disorders. 27(13):1652-1658]
• Is Pesticide Use Related to Parkinson Disease? Some Clues to Heterogeneity in Study Results
  

  Previous systematic reviews have indicated that pesticide exposure is possibly associated with Parkinson's disease (PD). However, considerable heterogeneity has been observed in study results. The study aimed at providing an update of the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis. In addition, we investigated whether methodological differences between studies could explain the heterogeneity in study results. The study identified studies through a systematic literature search. We calculated summary risk ratios (sRRs) for pesticide exposure and subcategories using random effects meta-analyses and investigated sources of heterogeneity by meta-regression and stratified analyses. Thirty-nine case–control studies, four cohort studies, and three cross-sectional studies were identified. An sRR of 1.62 [95% confidence interval (CI): 1.40, 1.88] for pesticide exposure (ever vs. never) was found. Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. Heterogeneity in individual study results was not related to study design, source of control population, adjustment of results for potential confounders, or geographical area. However, results were suggestive for heterogeneity related to differences in the exposure assessment. Job title–based exposure assignment resulted in a higher sRR (2.5; 95% CI: 1.5, 4.1) than did assignment based on self-reported exposure (e.g., for self-reported ever/never exposure, sRR = 1.5; 95% CI: 1.3, 1.8). This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.
  [van der Mark, M, Brouwer, M et al. 2012. Environ Health Perspect. 120(3):340-347]

• Occupational exposure to pesticides and Parkinson's disease: A systematic review and meta-analysis of cohort studies
  The aim of this study was to systematically review available cohort studies and estimate quantitatively the association between occupational exposure to pesticides and Parkinson's disease (PD). Relative risk (RR) estimates were extracted from 12 studies published between 1985 and 2011. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for gender, exposure characterisation, PD cases identification, geographic location, reported risk estimator and cohort study design.A statistically significant increased risk of PD was observed when all studies were combined. A significant increased risk was also seen for banana, sugarcane and pineapple plantation workers. Study concludes that there is some support for the hypothesis that occupational exposure to pesticides increases the risk of PD.
  [Van Maele-Fabry, G, Hoet, P, Vilain, F and Lison, D. 2012. Envrionment International. 46:30-43]
• Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease
  Traumatic brain injury (TBI) increased risk of Parkinson disease (PD) in many but not all epidemiologic studies, giving rise to speculations about modifying factors. The objective of this study was to investigate PD risk due to both TBI and paraquat exposure in humans.From 2001 to 2011, study enrolled 357 incident idiopathic PD cases and 754 population controls in central California. Study participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974. Study observed a 2-fold increase in risk of PD for subjects who reported a TBI and a weaker association for paraquat exposures. However, the risk of developing PD was 3-fold higher in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor. While TBI and paraquat exposure each increase the risk of PD moderately, exposure to both factors almost tripled PD risk. These environmental factors seem to act together to increase PD risk in a more than additive manner.
  [Lee PC, Bordelon Y, Bronstein J, Ritz B. 2012. Neurology. 79(20):2061-6]
• Association between environmental exposure to pesticides and neurodegenerative diseases
  Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
  [Parrón, T., Requena, M., Hernández, A.F. and Alarcón, R., 2011. Toxicology and applied pharmacology, 256(3), pp.379-385.]
• Parkinson’s disease risk from ambient exposure to pesticides
  A study has found that people whose workplaces were close to fields sprayed with chemicals — not just those who live nearby — are at higher risk of developing Parkinson’s disease (PD). From 2001 to 2007, researchers enrolled 362 incident PD cases and 341 controls living in the Central Valley of California and estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably. Daily News
  [Wang A, et al. 2011. Eur J Epidemiol. DOI: 10.1007/s10654-011-9574-5]
• Rotenone, Paraquat and Parkinson's Disease
  Study investigated whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Reserachers assessed lifetime use of pesticides selected by mechanism in a casecontrol study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists.n 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial Complex I including rotenone and with use of a group of pesticides that cause oxidative stress including paraquat.PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally: those which impair mitochondrial function and those which increase oxidative stress, supporting a role for these mechanisms in PD pathophysiology.
  [Tanner, CM. et al. 2011. Environ Health Perspect.doi:10.1289/ehp.1002839]
• Interaction Between ABCB1 and Professional Exposure to Organochlorine Insecticides in Parkinson Disease
  Study examined the association between Parkinson disease (PD) and 2 polymorphisms in ABCB1 among subjects enrolled in the French health system for agricultural workers, as well as the interaction between ABCB1 and organochlorine insecticides. Among 101 male cases and 234 matched controls, the odds ratio for organochlorines was 3.5 times higher among homozygous carriers of variant G2677(A,T) alleles than noncarriers. Among cases only, study found an association between carrying 2 variant G2677(A,T) alleles and organochlorines as well as with the number of cumulative lifetime number of hours of exposure. Findings suggest that the ABCB1 gene and exposure to organochlorine insecticides interact to increase PD risk: in subjects professionally exposed to organochlorines, polymorphisms associated with a decreased ability of ABCB1 to clear xenobiotics from the brain increased the risk of PD. These findings support the hypothesis of gene x pesticides interactions in PD.
  [Dutheil. F. et al. 2010. Arch Neurol;67(6):739-745]
• Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease
  Study found that participants with two copies of a common gene variant showed an increased risk of Parkinson's disease (PD) when exposed to pesticides used in agriculture. In the study group, 14 percent of the pesticide-exposed subjects and 10 percent of the control subjects had the genotype with two copies of the methionine PON1 variant - the MM PON1-55 genotype. Individuals with the variant genotype have an increased risk of Parkinson's disease with exposure to specific insecticides. Participants with the MM PON1-55 genotype and exposed to diazinon or chlorpyrifos showed a twofold increased risk of Parkinson's disease (PD) compared to exposed subjects with wildtype genotype or only one variant copy or non-pesticide exposed subjects. The authors found no increased risk of PD with parathion exposure regardless of genotype.
  [Manthripragada AD, et al. 2010. Epidemiology 21(1):87-94]
• Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease
  

  Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson’s disease (PD) risk. Methods: In 324 incident PD patients and 334 population controls from our rural California case–control study, we genotyped rs2652510, rs2550956 (for the DAT 5′ clades), and the 3′ variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele–pesticide interactions. PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08–2.57] and 3′ VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96–3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88–10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70–12.1). We obtained similar results for occupational pesticide measures. Using two independent pesticide measures, we a) replicated previously reported gene–environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

  
  [Ritz BR, et al. 2009. Environ Health Perspect 117(6)]
• Occupation and Risk of Parkinsonism:
  This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis). Risk of parkinsonism increased with pesticide use (odds ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75), and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48).
  [Tanner, C.M. 2009. Arch Neurol ;66(9):1106-1113]
• Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California
  In 1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.
  [Costello, S. et al. 2009. American Journal of Epidemiology, doi:10.1093/aje/kwp006]
• Professional exposure to pesticides and Parkinson disease
  Study found a positive association between PD and overall professional pesticide use (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1-3.1), with a dose-effect relation for the number of years of use (p = 0.01). In men, insecticides were associated with PD (OR = 2.2, 95% CI = 1.1-4.3), in particular organochlorine insecticides (OR = 2.4, 95% CI = 1.2-5.0). These associations were stronger in men with older onset PD than in those with younger onset PD, and were characterized by a dose-effect relation in the former group. Results support an association between PD and professional pesticide exposure, and show that some pesticides (ie, organochlorine insecticides) may be more particularly involved.
  [Elbaz, A.et al. 2009. Ann Neurol;66:494-504]
• Well-Water Consumption and Parkinson’s Disease in Rural California
  Study investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD.Cases were more likely to have consumed private well water and to have consumed it on average 4.3 years longer than controls. High levels of possible well-water contamination with methomyl, chlorpyrifos, and propargite resulted in approximately 70–90% increases in relative risk of PD. Exposure to a higher number of water-soluble pesticides and organophosphate pesticides also increased the relative risk of PD.
  [Gatto NM, et al. 2009. Environ Health Perspect 117:1912-1918]
• Neurotoxicity of pesticides: a brief review
  Pesticides are substances widely used to control unwanted pests such as insects, weeds, fungi and rodents. Most pesticides are not highly selective, and are also toxic to nontarget species, including humans. A number of pesticides can cause neurotoxicity. Insecticides, which kill insects by targeting their nervous system, have neurotoxic effect in mammals as well. This family of chemicals comprises the organophosphates, the carbamates, the pyrethroids, the organochlorines, and other compounds. Insecticides interfere with chemical neurotransmission or ion channels, and usually cause reversible neurotoxic effects, that could nevertheless be lethal. Some herbicides and fungicides have also been shown to possess neurotoxic properties. The effects of pesticides on the nervous system may be involved in their acute toxicity, as in case of most insecticides, or may contribute to chronic neurodegenerative disorders, most notably Parkinson's disease. This brief review highlights some of the main neurotoxic pesticides, their effects, and mechanisms of action.
  [Costa, L.G. et al. (2008) Neurotoxicity of pesticides: A brief review, Frontiers in Bioscience-Landmark. Available at: https://www.imrpress.com/journal/FBL/13/4/10.2741/2758. ]
• Pesticide exposure and risk of Parkinson's disease: A family-based case-control study
  Using 319 cases and 296 relative and other controls, associations of direct pesticide application, well-water consumption, and farming residences/occupations with PD were examined using generalized estimating equations while controlling for age-at-examination, sex, cigarette smoking, and caffeine consumption. Overall, individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives (odds ratio = 1.61; 95% confidence interval, 1.13–2.29). Frequency, duration, and cumulative exposure were also significantly associated with PD in a dose-response pattern (p = 0.013). Associations of direct pesticide application did not vary by sex but were modified by family history of PD, as significant associations were restricted to individuals with no family history. When classifying pesticides by functional type, both insecticides and herbicides were found to significantly increase risk of PD. Two specific insecticide classes, organochlorines and organophosphorus compounds, were significantly associated with PD. Consuming well-water and living/working on a farm were not associated with PD. Data corroborate positive associations of broadly defined pesticide exposure with PD in families, particularly for sporadic PD.
  [Hancock, D.B., et al. 2008. BMC Neurology 8(6):1471-2377]
• Ziram Causes Dopaminergic Cell Damage by Inhibiting E1 Ligase of the Proteasome
  Study measured the relative toxicity of ziram (a UPS inhibitor) and analogs to dopaminergic neurons and examined the mechanism of cell death. Results demonstrate that ziram causes selective dopaminergic cell damage in vitro by inhibiting an important degradative pathway implicated in the etiology of PD. Chronic exposure to widely used dithiocarbamate fungicides may contribute to the development of PD.
  [Chou, A. et al. 2008. Journal of Biological Chemistry; 283 pp.34696-34703]
• Developmental exposure to pesticides zineb and/or endosulfan renders the nigrostriatal dopamine system more susceptible to these environmental chemicals later in life.
  The purpose of this study was to test the hypothesis that exposure to pesticides such as endosulfan and/or zineb during critical periods of postnatal development could result in neuronal dysfunction and enhance the impact of these pesticides during exposure as adults. Mice exposed to these pesticides as juveniles and re-exposed at 8 months of age had significantly altered striatum and brain cortex neurotransmitter levels. Thus, mice re-exposed during adulthood to zineb, endosulfan and their mixtures showed a significantly depleted striatal dopamine levels, to 22, 16 and 35% of control, respectively. Acetylcholinesterase activity in the cerebral cortex was significantly increased in all pesticide treated groups (rho< or =0.05) upon repeated exposure, and pesticide mixture treatment also significantly increased levels of normal and aggregated alpha-synuclein. Collectively, these findings support our hypothesis that exposure to pesticides such as endosulfan and zineb during critical periods of postnatal development contributes to neurotransmitter changes upon re-challenge in adulthood.
  [Jia, Z., et al. 2007. Neurotoxicology 28(4):727-735]
• Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids.
  Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of this study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Study suggests that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.
  [Nasuti C, Gabbianelli R, Falcioni ML, et al.2007. Toxicology. 229(3):194-205.]
• Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study
  To investigate the associations between Parkinson’s disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. A case–control study of 959 prevalent cases of parkinsonism (767 with Parkinson’s disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson’s Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson’s disease. Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson’s disease/parkinsonism with an exposure–response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson’s disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson’s disease gave similar results. The association of pesticide exposure with Parkinson’s disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.
  [Dich, F.D. et al. 2007. Occup Environ Med;64:666-672]
• GSTpi expression mediates dopaminergic neuron sensitivity in experimental parkinsonism
  The cause of 95% of Parkinson's disease (PD) cases is unknown. It is hypothesized that PD arises from an interaction of free-radical-generating agents with an underlying genetic susceptibility to these compounds. Here we use the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism to examine the role of a dual function protein, GSTpi, in dopaminergic neuron death. GSTpi is the only GST family member expressed in substantia nigra neurons. GSTpi reduction by pharmacological blockade, RNA inhibition, and gene targeting increases sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, suggesting that differential expression of GSTpi contributes to the sensitivity to xenobiotics in the substantia nigra and may influence the pathogenesis of reactive oxygen species-induced neurological disorders including PD.
  [Smeyne, M., et al. 2007. Proceedings of the National Academy of Sciences 104(6)1977-1982]
• Interaction between genes and environment in neurodegenerative diseases.
  Study found that the inverse association between smoking and the risk of PD depended on a polymorphism of the iNOS (inducible NO synthase) gene. We also found that the cytochrome P450 2D6 gene could have a modifying effect on the risk of PD among persons exposed to pesticides. Both interactions have biological plausibility supported by laboratory studies and could contribute to better understand the aetiology of PD.
  [Elbaz, A. et al. 2007. Comptes Rendus Biologies 330(4):318-328]
• Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration
  Authors found that a single paraquat exposure was followed by an increase in the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including induction of NADPH-oxidase. If this microglial response was inhibited by the anti-inflammatory drug minocycline, subsequent exposures to the herbicide failed to cause oxidative stress and neurodegeneration. On the other hand, if microglial activation was induced by pre-treatment with lipopolysaccharide, a single paraquat exposure became capable of triggering a loss of dopaminergic neurons. Finally, mutant mice lacking functional NADPH-oxidase were spared from neurodegeneration caused by repeated paraquat exposures. Data indicate that microglial activation and consequent induction of NADPH-oxidase may act as risk factors for Parkinson’s disease by increasing the vulnerability of dopaminergic cells to toxic injury.
  [Purisai, M.G., et al. 2007. Neurobiology of Disease 25(2):392-400]
• Pesticide exposure and self-reported Parkinson's disease in the agricultural health study.
  The authors used data obtained from licensed private pesticide applicators and spouses participating in the Agricultural Health Study to evaluate the relation of self-reported PD to pesticide exposure. Cohort members, who were enrolled in 1993-1997, provided detailed information on lifetime pesticide use. Incident PD was associated with cumulative days of pesticide use at enrollment (for highest quartile vs. lowest, odds ratio (OR) = 2.3, 95% confidence interval: 1.2, 4.5; p-trend = 0.009), with personally applying pesticides more than half the time (OR = 1.9, 95% confidence interval: 0.7, 4.7), and with some specific pesticides (ORs > or = 1.4). Prevalent PD was not associated with overall pesticide use. This study suggests that exposure to certain pesticides may increase PD risk.
  [Kamel, F., et al. 2007. American Journal of Epidemiology 165(4):364-74]
• Pesticide exposure on southwestern Taiwanese with MnSOD and NQO1 polymorphisms is associated with increased risk of Parkinson's disease.
  From southwestern region of Taiwan, 153 patients with idiopathic PD and 155 healthy control subjects matched for age, sex and origin were studied. Exposure to pesticides associated with PD was significant among patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07-2.65), and this association remained significant after adjustment for age, sex, and cigarette smoking (aOR=1.68, 95%CI, 1.03-2.76, P=0.023). Considering genetic factors, there were no significant differences in frequencies of both genotypes of manganese-containing superoxide dismutase (MnSOD) and quinone oxidoreductase 1 (NQO1) polymorphisms between PD patients and the control subjects (P>0.05). However, this difference in genotype distribution was significant among subjects who had been exposed to pesticide, for MnSOD C allele and for NQO1 T allele, respectively. Moreover, among subjects exposed to pesticide, the combined MnSOD/NQO1 variant genotype was significantly associated with a 4.09-fold increased risk of PD (95%CI, 1.34-10.64, P=0.0052).
  [Fong, C., et al. 2007. Clinica Chimica Acta 378(1-2):136-141]
• Chemical exposures and Parkinson's disease: a population-based case-control study.
  Study identified all subjects who developed PD in Olmsted County, Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year) and sex to general population controls. Authors assessed exposures to chemical products by means of telephone interview with cases, controls, or their proxies (149 cases; 129 controls). Exposure to pesticides related or unrelated to farming was associated with PD in men (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.04). The association remained significant after adjustment for education or smoking. This population-based study suggests a link between pesticides use and PD that is restricted to men. Pesticides may interact with other genetic or nongenetic factors that are different in men and women.
  [Frigerio, R., et al. 2006. Movement Disorders 21(10): 1688-1692]
• Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease
  Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.
  [Richardson, J.R., et al. 2006. The FASEB Journal 20(10):1695-1697]
• Parkinson Disease: PD Gene and Oxidative Stress
  Drosophila flies lacking the DJ-1 gene showed selective sensitivity to widely used agricultural toxicants that kill neurons mainly through oxidative stress. DJ-1 mutant flies exposed to the herbicide paraquat died much sooner than normal flies. The mutants also showed marked sensitivity to the insecticide rotenone and to hydrogen peroxide-both agents that promote oxidative stress. These results suggest that DJ-1 normally protects against oxidative stress and that its inactivation may leave neurons susceptible to oxidative damage. The study also found that exposure to paraquat led to biochemical modification of the DJ-1ß protein, a change which may influence the ability of DJ-1 to protect neurons from oxidative damage. Studies of DJ-1 in Drosophila will provide greater understanding of fundamental activities of the gene, helping to elucidate how its function may be critical in PD.
  [Phillips, M.L. 2006. Environmental Health Perspectives 114(2)]
• Pesticide exposure and risk for Parkinson's disease
  Exposure to pesticides was reported by 7,864 participants (5.7%), including 1,956 farmers, ranchers, or fishermen. Individuals exposed to pesticides had a 70% higher incidence of PD than those not exposed (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.3; p = 0.002). The relative risk for pesticide exposure was similar in farmers and nonfarmers. No relation was found between risk for PD and exposure to asbestos, chemical/acids/solvents, coal or stone dust, or eight other occupational exposures. These data support the hypothesis that exposure to pesticides may increase risk for PD.
  [Ascherio, Al, et al. 2006. Annals of Neurology 60(2): 197-203.]
• Pesticides and Parkinson’s Disease—Is There a Link?
  A comprehensive review of the published epidemiologic and toxicologic literature and critical evaluation of whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure.
  [Brown, T.P., et al. 2006. Environmental Health Perspectives 114(2):156-164]
• Principles for evaluating health risks in children associated with exposure to chemicals
  The United Nation’s World Health Organization report on children’s heightened vulnerability to chemical exposures at different periods of their growth and development states, “neurotoxic insults during development that result in no observable phenotype at birth or during childhood could manifest later in life as earlier onset of neurodegenerative diseases such as [PD].”
  [Louis, G.B., et al. 2006. Environmental health criteria: 237. World Health Organization. Geneva, Switzerland]
• Pyrethroid pesticide-induced alterations in dopamine transporter function.
  Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Study reports that repeated exposure of mice to two commonly used pyrethroid pesticides, deltamethrin and permethrin, increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, study determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 microM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 microM) or 24 h (1, 5, and 10 microM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.
  [Elwan MA, Richardson JR, Guillot TS, et al. 2006. Toxicol Appl Pharmacol.211(3):188-97]
• Developmental pesticide exposures and the Parkinson's disease phenotype.
  Whereas Parkinson's disease is a neurodegenerative disorder that typically onsets after 60 years of age, the possibility that it could result from insults sustained during development has been proposed. Experimental evidence based on the combined paraquat + maneb model of the Parkinson's disease (PD) phenotype summarized here provides support for such an assertion. Postnatal exposures of mice to these pesticides led not only to a permanent and selective loss of dopaminergic neurons in the substantia nigra pars compacta but also enhanced the impact of these pesticides administered during adulthood relative to developmental only or adult only treatment. Exposure to maneb alone during gestation resulted in a dramatic response to paraquat in adulthood, including notable reductions in levels of dopamine and metabolites and a loss of nigral dopamine (DA) neurons, despite the fact that paraquat does not share structural similarity to or mechanisms of action with maneb. Collectively, these studies provide developmental environmental models of the PD phenotype. In addition, they demonstrate the fact that silent neurotoxicity produced by developmental insults can be unmasked by challenges later during life as well as the potential for cumulative neurotoxicity over the life span.
  [Cory-Slechta D.A., et al. 2005. Birth Defects Res A Clin Mol Teratol 73:136–139]
• Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease
  Parkinson's disease (PD) is a common neurodegenerative disorder that displays both sporadic and inherited forms. Exposure to several common environmental toxins acting through oxidative stress has been shown to be associated with PD. One recently identified inherited PD gene, DJ-1, may have a role in protection from oxidative stress, thus potentially linking a genetic cause with critical environmental risk factors. To develop an animal model that would allow integrative study of genetic and environmental influences, we have generated Drosophila lacking DJ-1 function. Fly DJ-1 homologs exhibit differential expression: DJ-1beta is ubiquitous, while DJ-1alpha is predominantly expressed in the male germline. DJ-1alpha and DJ-1beta double knockout flies are viable, fertile, and have a normal lifespan; however, they display a striking selective sensitivity to those environmental agents, including paraquat and rotenone, linked to PD in humans. This sensitivity results primarily from loss of DJ-1beta protein, which also becomes modified upon oxidative stress. These studies demonstrate that fly DJ-1 activity is selectively involved in protection from environmental oxidative insult in vivo and that the DJ-1beta protein is biochemically responsive to oxidative stress. Study of these flies will provide insight into the critical interplay of genetics and environment in PD.
  [Meulener, M., et. al. 2005. Current Biology 15(17): 1572-1577]
• Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells.
  Authors believe environmental contaminants such as pesticides make dopamine cells more vulnerable to damage from normal aging, infection, or subsequent exposure to pollutants. Study primarily utilized the PC12 cell line, which displays a catecholaminergic phenotype. Low concentrations of maneb (50-1000 ng/ml) had little effect on cell viability, as measured by LDH release. hese same concentrations, however, led to increases in glutathione (GSH) and its oxidized form, GSSG. Results suggest that following an insult to the GSH antioxidant system, maneb can act as an additional insult to the system and prevent the normal recovery of those defenses. Dopaminergic neurons, as a population, are inherently vulnerable to oxidative stress, and the disruption of antioxidant systems by the fungicide maneb may contribute to the neurodegeneration of these cells, especially with concurrent exposures to other environmentally relevant oxidative stressors.
  [Barlow, B.K., et al. 2005. Neurotoxicology 26(1):63-75]
• Paraquat Neurotoxicity is Distinct from that of MPTP and Rotenone
  Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP+, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP+, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of 3H-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP+ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP+, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.
  [Richardson, J. et al. (2005) Paraquat Neurotoxicity is Distinct from that of MPTP and Rotenone, Toxicological Sciences. Available at: https://www.sciencedirect.com/science/article/pii/S0160412020322996?via%3Dihub. ]
• Perinatal heptachlor exposure increases expression of presynaptic dopaminergic markers in mouse striatum.
  In this study, authors examined the effects of developmental exposure to heptachlor on the dopamine transporter (DAT), and other key components of the dopaminergic system, including the vesicular monoamine transporter 2 (VMAT2), tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC). On postnatal day 28, DAT, VMAT2, and TH levels were increased by 100, 70, and 30%, respectively, with no change in AADC levels or total dopamine levels. The ratio of DAT:VMAT2 was increased 29%. Since an increase in the DAT:VMAT2 ratio appears to predict susceptibility of brain regions to Parkinson's disease (PD) and results in increased toxicity of MPTP, these results suggest that alterations of the dopaminergic system by developmental heptachlor exposure may increase the susceptibility of dopamine neurons to toxic insult.
  [Caudle, W.M., et al. 2005. NeuroToxicology 26(4):721-728]
• Pesticides and risk of Parkinson disease: a population-based case-control study.
  Study investigated associations between pesticide exposures and idiopathic PD and found significantly increased ORs from lifelong well water consumption (OR, 1.81; 95% CI, 1.02-3.21). Study also found elevated ORs from herbicides (OR, 1.41; 95% CI, 0.51-3.88) and paraquat (OR, 1.67; 95% CI, 0.22-12.76).
  [J.A., et al. 2005. Archives of Neurology 62(1):91-95]
• A case-control study of Parkinson's disease in a horticultural region of British Columbia
  Study compared personal histories of 127 cases and 245 controls to identify possible environmental risk factors for idiopathic parkinsonism (IP). Data found a significant association between IP and having had an occupation in which exposure through handling or directly contacting pesticides was probable, but no specific chemicals were associated with IP. Study concluded that although occupations involving the use of agricultural chemicals may predispose to the development of IP, it seems likely that the pathogenesis is multifactorial rather than related to a specific agent.
  [Hertzman, C., et al. 2004. Movement Disorders 9(1):69-75]
• A fetal risk factor for Parkinson's disease.
  This study hypothesized that prenatal exposure to pesticides would disrupt the development of the nigrostriatal dopamine (DA) system and enhance its vulnerability to dopaminergic neurotoxicant exposures later in life. One week after the last exposure to maneb or paraquat, only male mice exposed to prenatal maneb and adulthood paraquat showed significant reductions in locomotor activity (95%) and changes in striatal neurochemistry. Stereological assessment of the substantia nigra pars compacta (SNpc) and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron loss in SNpc. The lack of changes in other exposure groups suggests a specificity to the sequence of exposures as well as gender specificity. These results suggest that prenatal exposure to maneb produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to paraquat exposure.
  [Barlow, B.K., et al. 2004. Dev Neurosci 26(1):11-23]
• No evidence for heritability of Parkinson disease in Swedish twins
  The aim of the study was to evaluate heritability of PD in same-sexed and opposite-sexed twin pairs in the Swedish Twin Registry (STR). For possible PD, there were only two concordant pairs, both female dizygotic. Similarly, concordances were low in all zygosity groups when the definition of affected was expanded to include twins with suspected parkinsonism or movement disorder in addition to possible PD. Sex differences in the relative importance of genetic and environmental effects were indicated with a marginally larger familial component in women. Results suggest that environmental factors are most important in the etiology of PD. Compared with other complex diseases, the importance of genetic effects in PD is notably low. The preponderance of discordant twin pairs provides an ideal material for studying environmental risk factors and potential genotype-by-environment interaction.
  [Wirdefeldt, K., et al. 2004. Neurology 63(2):305-311]
• Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype.
  Study tested exposed C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
  [Thiruchelvam, M., et al. 2003. Eur J Neurosci 18(3):589-600]
• Association between Parkinson’s disease and exposure to pesticides in southwestern France.
  A case-control study was performed in southwestern France in order to assess the relationship between pesticide exposure and Parkinson's disease (PD) in the elderly. During the period from 1997 to 1999, 84 cases were recruited together with 252 population-based controls. A positive association was found with occupational pesticide exposure (odds ratio = 2.2, 95% confidence interval 1.1-4.3) in conditional logistic multiple regression analysis taking into account age, sex, educational level and smoking; however, no clear dose relationship was found.
  [Baldi, I., et al. 2003. Neuroepidemiology 22(5):305-310]
• Neurodegenerative Diseases and Exposure to Pesticides in the Elderly.
  Study of 1,507 French elderly (1992–1998) shows lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson’s disease and Alzheimer’s disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively.
  [Baldi, I, et al. Am J Epidemiol 2003; 157:409-414.]
• Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype.
  This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. Mice exposed developmentally to PQ + MB and rechallenged as adults were the most affected, showing a 70% reduction in motor activity 2 weeks following the last rechallenge dose. Striatal DA levels were reduced by 37% following developmental exposure to PQ + MB only, butfollowing adult re-challenge levels were reduced by 62%. A similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB treated group exhibiting the greatest reduction, with this loss being amplified by adult re-challenge. Following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together, these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.
  [Thiruchelvam, M., et al. 2002. Neurotoxicology 23(4-5):621-633]
• Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy
  The etiology of Parkinson's disease remains unknown, although both genetic susceptibility and environmental factors are considered putative contributors to its origin. We performed a case-control study to investigate the association of familial and environmental risk factors with Parkinson's disease (PD). We studied 136 patients with neurologist confirmed PD and 272 age- and sex-matched controls, affected by neurological diseases not related to PD. The risk of developing idiopathic PD associated with the following familial and environmental factors: positive family history of PD, positive family history of essential tremor (ET), age of mother at subject's birth, rural birth, rural living, well water use, farming as an occupation, exposure to pesticides, head tremor, exposure to general anesthesia and to ionizing radiations, food restriction, concentration camp imprisonment and smoking has been assessed by using univariate and multivariate statistical techniques. In the conditional multiple logistic regression analysis, positive family history of PD (OR 41.7, 95% CI 12.2-142.5, P < 0.0001), positive family history of ET (OR 10.8, 95% CI 2.6-43.7, P < 0.0001), age of mother at subject's birth (OR 2.6, 95% CI 1.4-3.7, P=0.0013), exposure to general anesthesia (OR 2.2, 95% CI 1.3-3.8, P=0.0024), farming as an occupation (OR 7.7, 95% CI 1.4-44.1, P=0.0212) and well water use (OR 2.0, 95% CI 1.1-3.6, P=0.0308) exhibited a significant positive association with PD, whereas smoking showed a trend toward an inverse relationship with PD (OR 0.7, 95% CI 0.4-1.1, P < 0.06). We conclude that both familial and environmental factors may contribute to PD etiology.
  [Zorzon, M., et al. 2002. Acta Neurol Scand 105(2):77-82]
• Plantation work and risk of Parkinson disease in a population-based longitudinal study.
  Objective of this study was to determine whether working on a plantation in Hawaii and exposure to pesticides are associated with an increased risk of PD decades later. During follow-up, 116 men developed PD. Age-adjusted incidence increased significantly among men who worked more than 10 years on a plantation. The relative risk of PD was 1.0 (95% confidence interval, 0.6-1.6), 1.7 (95% confidence interval, 0.8-3.7), and 1.9 (95% confidence interval, 1.0-3.5) for men who worked on a plantation 1 to 10 years, 11 to 20 years, and more than 20 years compared with men who never did plantation work (P =.006, test for trend). These longitudinal observations regarding plantation work in Hawaii support case-control studies suggesting that exposure to pesticides increases the risk of PD.
  [Petrovitch, H., et al. 2002. Archives of Neurology 59(11):1787-1792]
• Environmental Risk Factors and Parkinson's Disease: A Metaanalysis
  The study aim was to examine the association between Parkinson's disease (PD) and exposure to environmental factors such as living in a rural area, well water use, farming, exposure to farm animals, or living on a farm, and pesticides. A series of metaanalyses of peer-reviewed studies were performed, using 16 studies for living in rural area, 18 studies for well water drinking, 11 studies for farming, and 14 studies for pesticides. Prior to the metaanalyses, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random and the fixed-effect models. The majority of the studies reported consistent elevation in the risk of PD with exposure to environmental factors such as rural living and farming. The combined OR for rural residence was 1.56 [95% confidence interval (95% CI) 1.18-2.07] for all the studies, and 2.17(95% CI 1.54-3.06) for studies performed in United States. The combined OR for well water use was 1.26 (95% CI 0.97-1.64) for all the studies, and 1.44(95% CI 0.92-2.24) for studies done in United States. The combined OR for farming, exposure to farm animals, or living on a farm was 1.42 (95% CI 1.05-1.91) for all studies, and 1.72(95% CI 1.20-2.46) for studies done in United States. The combined OR for pesticides exposure was 1.85(95% CI 1.31-2.60) for all studies, and 2.16(95% CI 1.95-2.39) for studies done in United States. Dose-response relationships could not be established due to the imprecise nature of the reported data. Our findings suggest that living in a rural area, drinking well water, farming, and exposure to pesticides may be a risk factor for developing PD.
  [Priyadarshi, A., et al. 2001.Environ Res 86(2):122-127]
• Parkinsonism and occupational exposure to pesticides
  Parkinsonism may be associated with long term occupational exposure to pesticides, although no associations with specific pesticides could be detected. This finding is consistent with most of the publications on this topic.
  [Engel, L.S., et al. 2001.Occupational and Environmental Medicine 58(9):582-589]
• A meta-analysis of Parkinson's disease and exposure to pesticides.
  A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999. The majority of the studies reported consistent elevation in the risk of PD with exposure to pesticides. The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53] for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed in United States. Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Findings suggest that exposure to pesticides may be a significant risk factor for developing PD.
  [Priyadarshi, A., et al. 2000. Neurotoxicology 21(4):435-440.]
• Agricultural work and the risk of Parkinson's disease in Denmark, 1981-1993
  This study examined the possible association between agricultural and horticultural work and the subsequent morbidity of Parkinson's disease. A high risk of Parkinson's disease was found for the men and women in agriculture and horticulture (134 cases, SHR 132, 95% CI 111-156). Statistically significantly high risks were found for farmers (79 cases, SHR 130, 95% CI 103-163) and for all men in agriculture and horticulture (109 cases, SHR 134, 95% CI 109-162).
  [Tuchsen, F., et al. 2000. Scand J Work Environ Health 26(4):359-362]
• Exposure to home pesticides linked to Parkinson disease.
  This study raises concerns for residential pesticide exposure. Stanford University researchers find a 70 percent increased risk of developing PD for individuals that use pesticides in their home. Exposure to garden insecticides carries a 50 percent increased risk of developing the disease. Among herbicide users, the risk of developing PD increases as the number of days in contact with herbicides grows. Respondents who reported handling or applying herbicides for up to 30 days are 40 percent more likely to develop the disease, whereas respondents that reported 160 days exposure, have a 70 percent increase.
  [Stephenson, J. 2000. JAMA 283:3055-3056]
• Parkinson's disease mortality and pesticide exposure in California 1984-1994.
  A California mortality study of individuals whose death certificates mention PD as an underlying cause of death and cross-referenced with agricultural and pesticide use data finds that the counties using restricted use pesticides (RUP) for agricultural purposes have about a 40 percent increase in PD mortality when compared to those counties reporting no RUP.
  [Ritz B, and Yu F. 2000. International Journal of Epidemiology 29(2):323-329]
• Nutritional and occupational factors influencing the risk of Parkinson's disease: a case-control study in southeastern Sweden.
  Study investigates the possible impact of nutritional and environmental risk factors for idiopathic Parkinson's disease (IP), a case-control study was performed in the county of Ostergötland in southeastern Sweden. The study involved 113 cases of IP and 263 control subjects. A reduced risk was found for coffee, wine, and liquor at various consumption levels but also for fried or broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. All these food and drink items contain niacin. As in many studies, the frequency of preceding and present smoking was reduced in IP patients. Various occupational groups and exposures were analyzed and increased risks of IP in men were found for agricultural work along with pesticide exposure; this was also the case for male carpenters and female cleaners.
  [Fall, P., et al. 1999. Movement Disorders 14(1):28-37]
• Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia.
  We had previously examined environmental, sociodemographic and clinical variables as predictors for Parkinson's disease with dementia (PD + D) and found that lower educational attainment, greater motor impairment and advanced age at disease onset were more common in PD + D than in subjects with Parkinson's disease without dementia (PD-D). We now explore the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of PD + D. The study cohort of 43 PD + D and 51 PD-D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers: poor debrisoquine metabolizer allele (CYP 2D6 29B+), monoamine oxidase B allele 1, and apolipoprotein E epsilon 4 allele. Variables were initially entered into a multivariate model singly. Again lower education, age at onset and motor impairment appeared as predictors of PD + D while other variables (including allele status) failed to emerge as significant individual risk factors for dementia. We then examined environmental and genetic variables analyzed in tandem to look for potential variable interactions. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D. Further assessment of the role of these putative risk factors in incident dementia in PD is indicated.
  [Hubble, J.P., et al. 1998. Neuroepidemiology 17(2):96-104]
• Genetic and environmental risk factors for Parkinson’s disease in a Chinese population
  An epidemiological study of the environmental and genetic factors as well as the possible interplay between them was conducted among 215 patients with Parkinson’s disease and 313 controls in a Chinese population in Hong Kong. In univariate analysis, a regular tea drinking habit was found to be a protective factor, which had not been reported before. Smoking (a protective factor), family history, duration of pesticide exposure (in years) in farming and pesticide exposure during farming in women (both risk factors) have been reported previously. In multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. By contrast with the common occurrence of polymorphism of the CYP2D6 gene (a gene involved with xenobiotic metabolism) in white people, it is very rare in China and is not thought to be a significant factor contributing to Parkinson’s disease in Chinese people.
  [Chan, D.K. 1998. Journal of Neurology, Neurosurgery and Psychiatry 65:781-784]
• Parkinson's disease, pesticides, and glutathione transferase polymorphisms.
  Study investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. Authors genotyped by PCR polymorphisms in four glutathione transferases (GST) classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.
  [Menegon, A., et al. 1998. The Lancet 352(9137):1344-1346]
• The Epidemiology of Parkinson’s Disease in an Australian Population
  A prevalence study of Parkinson’s disease (PD) was conducted in the rural town of Nambour, Australia. A positive family history of PD was the strongest risk factor for the development of the disease (odds ratio = 3.4; p < 0.001). In addition, rural residency was a significant risk factor for PD (odds ratio = 1.8, p < 0.001).
  [McCann, S.J., et al. 1998. Neuroepidemiology 17(6):310-317]
• The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living.
  Study assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population-based case-control study consisting of men and women > or = 50 years of age. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55). The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.
  [Gorell, J.M., et al. 1998. Neurology 50:1346-1350]
• Neurodegenerative diseases: occupational occurrence and potential risk factors, 1982 through 1991.
  To identify potential occupational risk factors, this study examined the occupational occurrence of various neurodegenerative diseases:presenile dementia, Alzheimer's disease, Parkinson's disease, and motor neuron disease. Excess mortality was observed for all four categories in the following occupational categories: teachers; medical personnel; machinists and machine operators; scientists; writers/designers/entertainers; and support and clerical workers. Clusters of three neurodegenerative diseases were also found in occupations involving pesticides, solvents, and electromagnetic fields and in legal, library, social, and religious work.
  [Schulte, P.A., et al. 1996. American Journal of Public Health 86(9):1281-1288]
• Possible environmental, occupational, and other etiologic factors for Parkinson's disease: A case-control study in Germany
  A case-control study investigated the possible etiologic relevance to Parkinson's disease (PD) of rural factors such as farming activity, pesticide exposures, well-water drinking, and animal contacts; toxicologic exposures such as wood preservatives, heavy metals, and solvents; general anesthesia; head trauma; and differences in the intrauterine environment. There were significantly elevated odds ratios (OR) for pesticide use, in particular, for organochlorines and alkylated phosphates, but no association was present between PD and other rural factors. A significantly elevated OR was present for exposure to wood preservatives.
  [Seidler, A. et al. 1996.Nuerology; 46:1275]
• The Role of the Environment in Parkinson's Disease
  Thirty leading scientists in the field of Parkinson's disease research attended a conference, "The Role of the Environment in Parkinson's Disease," 17-19 September 1995, sponsored and hosted by the National Institute of Environmental Health Sciences. The role of the environment was highlighted, but considerable attention was given to pathological neurochemistry and genetic issues in the etiopathogenesis of Parkinson's disease.
  [Gorrell, J.M. et al. 1996. Meeting Report. National Institute of Environmental Health Sciences. Environmental Health Perspectives;104(6)]
• Environmental antecedents of young-onset Parkinson's disease
  We conducted an exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk. This case-control study included 63 YOPD patients (diagnosis on or before age 50); controls (n = 68) were diagnosed with rheumatoid arthritis. Crude odds ratios (ORs) were computed to identify exposure variables for logistic regression analyses. After controlling for the variables of race, educational level, sex, age, age at diagnosis, and family history of Parkinson's disease (PD), PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = 5.25, p = 0.046), herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years before diagnosis (OR = 1.49, p = 0.021). PD was inversely associated with cigarette smoking at 5 years (OR = 0.50, p = 0.027), 10 years (OR = 0.43, p = 0.012), and 15 years (OR = 0.37, p = 0.005) before diagnosis, farm residency (OR = 0.38, p = 0.018), and exposure to dimethyl sulfoxide (OR = 0.10, p < 0.001). These findings are consistent with hypotheses linking PD to exposure to pesticide agents.
  [Butterfield, P.G., et al. 1993. Neurology 43(6):1150-1158.]
• Risk factors for Parkinson's disease
  Study examined social and medical histories of predominantly rural populations to determine relative risk factors for PD. Significant predictors of PD emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. The predicted probability of PD was 92.3% (odds ratio = 12.0) with all three predictors positive. Pesticide use (distinguishable from rural living) can be considered a risk factor for the development of PD, with family history of neurologic disease and history of depression serving as weaker predictors of PD.
  [Hubble, J.P., et al. 1993. Neurology 43:1693-97]
• Parkinson's disease and exposure to agricultural work and pesticide chemicals.
  A population-based case-control study of 130 Calgary residents with neurologist-confirmed idiopathic Parkinson's disease (PD) and 260 randomly selected age- and sex-matched community controls to determine whether agricultural work or the occupational use of pesticide chemicals is associated with an increased risk for PD. In the multivariate analysis, which controlled for potential confounding or interaction between the exposure variables, previous occupational herbicide use was consistently the only significant predictor of PD risk.
  [Semchuk, K.M., et al. 1992. Neurology 42:1328-1335]
• Parkinson's disease in Ferrara, Italy, 1967 through 1987
  Authors studied the frequency of Parkinson's disease in the Local Health Service of Ferrara, northeastern Italy. The study revealed a significantly higher incidence rate among agricultural workers (20.6/100,000). These results would seem to give further support to the hypothesis of a possible causal role of environmental factors that are mainly linked to agriculture, most likely due to the continual exposure to toxic agents in this area.
  [Granieri, E., et al. 1991. Archives of Neurology 48(8):854-857]
• Environmental risk factors in Parkinson's disease
  To investigate possible risk factors for Parkinson's disease (PD) [the study] conducted a case-control study of 150 PD patients and 150 age- and sex-matched controls. [The study] interviewed and examined all 300 subjects. [Study] collected demographic data including lifetime histories of places of residence, source of drinking water, and occupations such as farming. Subjects completed a detailed questionnaire regarding herbicide/pesticide exposure. Rural living and drinking well water were significantly increased in the PD patients. This was observed regardless of age at disease onset. Drinking well water was dependent on rural living. There were no significant differences between cases and controls for farming or any measure of exposure to herbicides or pesticides. These data provide further evidence that an environmental toxin could be involved in the etiology of PD.
  [Koller, W. et al. 1990. Neurology. 40(8):1218-1221]
• Ecogenetics of Parkinson's disease: prevalence and environmental aspects in rural areas.
  The study makes use of the unique combination of a homogeneous genetic and racial origin in the rural population of Quebec and the facilities of free and universal access to medical care, to study the distribution of the prevalence of Parkinson's disease in the 9 rural hydrographic regions of the Province. Through 3 different methods of ascertainment, confirmed by two control probes, we demonstrate that the prevalence of Parkinson's disease is of uneven distribution within rural areas. We further investigated the characteristics of the regions of high prevalence. These regions which are predominantly agricultural and areas of intensive market gardening were also the areas with the highest use of pesticides.
  [Barbeau, A., et al. 1987. Can J Neurol Sci 14(1) 36-41]

• Pesticide exposure and risk of Central Nervous System tumors in children: a systematic review with meta-analysis.
  Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.
  [Mota, A.L.C., Barbosa, I.M., Rodrigues, A.B., Chaves, E.M.C. and Almeida, P.C.D., 2023. Ciência & Saúde Coletiva, 28, pp.2583-2594.]
• Central nervous system tumors and agricultural exposures in the prospective cohort AGRICAN.
  Studies in farmers suggest a possible role of pesticides in the occurrence of Central Nervous System (CNS) tumors but scientific evidence is still insufficient. Using data from the French prospective agricultural cohort AGRICAN (Agriculture & Cancer), authors investigated the associations between exposure of farmers and pesticide users to various kinds of crops and animal farming and the incidence of CNS tumors, overall and by subtypes. Over the 2005-2007, 181,842 participants completed the enrollment questionnaire that collected a complete job calendar with lifetime history of farming types. Associations were estimated using proportional hazards models with age as underlying timescale. During a 5.2 years average follow-up, 273 incident cases of CNS tumors occurred, including 126 gliomas and 87 meningiomas. Analyses showed several increased risks of CNS tumors in farmers, especially in pesticide users (hazard ratio = 1.96; 95% confidence interval: 1.11-3.47). Associations varied with tumor subtypes and kinds of crop and animal farming. The main increases in risk were observed for meningiomas in pig farmers and in farmers growing sunflowers, beets and potatoes and for gliomas in farmers growing grasslands. In most cases, more pronounced risk excesses were observed among pesticide applicators. 
  [Piel C, Pouchieu C, Tual S, Migault L., et al. 2017. Int J Cancer. doi: 10.1002/ijc.30879. ]
• A patient fatality following the ingestion of a small amount of chlorfenapyr
  Chlorfenapyr has been used worldwide for agricultural pest control since 1995. Despite its widespread use, acute human poisoning data are insufficient; only a small number of fatalities from chlorfenapyr poisoning have been reported. The signs and symptoms of chlorfenapyr toxicity include nausea, vomiting, fever, rhabdomyolysis, among others. In addition, central nervous system effects in association with delayed toxicity have also been observed. Here, we detail a fatality resulting from delayed chlorfenapyr toxicity following the ingestion of a small amount of pesticide.
  [Kang, C. et al. (2014) A patient fatality following the ingestion of a small amount of Chlorfenapyr, Journal of Emergencies, Trauma, and Shock. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126128/.]
• Childhood cancer in Texas counties with moderate to intense agricultural activity
  With few established risk factors, cancer remains the second leading cause of death for children in the U.S. Agricultural pesticide use is one of many suspected factors that may contribute to the etiology of childhood cancer. This study tests the hypothesis that birth in Texas counties with moderate to intense agricultural activity increases childhood cancer risk. This case-control study analyzed 6974 cases and controls ages 0 to 14, identified through the Texas Cancer Registry and Texas birth records, respectively. Exposure data were obtained from the Census of Agriculture. Percent cropland in the county of birth and total county-specific pesticide exposure incorporating the EPA's carcinogenicity classification served as surrogates for pesticide exposure. Cancer sites examined include: all cancers, leukemia, lymphoma, CNS tumors, and several specific subsites. Elevated, although not statistically significant, ORs for the association between birth in counties with > or =50% cropland were produced for all CNS tumors (OR = 1.3, 95% CI = 0.9-1.8), astrocytoma (OR = 1.4, 95% CI = 0.8-2.2), and PNET (OR = 1.3, 95% CI = 0.7-2.5). A similar pattern was not observed using the index of total county-specific pesticide exposure. Although imprecise, these exposure assessment methods represent novel applications of agricultural census data. Although a pattern of increased risk was observed between percent cropland and CNS tumors, this study's results do not support an association between birth in Texas counties with moderate to intense agricultural activity and childhood cancer. Due to study limitations, such an association should not be ruled out. Future research should incorporate individual-level data from various sources to increase precision and decrease misclassification in the exposure assessment.
  [Walker, K.M., et al. 2007. J Agric Saf Health 13(1):9-24.]

• Association of activities related to pesticide exposure on headache severity and neurodevelopment of school-children in the rural agricultural farmlands of the Western Cape of South Africa
  

  Children and adolescents living in agricultural areas are likely to be exposed to mixtures of pesticides during their daily activities, which may impair their neurodevelopment. We investigated various such activities in relation to headache severity and neurodevelopment of school-children living in rural agricultural areas in the Western Cape of South Africa. We used baseline date from 1001 school-children of the Child Health Agricultural Pesticide Cohort Study in South Africa (CapSA) aged 9–16 from seven schools and three agriculture areas in the Western Cape. Questionnaires were administrated to assess activities related to pesticide exposure and health symptoms addressing four types of activities: 1) child farm activities related to pesticide handling, 2) eating crops directly from the field, 3) contact with surface water around the field, and 4) seen and smelt pesticide spraying activities. Neurocognitive performance across three domains of attention, memory and processing speed were assessed by means of an iPad-based cognitive assessment tool, Cambridge Automated NeuroPsychological Battery (CANTAB). Headache severity was enquired using a standard Headache Impact Test (HIT-6) tool. Cross-sectional regression analysis was performed. About 50% of the cohort report to have ever been engaged in activities related to pesticide exposure including farm activities, eating crops directly from the field and leisure activities. Headache severity score was consistently increased in relation to pesticide-related farm activities (score increase of 1.99; 95% CI: 0.86, 3.12), eating crops (1.52; 0.41, 2.67) and leisure activities of playing, swimming or bathing in nearby water (1.25; 0.18, 2.33). For neurocognitive outcomes, an overall negative trend with pesticide exposure-related activities was observed. Among others, involvement in pesticide-related farm activities was associated with a lower multi-tasking accuracy score (−2.74; −5.19, −0.29), while lower strategy in spatial working memory (−0.29; −0.56; −0.03) and lower paired associated learning (−0.88; −1.60, −0.17) was observed for those who pick crops off the field compared to those who do not pick crops off the field. Eating fruits directly from the vineyard or orchard was associated with a lower motor screening speed (−0.06; −0.11, −0.01) and lower rapid visual processing accuracy score (−0.02; −0.03, 0.00). Children who indicate activities related to pesticide exposure may be at higher risk for developing headaches and lower cognitive performance in the domains of attention, memory and processing speed. However, self-reported data and cross-sectional design are a limitation. Future research in CapSA will consider pesticide exposure estimations via urinary biomarkers and longitudinal assessment of cognitive functions.

  
  [Chetty-Mhlanga, S., Fuhrimann, S., Basera, W., Eeftens, M., Röösli, M. and Dalvie, M.A., 2020. Environment International, 146, p.106237.]
• Headache caused by pesticides--a review of the literature
  Headache makes one of the most common side effects of frequently pesticide application. This is to be taken care of in rural areas. Headaches have been reported with the use of ivermectin, ivermectin-diethylcarbamazine, organophosphates, and also with the fungicide maneb and copper sulfate, carbofuran, hexonal, dioxin, methomyl and its salts, as well as rare cases of poisoning with the fungicide combination of propineb and cymoxanil. Headache often occurs after long term work with pesticides and/or in laboratories. There are numerous symptoms accompanying headache in pesticide poisoning the most common being elevated body temperature, lassitude, dizziness, irritability, nausea, vomiting, epigastric pain, diarrhea, myalgia, pains in the arms and legs, sleepiness, pains in joints, irritation of eyes/face/skin, sweating. Much less common are respiratory disturbances, tachycardia, tachypnea and other cardiac distur bances, fall of blood pressure, gastrointestinal discomforts, constipation, poor appetite, significant decrease in leukocyte count, anemia, albuminuria, azotemia, fasciculations, miosis, blurred vision, memory disturbances and other neurologic disturbances, postural tremor, signs of cerebral function damage, bradykinesia, etc.
  [Titlić, M., Josipović-Jelić, Z. and Punda, A., 2008. Acta medica Croatica: casopis Hravatske akademije medicinskih znanosti, 62(2), pp.233-236.]

• Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s disease
  We hypothesized that expression of mutant Huntingtin (HTT) would modulate the neurotoxicity of the commonly used organophosphate insecticide, chlorpyrifos (CPF), revealing cellular mechanisms underlying neurodegeneration. Using a mouse striatal cell model of HD, we report that mutant HD cells are more susceptible to CPF-induced cytotoxicity as compared to wild-type. This CPF-induced cytotoxicity caused increased production of reactive oxygen species, reduced glutathione levels, decreased superoxide dismutase activity, and increased malondialdehyde levels in mutant HD cells relative to wild-type. Furthermore, we show that co-treatment with antioxidant agents attenuated the CPF-induced ROS levels and cytotoxicity. Co-treatment with a NADPH oxidase (NOX) inhibitor, apocynin, also attenuated the CPF-induced ROS production and neurotoxicity. CPF caused increased NOX activity in mutant HD lines that was ameliorated following co-treatment with apocynin. Finally, CPF-induced neurotoxicity significantly increased the protein expression of nuclear factor erythroid 2-related factor (Nrf2) in mutant HD cells as compared to wild-type. This study is the first report of CPF-induced toxicity in HD pathophysiology and suggests that mutant HTT and CPF exhibit a disease-toxicant interaction wherein expression of mutant HTT enhances CPF-induced neurotoxicity via a NOX-mediated oxidative stress mechanism to cause neuronal loss in the full length HTT expressing striatal cells.
  [Dominah, G.A., McMinimy, R.A., Kallon, S. and Kwakye, G.F., 2017. Neurotoxicology, 60, pp.54-69.]

• Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort
  

  Abstract

  Introduction

  N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment.

  Methods

  Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1–3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure.

  Results

  Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = −5.32; 95%CI: 9.04, −1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = −3.15; 95%CI: 6.05, −0.25; p = 0.038), personal-social (%change = −4.37; 95%CI: 7.48, −1.26; p = 0.008), communication (%change = −7.00; 95%CI: 11.75, −2.26; p = 0.005), and cognitive (%change = −4.02; 95%CI: 6.72, −1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months.

  Conclusions

  Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.

  
  [Jenkins, H.M. et al. (2024) ‘Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort’, Environmental Research, 246, p. 118114. doi:10.1016/j.envres.2024.118114. ]
• Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults
  Background
  Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years.

  Methods
  We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language.

  Results
  There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: −0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = −3.10; 95% CI: −6.43, 0.22 and β = −3.67; 95% CI: −7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task.

  Discussion
  We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.
  [Sagiv, S. et al. (2024) Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults, Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S0013935123025604?via%3Dihub. ]

• Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study
  Background
  Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive.
  Objectives
  This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function.
  Methods
  The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function.
  Results
  The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (β = -6.21, 95 % confidence interval [CI]: −12.21, −0.21), with more pronounced associations observed among girls (β = -9.57, 95 % CI: −18.33, −0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ.
  Conclusions
  Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.
  [Zhang, B. et al. (2024) Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412024003064. ]
• Science evolves but outdated testing and static risk management in the US delay protection to human health
  There is increasing concern amongst public health professionals, environmental health scientists, and medical organizations about exposures to synthetic chemicals via polluted air and water, consumer products such as cosmetics, fabrics and upholstery, and food and packaging. These organizations’ concerns are based on the overwhelming evidence showing associations between chemical exposures and adverse health outcomes in human populations.
  [Maffini, M. and Vandenberg, L. (2024) Science evolves but outdated testing and static risk management in the US delay protection to human health, Frontiers. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1444024/full.]
• Tannic acid inhibits pain mediators, inflammation and oxidative stress in mice exposed to glyphosate-based herbicide
  Chronic exposure to glyphosate-based herbicide (Gly) has been associated with neurological disorders. Tannic acid (TA) is an antioxidant with attenuating action against neuroinflammation-associated conditions. This study evaluated the effect of Gly on pain perception alongside antinociceptive and anti-inflammatory actions of TA in Gly-exposed mice. Male Swiss mice were randomly divided into six groups (n=8): control (distilled water 0.2 ml/kg), Gly (Gly 500 mg/kg), Pre-TA + Gly (TA 50 mg/kg pre-treatment, afterwards Gly-administered), TA + Gly (TA 50 mg/kg and Gly co-administered), Pre-AA + Gly (ascorbic acid (AA) 10 mg/kg pre-treatment, afterwards Gly-administered), and AA + Gly (AA 10 mg/kg and Gly co-administered). Mechanical, thermal, and chemical pain were evaluated six weeks post vehicle/drugs administrations orally, followed by brain biochemical measurements. TA treatment alleviated Gly-induced hyperalgesia in similar version to the values of control and AA groups by increasing significantly (p < 0.05) nociceptive thresholds. Moreover, TA-treatment significantly decreased malondialdehyde (MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, significantly increased anti-inflammatory cytokines (IL-10, IL-4, and TGF-1β) levels, and antioxidant enzymes, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities compared to Gly-treated mice (p < 0.05). Conclusively, TA treatment exerted antinociceptive and anti-inflammatory actions, possibly through its antioxidant and anti-inflammatory actions in Gly-exposed mice. Notably, TA pre-treatment showed a better response than TA and Gly co-administration. We propose the potential neuroprotective and ameliorative functions of TA in Gly-induced hyperalgesia. This merits further clinical research into protective roles of TA against pesticide-related conditions.
  [Abolarin, P.O. and Owoyele, B.V. (2024) Tannic acid inhibits pain mediators, inflammation and oxidative stress in mice exposed to glyphosate-based herbicide, Environmental Analysis Health and Toxicology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294660/. ]
• Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food
  The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE-28, -47, -49, -99, -100, -138, -153, -154, -183 and ‑209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE-47, -99, -153, -209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint-specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.
  [Schrenk, D. et al. (2024) Update of the risk assessment of polybrominated diphenyl ..., EFSA Journal. Available at: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2024.8497. ]
• Association between glyphosate exposure and cognitive function, depression, and neurological diseases in a representative sample of US adults: NHANES 2013–2014 analysis
  Glyphosate, the most widely used herbicide globally, has been linked to neurological impairments in some occupational studies. However, the potential neurotoxic effects of glyphosate exposure in the general population are still not fully understood. We conducted analyses on existing data collected from 1532 adults of the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the possible relationship between glyphosate exposure and cognitive function, depressive symptoms, disability, and neurological medical conditions. Our results showed a significant negative association between urinary glyphosate levels and the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD-WLT) trial 3 recall and delayed recall scores in both models, with ß coefficients of -0.288 (S.E. = 0.111, P = 0.021) and -0.426 (S.E. = 0.148, P = 0.011), respectively. Furthermore, the odds ratio did not show a significant increase with the severity of depressive symptoms with a one-unit increase in ln-glyphosate levels. However, the odds ratio for severe depressive symptoms was significantly higher than for no symptoms (odds ratio = 4.148 (95% CI = 1.009-17.133), P = 0.049). Notably, the odds ratio showed a significant increase for individuals with serious hearing difficulty (odds ratio = 1.354 (95% CI = 1.018-1.800), P = 0.039) with a one-unit increase in ln-glyphosate levels, but not for other neurological medical conditions. In conclusion, our findings provide the first evidence that glyphosate exposure may be associated with neurological health outcomes in the US adult population. Additional investigation is necessary to understand the potential mechanisms and clinical significance of these correlations.
  [Hsiao, C.C., Yang, A.M., Wang, C. and Lin, C.Y., 2023. NHANES 2013–2014 analysis. Environmental Research, p.116860.]
• Association between organophosphorus pesticide exposure and depression risk in adults: A cross-sectional study with NHANES data.
  Organophosphorus pesticides (OPPs) are widely used pesticides, and previous studies showed that OPPs can increase the risk of central nervous system disorders (e.g., Parkinson's and Alzheimer's disease). However, few studies have comprehensively explored their association with depression in general adults. We analyzed data from 5206 participants aged 20 years or more based on four National Health and Nutrition Examination Survey (NHANES) cycles. OPPs exposure was estimated using measures of urinary concentrations for six OPPs metabolites. Survey-weighted generalized linear regression model (SWGLM) was used to explore the association of OPPs metabolites with depression. Subgroup analyses were performed by age (≦60 years and >60 years) and gender. The weighted quantile sum (WQS) regression model was used to explore the overall association of six OPPs metabolites with depression. In addition, The Bayesian kernel machine regression (BKMR) model was applied to investigate the interaction and joint effects of multiple OPPs metabolites with depression. The SWGLM showed that dimethyl phosphate (DMP) and dimethyl thiophosphate (DMTP), whether taken as continuous or quartile variables, had a positive correlation with depression. Diethyl phosphate (DEP) and dimethyl dithiophosphate (DMDTP) in the highest quartile were positively associated with depression compared to the lowest quartile. In subgroup analysis, we found that the effects of the above chemicals on depression existed in the male and young middle-aged population, while DMP was present in the female. There was a significant combined overall effect of six OPPs metabolites with depression [OR = 1.232, 95%CI: (1.011, 1.504)] in WQS. Furthermore, the BKMR model also showed a positive trend in the overall effect of six OPPs metabolites with depression. In conclusion, our results suggest that exposure to OPPs may increase the risk of depression in US adults. Men and young and middle-aged populations are more vulnerable to OPPs and the mixture of OPPs metabolites may induce depression.
  [Wu, Y., Song, J., Zhang, Q., Yan, S., Sun, X., Yi, W., Pan, R., Cheng, J., Xu, Z. and Su, H., 2023. Environmental Pollution, 316, p.120445.]
• Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.
  Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery–replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.
  [Curtis, M.A., Dhamsania, R.K., Branco, R.C., Guo, J.D., Creeden, J., Neifer, K.L., Black, C.A., Winokur, E.J., Andari, E., Dias, B.G. and Liu, R.C., 2023.PNAS nexus, 2(4), p.pgad085.]
• Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
  Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
  [Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Mixture Effects of Polychlorinated Biphenyls (PCBs) and Three Organochlorine Pesticides on Cognitive Function in Mohawk Adults at Akwesasne
  The Mohawks at Akwesasne have been highly exposed to polychlorinated biphenyls (PCBs), via releases from three aluminum foundries located near the reserve. They are also exposed to organochlorine pesticides, namely hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (DDE), and mirex. Previous studies have demonstrated reduced cognition in relation to total PCBs, but the effects of the mixtures of different PCB congener groups, HCB, DDE, and mirex on cognitive function have not been studied. Therefore, cognitive performance for executive function, scored via the digit symbol substitution test (DSST), in Mohawk adults aged 17-79 years (n = 301), was assessed in relation to serum concentrations of low-chlorinated PCBs, high-chlorinated PCBs, total PCBs, HCB, DDE, and mirex. We used mixture models employing the quantile-based g-computation method. The mixture effects of low-chlorinated PCBs, high-chlorinated PCBs, HCB, DDE, and mirex were significantly associated with 4.01 DSST scores decrements in the oldest age group, 47-79 years old. There were important contributions to mixture effects from low-chlorinated PCBs, high-chlorinated PCBs, and total PCBs, with smaller contributions of HCB and DDE. Our findings indicate that exposures to both low- and high-chlorinated PCBs increase the risk of cognitive decline in older adults, while DDE and HCB have less effect.
  [Sasaki, N., Jones, L.E., Morse, G.S., Carpenter, D.O. and Akwesasne Task Force on the Environment, 2023. International Journal of Environmental Research and Public Health, 20(2), p.1148.]
• Neurodevelopmental Disorders (NDDs): Beyond the Clinical Definition and Translational Approach
  

  Neurodevelopmental disorders (NDDs) are complex and heterogeneous disorders that affect the growth and development of the brain and are often associated with impairments in cognitive and motor functions, communication, and adaptive behavior. Although the diagnostic manuals define NDDs as separate entities, they co-occur with high frequency, determining a more complex clinical presentation, and therefore a more challenging evaluation and treatment. Moreover, they are frequently associated with other health conditions, causing increased negative individual and family burden and very high costs. Thus, the aim of this Special Issue of Children was to shed light on recent data in the field of NDDs, with regard to the etiopathogenesis of these disorders, as well as common and specific underpinnings, in order to raise awareness about the need for a deeper awareness of the specificities within these disorders and their common transdiagnostic mechanisms, with the goal of identifying new therapeutic targets and options.

   
  [Pallanti, S. and Salerno, L. (2023) ‘Neurodevelopmental Disorders (ndds): Beyond the clinical definition and translational approach’, Children, 10(1), p. 99. doi:10.3390/children10010099. ]

• Occupational Exposure to Pesticides as a Risk Factor for Sleep Disorders.
  Inadequate sleep has been linked to a variety of impairments in bodily functions, including endocrine, metabolic, higher cortical function, and neurological disorders. For this reason, the aim of this study was to analyze the link between occupational pesticide exposure and sleep health among farmers in Almeria. A cross-sectional study was conducted among a population living on the coast of Almeria (southeastern Spain), where about 33,321 hectares of land are used for intensive agriculture in plastic greenhouses. A total of 380 individuals participated in the study: 189 greenhouse workers and 191 control subjects. The participants were contacted during their annual scheduled occupational health survey. Data on sleep disturbances were collected using the Spanish version of the Oviedo Sleep Questionnaire. Agricultural workers were found to be at a significantly higher risk of insomnia, especially among those who did not wear protective gloves (OR = 3.12; 95% C.I. = 1.93–3.85; p = 0.04) or masks (OR = 2.43; 95% C.I. = 1.19–4.96; p = 0.01). The highest risk of insomnia related to pesticide applicators was observed in those who did not wear a mask (OR = 4.19; 95% C.I. = 1.30–13.50; p = 0.01) or goggles (OR = 4.61; 95% C.I. = 1.38–10.40; p = 0.01). This study supports previous findings indicating an increased risk of sleep disorder in agricultural workers exposed to pesticides at work.
  [Zheng, R., García-González, J., Romero-del Rey, R., López-Villén, A., García-Alvarez, R., Fadul-Calderon, R., Requena-Mullor, M. and Alarcón-Rodríguez, R., 2023. International Journal of Environmental Research and Public Health, 20(4), p.3149.]
• Pesticide exposure and the microbiota-gut-brain axis
  The gut microbiota exist within a dynamic ecosystem shaped by various factors that includes exposure to xenobiotics such as pesticides. It is widely regarded that the gut microbiota plays an essential role in maintaining host health, including a major influence on the brain and behaviour. Given the widespread use of pesticides in modern agriculture practices, it is important to assess the long-term collateral effects these xenobiotic exposures have on gut microbiota composition and function. Indeed, exposure studies using animal models have shown that pesticides can induce negative impacts on the host gut microbiota, physiology and health. In tandem, there is a growing body of literature showing that the effects of pesticide exposure can be extended to the manifestation of behavioural impairments in the host. With the increasing appreciation of the microbiota-gut-brain axis, in this review we assess whether pesticide-induced changes in gut microbiota composition profiles and functions could be driving these behavioural alterations. Currently, the diversity of pesticide type, exposure dose and variation in experimental designs hinders direct comparisons of studies presented. Although many insights presented, the mechanistic connection between the gut microbiota and behavioural changes remains insufficiently explored. Future experiments should therefore focus on causal mechanisms to examine the gut microbiota as the mediator of the behavioural impairments observed in the host following pesticide exposure.
  [Matsuzaki, R., Gunnigle, E., Geissen, V., Clarke, G., Nagpal, J., & Cryan, J. F. (2023). Pesticide exposure and the microbiota-gut-brain axis. The ISME Journal, 17(8), 1153-1166. https://academic.oup.com/ismej/article/17/8/1153/7505820 ]
• Pesticides and tremor: An overview of association, mechanisms and confounders
  Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.
  [Dardiotis, E., Skouras, P., Varvarelis, O.P., Aloizou, A.M., Hernández, A.F., Liampas, I., Rikos, D., Dastamani, M., Golokhvast, K.S., Bogdanos, D.P. and Tsatsakis, A., 2023. Environmental research, p.115442.]
• Pesticides at brain borders: Impact on the blood-brain barrier, neuroinflammation, and neurological risk trajectories
  Pesticides are omnipresent, and they pose significant environmental and health risks. Translational studies indicate that acute exposure to high pesticide levels is detrimental, and prolonged contact with low concentrations of pesticides, as single and cocktail, could represent a risk factor for multi-organ pathophysiology, including the brain. Within this research template, we focus on pesticides' impact on the blood-brain barrier (BBB) and neuroinflammation, physical and immunological borders for the homeostatic control of the central nervous system (CNS) neuronal networks. We examine the evidence supporting a link between pre- and postnatal pesticide exposure, neuroinflammatory responses, and time-depend vulnerability footprints in the brain. Because of the pathological influence of BBB damage and inflammation on neuronal transmission from early development, varying exposures to pesticides could represent a danger, perhaps accelerating adverse neurological trajectories during aging. Refining our understanding of how pesticides influence brain barriers and borders could enable the implementation of pesticide-specific regulatory measures directly relevant to environmental neuroethics, the exposome, and one-health frameworks.
  [Cresto, N., Forner-Piquer, I., Baig, A., Chatterjee, M., Perroy, J., Goracci, J. and Marchi, N., 2023. Chemosphere, p.138251.]
• Prenatal and childhood chlordecone exposure, cognitive abilities and problem behaviors in 7-year-old children: the TIMOUN mother-child cohort in Guadeloupe
  Background: Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys.

  Objective: To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe.

  Methods: We examined 576 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children's blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child's mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex.

  Results: Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children's blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls.

  Conclusions: These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.
  [Oulhote, Y., Rouget, F., Michineau, L., Monfort, C., Desrochers-Couture, M., Thomé, J.P., Kadhel, P., Multigner, L., Cordier, S. and Muckle, G., 2023. Environmental Health, 22(1), pp.1-13.]

• The association of prenatal phthalates, organophosphorus pesticides, and organophosphate esters with early child language ability in Norway.
  This study examines the influence of prenatal exposure to phthalates, organophosphate esters, and organophosphorous pesticides, on children's language ability from toddlerhood to the preschool period. This study includes 299 mother-child dyads from Norway in the Norwegian Mother, Father and Child Cohort Study (MoBa). Prenatal exposure to chemicals were assessed at 17 weeks’ gestation, and child language skills were assessed at 18 months using the Ages and Stages Questionnaire communication subscale and at preschool age using the Child Development Inventory. We ran two structural equation models to examine the simultaneous influences of chemical exposures on parent-reported and teacher-reported child language ability. Prenatal organophosphorous pesticides were negatively associated with preschool language ability through language ability at 18 months. Additionally, there was a negative association between low molecular weight phthalates and teacher-reported preschool language ability. There was no effect of prenatal organophosphate esters on child language ability at either 18 months or preschool age. This study adds to the literature on prenatal exposure to chemicals and neurodevelopment and highlights the importance of developmental pathways in early childhood.
  [Ramos, A.M., Herring, A.H., Villanger, G.D., Thomsen, C., Sakhi, A.K., Cequier, E., Aase, H. and Engel, S.M., 2023. Environmental Research, 225, p.115508.]
• Widespread use of toxic agrochemicals and pesticides for agricultural products storage in Africa and developing countries: Possible panacea for ecotoxicology and health implications
  Chemicals used for storage majorly possess insecticidal activities - deterring destructive insect pests and microorganisms from stored agricultural produce. Despite the controversy about their safety, local farmers and agro-wholesalers still predominantly use these chemicals in developing countries, especially Africa, to ensure an all-year supply of agriproducts. These chemicals could have short- or long-term effects. Despite the state-of-the-art knowledge, factors such as poor education and awareness, limited agricultural subventions, quests for cheap chemicals, over-dosage, and many more are the possible reasons for these toxic chemicals' setback and persistent use in developing countries. This paper provides an up-to-date review of the environmental and ecological effects, as well as the health impacts arising from the indiscriminate use of toxic chemicals in agriproducts. Existing data link pesticides to endocrine disruption, genetic mutations, neurological dysfunction, and other metabolic disorders, apart from the myriad of acute effects. Finally, this study recommended several naturally sourced preservatives as viable alternatives to chemical counterparts and emphasized the invaluable role of education and awareness programs in mitigating the use in developing nations for a sustainable society.
  [Anaduaka, E.G., Uchendu, N.O., Asomadu, R.O., Ezugwu, A.L., Okeke, E.S. and Ezeorba, T.P.C., 2023. Heliyon.]
• Chronic Effects of Dietary Pesticides on the Gut Microbiome and Neurodevelopment
  Many agricultural pesticides include substances that are known to be harmful to human health and while some have been banned from developed countries, they are still being used in developing countries such as Brazil. Recent studies have shown that low-level chronic dietary exposure to pesticides can affect the human gut microbiota. This possible hazardous effect of pesticides on human health has not been specifically recognized by government regulatory agencies. In Brazil, for instance, of the 10 best-selling active ingredients in pesticides in 2019, two are considered extremely toxic, Paraquat and Chlorpyrifos. Even though Paraquat has been banned in Brazil since 2020, the values of maximum residue limits (MRLs) of toxic pesticides allowed in the country are still higher than in other countries. Unfortunately, many developing countries still lack the resources and expertise needed to monitor adequately and systematically the presence of pesticide residues on food. In this work, we raise awareness to the danger the chronic exposure to high dietary levels of pesticides can pose to the public, especially considering their prolonged effects on the gut microbiome.
  [Gama, J., Neves, B., & Pereira, A. (2022). Chronic effects of dietary pesticides on the gut microbiome and neurodevelopment. Frontiers in Microbiology, 13, 931440. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.931440/full ]
• Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
  Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
  [Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ]
• Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid hormones, and infant neurodevelopment
  Background
  Per- and polyfluoroalkyl substances (PFAS) are believed to impair early neurodevelopment and disrupt thyroid hormone (TH) levels. However, there are limited epidemiological data on the neurodevelopmental effects in infancy of prenatal PFAS exposure and the potential mediating effects of TH.
  Objectives
  To evaluate potential associations between prenatal PFAS exposure and early neurodevelopmental deficiencies, and assess mediator effects of TH.
  Methods
  From 2010 to 2013, 274 mother-infant pairs were recruited to the Laizhou Wan Birth Cohort in China. Ten PFAS and five TH were measured in cord serum. Developmental quotient (DQ) from 5 domains (adaptive, social, language, gross and fine motor) was assessed using Gesell Developmental Schedules for each child at 1 year of age. The associations between PFAS and DQs were evaluated using multivariable linear regressions. TH-mediated effects of PFAS on DQs were calculated by mediation analyses.
  Results
  Among our study population, PFAS exposures were common and associated with DQ decrement in infants. For each 10-fold increase in PFBS concentrations, gross motor and adaptive DQ decreased by 8.56 (95%CI: −15.15, −1.97) and 5.87 (95%CI: −8.07, −3.67) points, respectively. TSH mediated 12.90% of the association of PFBS with gross motor DQ and FT4 explained 19.63% of the association of PFBS with adaptive DQ. The negative association was also found between PFHxS exposure and gross motor DQ (β = 8.14, 95%CI: −15.39, −0.98).
  Conclusions
  PFBS and PFHxS were negatively associated with early neurodevelopment, especially consistent in gross motor domain. The associations were partly explained by TSH and FT4.
  [Yao, Q. et al. (2021) Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid hormones, and infant neurodevelopment, Environmental Research. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0013935121018624. ]
• Association of activities related to pesticide exposure on headache severity and neurodevelopment of school-children in the rural agricultural farmlands of the Western Cape of South Africa
  

  Children and adolescents living in agricultural areas are likely to be exposed to mixtures of pesticides during their daily activities, which may impair their neurodevelopment. We investigated various such activities in relation to headache severity and neurodevelopment of school-children living in rural agricultural areas in the Western Cape of South Africa. We used baseline date from 1001 school-children of the Child Health Agricultural Pesticide Cohort Study in South Africa (CapSA) aged 9–16 from seven schools and three agriculture areas in the Western Cape. Questionnaires were administrated to assess activities related to pesticide exposure and health symptoms addressing four types of activities: 1) child farm activities related to pesticide handling, 2) eating crops directly from the field, 3) contact with surface water around the field, and 4) seen and smelt pesticide spraying activities. Neurocognitive performance across three domains of attention, memory and processing speed were assessed by means of an iPad-based cognitive assessment tool, Cambridge Automated NeuroPsychological Battery (CANTAB). Headache severity was enquired using a standard Headache Impact Test (HIT-6) tool. Cross-sectional regression analysis was performed. About 50% of the cohort report to have ever been engaged in activities related to pesticide exposure including farm activities, eating crops directly from the field and leisure activities. Headache severity score was consistently increased in relation to pesticide-related farm activities (score increase of 1.99; 95% CI: 0.86, 3.12), eating crops (1.52; 0.41, 2.67) and leisure activities of playing, swimming or bathing in nearby water (1.25; 0.18, 2.33). For neurocognitive outcomes, an overall negative trend with pesticide exposure-related activities was observed. Among others, involvement in pesticide-related farm activities was associated with a lower multi-tasking accuracy score (−2.74; −5.19, −0.29), while lower strategy in spatial working memory (−0.29; −0.56; −0.03) and lower paired associated learning (−0.88; −1.60, −0.17) was observed for those who pick crops off the field compared to those who do not pick crops off the field. Eating fruits directly from the vineyard or orchard was associated with a lower motor screening speed (−0.06; −0.11, −0.01) and lower rapid visual processing accuracy score (−0.02; −0.03, 0.00). Children who indicate activities related to pesticide exposure may be at higher risk for developing headaches and lower cognitive performance in the domains of attention, memory and processing speed. However, self-reported data and cross-sectional design are a limitation. Future research in CapSA will consider pesticide exposure estimations via urinary biomarkers and longitudinal assessment of cognitive functions.

  
  [Chetty-Mhlanga, S., Fuhrimann, S., Basera, W., Eeftens, M., Röösli, M. and Dalvie, M.A., 2020. Environment International, 146, p.106237.]
• Environment, lifestyle, and Parkinson's disease: Implications for prevention in the next decade
  There is evidence from observational studies for a role of a number of environmental exposures and lifestyle habits in modulating the risk for Parkinson's disease. Environmental and lifestyle associations, if causal, represent opportunities for Parkinson's disease prevention or disease modification at individual and population levels. In the past decade, additional evidence has been published that improves causal inference and/or enhances our understanding of the complexity of these associations. A number of gene–environment interactions have been elucidated, and our understanding of the roles of physical activity, pesticide and other chemical exposures, dietary habits, emotional stress, head injury, and smoking has been refined. In the next decade, better techniques will help us to close the gaps in our knowledge, including taking into account Parkinson's disease heterogeneity and gene and risk factor interactions in observational studies. To do this, larger datasets, global consortia, genomewide environment interaction studies, prospective studies throughout the lifespan, and improvements in the methodology of clinical trials of physical activity will be key. Despite the caveats of observational studies, a number of low-risk and potentially high-yield recommendations for lifestyle modification could be made to minimize the individual and societal burdens of Parkinson's disease, including dietary modifications, increasing physical activity, and head injury avoidance. Furthermore, a reduction in pesticide use could have a major impact on global health related to and beyond Parkinson's disease. Given the increasing prevalence of this disorder, formulating and promoting these recommendations should be a high priority.
  [Marras, C., Canning, C. G., & Goldman, S. M. (2019). Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade. Movement Disorders, 34(6), 801-811. https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.27720 ]
• Gut Inflammation in Association With Pathogenesis of Parkinson’s Disease
  Parkinson’s disease (PD) is a neurodegenerative disease that is generally thought to be caused by multiple factors, including environmental and genetic factors. Emerging evidence suggests that intestinal disturbances, such as constipation, are common non-motor symptoms of PD. Gut inflammation may be closely associated with pathogenesis in PD. This review aims to discuss the cross-talk between gut inflammation and PD pathology initiation and progression. Firstly, we will highlight the studies demonstrating how gut inflammation is related to PD. Secondly, we will analyze how gut inflammation spreads from the gastro-intestine to the brain. Here, we will mainly discuss the neural pathway of pathologic α-syn and the systemic inflammatory routes. Thereafter, we will address how alterations in the brain subsequently lead to dopaminergic neuron degeneration, in which oxidative stress, glutamate excitotoxicity, T cell driven inflammation and cyclooxygenase-2 (COX-2) are involved. We conclude a model of PD triggered by gut inflammation, which provides a new angle to understand the mechanisms of the disease.
  [Chen, Q. Q., Haikal, C., Li, W., & Li, J. Y. (2019). Gut inflammation in association with pathogenesis of Parkinson’s disease. Frontiers in molecular neuroscience, 12, 218. https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00218/full ]
• Gut microbiota in neurodegenerative disorders
  Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.

   
  [Sarkar, S. R., & Banerjee, S. (2019). Gut microbiota in neurodegenerative disorders. Journal of neuroimmunology, 328, 98-104. https://www.sciencedirect.com/science/article/pii/S0165572818304545 ]

• Paraquat exposure and Parkinson’s disease: A systematic review and meta-analysis
  To reconcile and unify available results regarding paraquat exposure and Parkinson’s disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27–2.13; I2 = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson’s disease are warranted.
  [Tangamornsuksan, W., Lohitnavy, O., Sruamsiri, R., Chaiyakunapruk, N., Norman Scholfield, C., Reisfeld, B., & Lohitnavy, M. (2019). Paraquat exposure and Parkinson’s disease: A systematic review and meta-analysis. Archives of Environmental & Occupational Health, 74(5), 225-238. https://www.tandfonline.com/doi/abs/10.1080/19338244.2018.1492894 ]
• Case Control Study of Impulsivity, Aggression, Pesticide Exposure and Suicide Attempts Using Pesticides among Farmers
  A case-control study was conducted to investigate associations between organophosphate pesticide (OP) exposure, aggression, impulsivity, and attempted suicide. Questionnaires were used to collect information; impulsivity and aggression were measured by the Barratt Impulsivity Scale (BIS) and the Aggression Inventory (AI). A greater number of OP symptoms was associated with an increased odds of a suicide attempt after adjusting for marital status and income (OR = 1.45; CI 1.14-1.86). Attempted suicide was significantly associated with high impulsivity scores (means: 72.4 vs. 60.6, P < 0.0001) and high aggression scores (means: 38.5 vs. 26.1, P < 0.0001). Suicide attempters had a higher number of OP exposure symptoms than controls and scored higher on scales of impulsivity and aggression.
  [Lyu, C.P., Pei, J.R., Beseler, L.C., Li, Y.L., Li, J.H., Ming, R.E.N., Stallones, L. and Ren, S.P., 2018. Biomedical and environmental sciences, 31(3), pp.242-246.]
• Case Control Study of Impulsivity, Aggression, Pesticide Exposure and Suicide Attempts Using Pesticides among Farmers
  A case-control study was conducted to investigate associations between organophosphate pesticide (OP) exposure, aggression, impulsivity, and attempted suicide. Questionnaires were used to collect information; impulsivity and aggression were measured by the Barratt Impulsivity Scale (BIS) and the Aggression Inventory (AI). A greater number of OP symptoms was associated with an increased odds of a suicide attempt after adjusting for marital status and income (OR = 1.45; CI 1.14-1.86). Attempted suicide was significantly associated with high impulsivity scores (means: 72.4 vs. 60.6, P < 0.0001) and high aggression scores (means: 38.5 vs. 26.1, P < 0.0001). Suicide attempters had a higher number of OP exposure symptoms than controls and scored higher on scales of impulsivity and aggression.
  [Lyu, C.P., Pei, J.R., Beseler, L.C., Li, Y.L., Li, J.H., Ming, R.E.N., Stallones, L. and Ren, S.P., 2018. Biomedical and environmental sciences, 31(3), pp.242-246.]
• Bifenthrin-induced neurotoxicity in rats: involvement of oxidative stress.
  Extensive use of synthetic pyrethroids has resulted in serious human health issues. Induction of oxidative stress is an important mechanism of action of most pesticides including pyrethroids. In the present study, we have elucidated the possible role of oxidative stress in bifenthrin-induced neurotoxicity. Adult male Wistar rats were administered bifenthrin (3.5 and 7 mg per kg body weight p.o.) for 30 days. Behavioral studies were conducted on a set of randomly selected rats from each treatment group after completion of treatment. Neurochemical parameters were assessed 24 h after the last dose was administered. The selected behavioral and neurochemical endpoints were also assessed 15 days after cessation of exposure to reveal whether the neurobehavioral changes produced by bifenthrin were temporary or permanent. Deficits in motor activity, motor incoordination, and cognitive impairment were observed after exposure to bifenthrin. Levels of biogenic amines viz. dopamine (DA) and its metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), epinephrine (EPN), norepinephrine (NE), and serotonin (5-HT) altered in the frontal cortex, corpus striatum, and hippocampus of bifenthrin-treated rats. A decrease in the activity of acetylcholinesterase (AChE) occurred in all regions of the brain. Both doses of bifenthrin significantly induced lipid peroxidation (LPO) and increased protein carbonyl levels in the frontal cortex, corpus striatum, and hippocampus of rats. The activities of antioxidant enzymes, i.e. catalase, superoxide dismutase, and glutathione peroxidase, were also suppressed in all selected regions of the brain. A trend of recovery was, however, observed in all the behavioral and neurochemical endpoints 15 days after withdrawal of exposure. Oxidative stress seems to play an important role in bifenthrin-induced neurotoxicity. Our study suggests that long-term exposure to these compounds can produce detrimental effects.
  [Syed F, Awasthi KK, Chandravanshi LP, et al 2017. Toxicol Res (Camb). 7(1):48-58.]
• Diazinon and parathion diverge in their effects on development of noradrenergic systems
  Organophosphate pesticides elicit developmental neurotoxicity through mechanisms over and above their shared property as cholinesterase inhibitors. We compared the consequences of neonatal exposure (postnatal days PN1-4) to diazinon or parathion on development of norepinephrine systems in rat brain, using treatments designed to produce equivalent effects on cholinesterase, straddling the threshold for barely-detectable inhibition. Norepinephrine levels were measured throughout development from the immediate posttreatment period (PN5), to early adolescence (PN30), young adulthood (PN60) and full adulthood (PN100); we assessed multiple brain regions containing all the major noradrenergic synaptic projections. Diazinon elicited a significant overall deficit of norepinephrine, whereas parathion produced a net increase. The effects were not immediately apparent (PN5) but rather emerged over the course of development, indicating that the organophosphate effects represent alteration of the trajectory of development, not just continuance of an initial injury. There were no comparable effects on β-adrenergic receptors, indicating that the presynaptic changes were not an adaptation to an underlying, primary effect on postsynaptic receptor signaling. Because we used the cholinesterase inhibition benchmark, the absolute dose of diazinon was much higher than that of parathion, since the latter is a more potent cholinesterase inhibitor. Our results are consistent with the growing evidence that the various organophosphates can differ in their impact on brain development and that consequently, the cholinesterase benchmark is an inadequate predictor of adverse neurodevelopmental effects.
  [Slotkin TA, Skavicus S, Seidler FJ. 2017. Brain Res Bull. 130:268-273.]
• Effect of exposure to p,p´-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area.
  Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy. To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy we analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models. Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (β=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis.Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy.
  [Hernández-Mariano JÁ, Torres-Sánchez L, Bassol-Mayagoitia S, et al. 2017. Environ Res. 156:597-604.]
• Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat.
  Attention deficit hyperactivity disorder (ADHD) is characterized by behavioral and cognitive symptoms. Longitudinal studies demonstrated that the symptoms remains clinically significant for the majority of ADHD children into adulthood. Furthermore, a population-based birth cohort provided the initial evidence of adult ADHD that lacks a history of childhood ADHD. We previously demonstrated that neonatal exposure to bisphenol A, an environmental chemical caused hyperactivity in the juvenile. Here, we extend to examine other chemical such as rotenone, a dopaminergic toxins. Oral administration of rotenone (3mg/kg) into 5-day-old male Wistar rats significantly caused hyperactivity at adulthood (8∼11 weeks old; p<0.05). It was about 1.3∼1.4-fold more active in the nocturnal phase after administration of rotenone than control rats. Higher dose (16mg/kg) or repeated lower dose of rotenone (1mg/kg/day for 4days) caused hyperactivity in the juvenile. Furthermore, DNA array analyses showed that neonatal exposure to rotenone altered the levels of gene expression of several molecules related to apoptosis/cell cycle, ATPase, skeletal molecule, and glioma. Bivariate normal distribution analysis indicates no correlation in gene expression between a hyperactivity disorder model and a Parkinson's disease model by rotenone. Thus, we demonstrate a rotenone models of ADHD whose onset varies during juvenile and adulthood.
  [Ishido M, Suzuki J, Masuo Y. 2017. Toxicol Lett. 266:42-48]
• Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum
  Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children's health. Here we examined the effects of longterm (14 days) and low dose (1 μM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, ≥1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain.
  [Kimura-Kuroda J, Nishito Y, Yanagisawa H, Kuroda Y, et al. 2017. Int J Environ Res Public Health. 13(10). pii: E987.]
• Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application
  A number of studies have implicated pesticides in childhood developmental delay (DD) and autism spectrum disorder (ASD). The influence of the route of pesticide exposure on neurodevelopmental delay is not well defined. To study this factor, we examined ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis. The aim of this study was to determine if areas with aerial pesticide exposure had higher rates of ASD/DD diagnoses. This regional study identified higher rates of ASD/DD diagnoses in an area with aerial pesticides application. Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD (adjusted RR = 1.37, 95% CI = 1.06-1.78, p = 0.02). A Poisson regression model controlling for regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates) identified a significant relationship between aerial pesticide use and ASD/DD rates. The relationship between pesticide application and human neurodevelopment deserves additional study to develop safe and effective methods of mosquito prevention, particularly as communities develop plans for Zika virus control.
  [Hicks SD, Wang M, Fry K, Doraiswamy V, Wohlford EM. 2017. Front Pediatr. 5:116.]
• Neurodevelopmental disorders and pesticide exposure: the northeastern Italian experience.
  Endocrine disruptors are chemical substances that can interfere with the endocrine system. They include pesticides, metals, additives or contaminants in food, and personal care products. Pesticides are the only substances intentionally released into our environment to kill living things (herbicides, insecticides, fungicides, rodenticides). There is scientific evidence that exposure to pesticides produces a growing number of human pathological conditions; among these, stillbirth is an emerging issue.
  [Roncati L, Pusiol T, Piscioli F, Lavezzi AM. Arch Toxicol. 91(2):603-604.]
• Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds
  Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, the experimental models of occupational OP exposure currently used in the field. Animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.
  [Voorhees JR, Rohlman DS, Lein PJ, Pieper AA. 2017. Front Neurosci. 10:590]
• Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.
  Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.
  [Voorhees JR, Rohlman DS, Lein PJ, Pieper AA. 2017. Front Neurosci. 10:590.]
• Prenatal and postnatal exposure to organophosphate pesticides and childhood neurodevelopment in Shandong, China.
  Although studies in laboratory animals demonstrate neurodevelopmental deficits caused by prenatal or postnatal organophosphate pesticide (OP) exposure, there is limited evidence on effects induced by not only prenatal but also postnatal exposure of children to OPs. We measured diethylphosphate (DE), dimethylphosphate (DM), and total dialkylphosphate (DAP) metabolites in maternal and child urine at 12 and 24months of age and examined their relationship with developmental quotients (DQs) in 12-month-old infants and 24-month-old children in Shandong, China.The median concentrations of total DAP metabolites (DAPs) in child urine [371.97nmol/g creatinine (12-month-old infants), 538.64nmol/g creatinine (24-month-old children)] were higher than those in maternal urine (352.67nmol/g creatinine). Prenatal OP exposure was negatively associated with 24-month-old children's DQs, especially among boys. A 10-fold increase in prenatal DEs and DAPs was associated with a 2.59- and 2.49-point decrease in social domain DQ scores in 24-month-old children (n=262), respectively. However, positive association of postnatal exposure to OPs and 24-month-old children's DQs was observed (n=237). Neither prenatal nor postnatal exposure to OPs was related to 12-month-old infants' DQs.These data suggested that prenatal OP exposure could adversely affect children's neurodevelopment at 24months of age, especially among boys. The prenatal period might be a critical window of OP exposure. In view of the positive association with postnatal OP exposure, it is necessary to interpret findings with caution.
  [Wang Y, Zhang Y, Ji L, Hu Y, et al. 2017. Environ Int. 108:119-126.]
• Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes.
  Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6-9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ - 0.13, 95% CI - 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ - 0.17, 95% CI - 0.33, - 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision.
  [Furlong MA, Herring A, Buckley JP, Goldman BD, et al. 2017. Environ Res.158:737-747. ]
• Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning.
  Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β -4.50, 95% CI -8.05, -0.95), Depression (β -3.21, 95% CI -6.38, -0.05), Somatization (β -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (β -3.59, 95% CI -6.97, -0.21), Emotional Control (β -3.35, 95% CI -6.58, -0.12), Shifting (β -3.42, 95% CI -6.73, -0.11), and Monitoring (β -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β -4.74, 95% CI -9.37, -0.10), Conduct Problems (β -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (β -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (β -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits.
  [Furlong MA, Barr DB, Wolff MS, Engel SM. 2017. Neurotoxicology. 62:231-238.]
• Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children.
  Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism, but more subtle outcomes such as cognition have not been studied.We evaluated the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year-old children.Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within 1 km of maternal residences during pregnancy using a geographic information system, residential location, and California’s comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion, and oxydemeton-methyl) and cognition in 7-year-old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.We observed a decrease of 2.2 points [95% confidence interval (CI): −3.9, −0.5] in Full-Scale IQ and 2.9 points (95% CI: −4.4, −1.3) in Verbal Comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children. 
  [Gunier RB, Bradman A, Harley KG, Kogut K, Eskenazi B. 2017. Environ Health Perspect. 125(5):057002]
• Residential proximity to agricultural fumigant use and IQ, attention and hyperactivity in 7-year old children
  Our objective was to examine the relationship between residential proximity to agricultural fumigant use and neurodevelopment in 7-year old children. Participants were living in the agricultural Salinas Valley, California and enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We administered the Wechsler Intelligence Scale for Children (4th Edition) to assess cognition and the Behavioral Assessment System for Children (2nd Edition) to assess behavior. We estimated agricultural fumigant use within 3, 5 and 8km of residences during pregnancy and from birth to age 7 using California's Pesticide Use Report data. We evaluated the association between prenatal (n = 285) and postnatal (n = 255) residential proximity to agricultural use of methyl bromide, chloropicrin, metam sodium and 1,3-dichloropropene with neurodevelopment. We observed decreases of 2.6 points (95% Confidence Interval (CI): -5.2, 0.0) and 2.4 points (95% CI: -4.7, -0.2) in Full-Scale intelligence quotient for each ten-fold increase in methyl bromide and chloropicrin use within 8km of the child's residences from birth to 7-years of age, respectively. There were no associations between residential proximity to use of other fumigants and cognition or proximity to use of any fumigant and hyperactivity or attention problems. These findings should be explored in larger studies.
  [Gunier RB, Bradman A, Castorina R, Holland NT, et al. 2017. Environ Res. 158:358-365]
• Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies
  The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.
  [Tartaglione AM, Venerosi A, Calamandrei G. 2016. Curr Top Behav Neurosci. 29:231-64]
• Effect of Prenatal Exposure to Pesticides on Children's Health.
  The aim of this study was to summarize the current state of knowledge on pesticide-related fertility problems and disadventeges of childrens due to prenatal pesticides exposure. Available literature was analyzed. Due to the extent of the issue, the study focuses on epidemiological studies conducted in humans, despite evidence from in vitro and animal studies. It seems certain that exposure to harmful chemicals is one of the factors that may cause a decline in fertility and problems with conceiving, whereas exposure during pregnancy can impair foetal development. Prenatal exposure may also result in the occurrence of childhood cancer and neurobehavioral disorders. The meaning of the project is to summarize the role of pesticides in the process of reproduction. This applies especially to people working in agriculture, since they might be occupationally exposed to pesticides.
  [Matysiak M, Kruszewski M, Jodlowska-Jedrych B, Kapka-Skrzypczak L. 2016. J Environ Pathol Toxicol Oncol. 35(4):375-386.]
• Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study
  The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors. This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals. Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree. We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. 
  [Litvan I, Lees PS, Cunningham CR, Rai SN, et al. 2016. Mov Disord. 31(5):644-52. ]
• Environmental pollutants and child health-A review of recent concerns
  In recent years, many new studies have evaluated associations between environmental pollutants and child health. This review aims to provide a broad summary of this literature, comparing the state of epidemiological evidence for the effects of a wide range of environmental contaminants (air pollutants, heavy metals, organochlorine compounds, perfluoroalkyl substances, polybrominated diphenyl ethers, pesticides, phthalates and bisphenol A) on child health outcomes. The review addresses effects on foetal growth and prematurity, neurodevelopment, respiratory and immune health, and childhood growth and obesity. Findings of recent prospective studies and meta-analyses have corroborated previous good evidence, often at lower exposure levels, for effects on foetal growth of air pollution and polychlorinated biphenyls (PCBs), for neurotoxic effects of lead, methylmercury, PCBs and organophosphate pesticides, and for respiratory health effects of air pollution. Moderate evidence has emerged for a potential role of environmental pollutants in attention deficit hyperactivity disorder and autism (lead, PCBs, air pollution), respiratory and immune health (dichlorodiphenyldichloroethylene - DDE - and PCBs), and obesity (DDE). In addition, there is now moderate evidence that certain chemicals of relatively recent concern may be associated with adverse child health outcomes, specifically perfluorooctanoate and foetal growth, and polybrominated diphenyl ethers and neurodevelopment. For other chemicals of recent concern, such as phthalates and bisphenol A, the literature is characterised by large inconsistencies preventing strong conclusions. In conclusion, since most of the recent literature evaluates common exposures in the general population, and not particularly high exposure situations, this accumulating body of evidence suggests that the unborn and young child require more protection than is currently provided. Large, coordinated research efforts are needed to improve understanding of long-term effects of complex chemical mixtures.
  [Vrijheid M, Casas M, Gascon M, Valvi D, Nieuwenhuijsen M. 2016. Int J Hyg Environ Health. 219(4-5):331-42]
• Exposure to pesticides and mental disorders in a rural population of Southern Brazil.
  Exposure to pesticides has been associated with mental disorders, especially in occupationally exposed populations, such as farmers. This effect has been attributed to the neurotoxic and endocrine-disrupting activity of pesticides, as suggested by experimental studies.To determine the prevalence of common mental disorders and self-reported depression, and analyze their association with the exposure to pesticides in a rural population resident in the municipality of Dom Feliciano, Rio Grande do Sul, where tobacco farming is the main economic activity. A cross-sectional study evaluating the prevalence of common mental disorders and self-reported depression in a sample of 869 adult individuals resident in Dom Feliciano, between October 2011 and March 2012 was performed. The evaluation of common mental disorders was performed using the Self-Reporting Questionnaire (SRQ-20), setting a cutoff point of 8 for both genders.The prevalence of common mental disorders and self-reported depression in the sample population were 23% and 21%, respectively. Among individuals who reported depression, an increase of 73% was observed in the odds of pesticide exposure at an age equal to or less than 15 years. There was a positive association between self-reported pesticide poisoning and common mental disorders (OR=2.63; 95% CI, 1.62-4.25) as well as self-reported depression (OR=2.62; 95% CI, 1.63-4.21). Individuals who reported depression had a greater odds of exposure to pyrethroids (OR=1.80; 95% CI, 1.01-3.21) and aliphatic alcohol (OR=1.99; 95% CI, 1.04-3.83). An SRQ-20≥8 was associated with an approximately seven times higher odds of exposure to aliphatic alcohol (95% CI, 1.73-27.53). Self-reported depression positively correlated with a greater period of exposure to dinitroaniline (OR=2.20; 95% CI, 1.03-4.70) and sulphonylurea (OR=4.95; 95% CI, 1.06-23.04).The results suggest that exposure to pesticides could be related mental disorders. However, other common risk factors in tobacco farming, the main local economic activity, cannot be excluded.
  [Campos Ÿ, Dos Santos Pinto da Silva V, Sarpa Campos de Mello M, Barros Otero U. 2016. Neurotoxicology. 56:7-16.]
• Negative Role of the Environmental Endocrine Disruptors in the Human Neurodevelopment
  The endocrine disruptors (EDs) are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS) the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected by centralization in the last year (2015). More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs), chlorpyrifos and chlorfenvinfos, have been found in seven and three samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers but simply time-deferral mechanisms of absorption.
  [Roncati L, Termopoli V, Pusiol T. 2016. Front Neurol. 7:143.]
• Occupational exposure to pesticides as a possible risk factor for the development of chronic diseases in humans (Review).
  It is well known that pesticides are widely used compounds. In fact, their use in agriculture, forestry, fishery and the food industry has granted a huge improvement in terms of productive efficiency. However, a great number of epidemiological surveys have demonstrated that these toxic compounds can interact and exert negative effects not only with their targets (pests, herbs and fungi), but also with the rest of the environment, including humans. This is particularly relevant in the case of workers involved in the production, transportation, preparation and application of these toxicants. Accordingly, a growing body of evidence has demonstrated the correlation between occupational exposure to pesticides and the development of a wide spectrum of pathologies, ranging from eczema to neurological diseases and cancer. Pesticide exposure is often quite difficult to establish, as many currently used modules do not take into account all of the many variables that can occur in a diverse environment, such as the agricultural sector, and the assessment of the real risk for every single worker is problematic. Indeed, the use of personal protection equipment is necessary while handling these toxic compounds, but education of workers can be even more important: personal contamination with pesticides may occur even in apparently harmless situations. This review summarises the most recent findings describing the association between pesticide occupational exposure and the development of chronic diseases.
  [Gangemi S, Miozzi E, Teodoro M, Briguglio G, et al. 2016. Mol Med Rep. 14(5):4475-4488. ]
• Pesticides, Neurodevelopmental Disagreement, and Bradford Hill's Guidelines
  Neurodevelopmental disorders such as autism affect one-eighth of all U.S. newborns. Yet scientists, accessing the same data and using Bradford-Hill guidelines, draw different conclusions about the causes of these disorders. They disagree about the pesticide-harm hypothesis, that typical United States prenatal pesticide exposure can cause neurodevelopmental damage. This article aims to discover whether apparent scientific disagreement about this hypothesis might be partly attributable to questionable interpretations of the Bradford-Hill causal guidelines. Key scientists, who claim to employ Bradford-Hill causal guidelines, yet fail to accept the pesticide-harm hypothesis, fall into errors of trimming the guidelines, requiring statistically-significant data, and ignoring semi-experimental evidence. However, the main scientists who accept the hypothesis appear to commit none of these errors. Although settling disagreement over the pesticide-harm hypothesis requires extensive analysis, this article suggests that at least some conflicts may arise because of questionable interpretations of the guidelines.
  [Shrader-Frechette K, ChoGlueck C. 2016. Account Res. 1-13]
• Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
  Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
  [Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64.]
• Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
  Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
  [Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64]
• Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts.
  Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001.We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months. Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (ΣDAP), diethyl (ΣDEP), and dimethylphosphate (ΣDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype.There was significant heterogeneity in the center-specific estimates of association for ΣDAP and ΣDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for ΣDAP (p = 0.06) and ΣDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in ΣDAP (β = -4.17; 95% CI: -7.00, -1.33) and ΣDMP (β = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (β per 10-fold increase in ΣDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of ΣDAP and ΣDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics. Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure.
  [Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, et al. 2016. Environ Health Perspect. 124(6):822-30]
• Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment.
  Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.
  [Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M. 2016. Environ Int. 92-93:657-79. ]
• Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin.
  Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.
  [Lee I, Eriksson P, et al. 2015. Toxicology. 335:1-10.]
• Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome.
  Organohalogens are persistent organic pollutants that have a wide range of chemical application. There is growing evidence that several of these chemical compounds interfere with human development in various ways. The aim of this review is to provide an update on the relationship between various persistent organic pollutants and childhood neurodevelopmental outcome from studies from the past 10 years. This review focuses on exposure to polychlorinated biphenyls (PCBs), hydroxylated PCBs (OH-PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyldichloroethylene (DDE), and in addition on exposure to phthalates, bisphenol A, and perfluorinated compounds and their associations with neurodevelopmental outcome in childhood, up to 18 years of age. This review shows that exposure to environmental chemicals affects neurodevelopmental outcome in children. Regarding exposure to PCBs and OH-PCBs, most studies report no or inverse associations with neurodevelopmental outcomes. Regarding exposure to PBDEs, lower mental development, psychomotor development and IQ were found at preschool age, and poorer attention at school age. Regarding exposure to DDE, most studies reported inverse associations with outcome, while others found no associations. Significant relations were particularly found at early infancy on psychomotor development, on attention and ADHD, whereas at school age, no adverse relationships were described. Additionally, several studies report gender-related vulnerability. Future research should focus on the long-term effects of prenatal and childhood exposure to these environmental chemicals, on sex-specific and combined exposure effects of environmental chemicals, and on possible mechanisms by which these chemicals have their effects on neurodevelopmental and behavioral outcomes.
  [Berghuis SA, Bos AF, Sauer PJ, Roze E. 2015. Arch Toxicol. 89(5):687-709]
• Pre- and postnatal exposures to pesticides and neurodevelopmental effects in children living in agricultural communities from South-Eastern Spain.
  Childrens exposure to neurotoxic compounds poses a major problem to public health because oftheir actively developing brain that makes them highly vulnerable. However, limited information is available on neuropsychological effects in children associated with pre- and postnatal exposures to pesticides.Study's aim was to evaluate the association between current and pre- and postnatal exposures to pesticides and their effects on neurodevelopment in children aged 6–11 years living in agricultural communities from South-Eastern Spain.An ambispective study was conducted on 305 children aged 6–11 years randomly selected from public schools of the study area. Current exposure to organophosphate pesticides was assessed measuring children's urinary levels of dialkylphosphates (DAPs). Both prenatal and postnatal residential exposure to pesticides was estimated by developing a geographical information system (GIS) technology-based index that integrated distance-weighted measure of agricultural surface, time-series of crop areas per municipality and year, and land-use maps. Neuropsychological performance was evaluated with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV).Greater urinary DAP levels were associated with a poorer performance on intelligence quotient and verbal comprehension domain, with effects being more prominent in boys than in girls. The influence of an increase in 10 ha per year in crop surface around the child's residence during the postnatal period was associated with decreased intelligence quotient, processing speed and verbal comprehension scores. As regards prenatal exposure to pesticides, a poor processing speed performance was observed. These effects were also more prominent in boys than in girls.Our results suggest that postnatal exposure to pesticides can negatively affect children's neuropsychological performance. Prenatal exposure was weakly associated to neurodevelopment impairment.
  [González-Alzaga B, Hernández AF, Rodríguez-Barranco M, et al. 2015. Environ Int. 85:229-37. ]
• Prenatal DDT and DDE exposure and child IQ in the CHAMACOS cohort.
  Although banned in most countries, dichlorodiphenyl-trichloroethane (DDT) continues to be used for vector control in some malaria endemic areas. Previous findings from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study found increased prenatal levels of DDT and its breakdown product dichlorodiphenyl-dichloroethylene (DDE) to be associated with altered neurodevelopment in children at 1 and 2years of age. In this study, we combined the measured maternal DDT/E concentrations during pregnancy obtained for the prospective birth cohort with predicted prenatal DDT and DDE levels estimated for a retrospective birth cohort. Using generalized estimating equation (GEE) and linear regression models, we evaluated the relationship of prenatal maternal DDT and DDE serum concentrations with children's cognition at ages 7 and 10.5years as assessed using the Full Scale Intelligence Quotient (IQ) and 4 subtest scores (Working Memory, Perceptual Reasoning, Verbal Comprehension, and Processing Speed) of the Wechsler Intelligence Scale for Children (WISC). In GEE analyses incorporating both age 7 and 10.5 scores (n=619), we found prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales (p-value>0.05). In linear regression analyses assessing each time point separately, prenatal DDT levels were inversely associated with Processing Speed at age 7years (n=316), but prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales at age 10.5years (n=595). We found evidence for effect modification by sex. In girls, but not boys, prenatal DDE levels were inversely associated with Full Scale IQ and Processing Speed at age 7years. We conclude that prenatal DDT levels may be associated with delayed Processing Speed in children at age 7years and the relationship between prenatal DDE levels and children's cognitive development may be modified by sex, with girls being more adversely affected.
  [Gaspar FW, Harley KG, Kogut K, Chevrier J, et al. 2015. Environ Int. 85:206-12]
• Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism
  Autism spectrum disorders are characterized by impaired social and communicative skills and repetitive behaviors. Emerging evidence supported the hypothesis that these neurodevelopmental disorders may result from a combination of genetic susceptibility and exposure to environmental toxins in early developmental phases. This study assessed the effects of prenatal exposure to chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioral traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behavior and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behavior patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (i.e., persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders.
  [De Felice A, Scattoni ML, Ricceri L, Calamandrei G. 2015. PLoS One. 10(3):e0121663]
• The neurotoxicity of organochlorine and pyrethroid pesticides
  Organochlorine and pyrethroid compounds represent an old and a new class, respectively, of insecticides. Organochlorines such as DDT, dieldrin, or chlordecone, have been banned, primarily because of environmental issues. DDT is still used in certain countries to fight malaria-bearing mosquitoes, while lindane still finds some limited used against head lice. In contrast, pyrethroids find widespread use because of their efficacy, low environmental persistence, and relatively low mammalian toxicity. Like all insecticides, organochlorines and pyrethroids target the nervous system of insects and of nontarget species. All pyrethroids and DDT interact with the sodium channel; by keeping it open longer, they increase the likelihood of action potentials developing, thus creating a condition of hyperexcitability, whose main clinical sign is tremors. Most other organochlorines (except chlordecone), as well as certain (type II) pyrethroids, block the chloride channels of the GABA-A receptor, and cause seizures. Evidence of an association between exposure to organochlorine and pyrethroid insecticides and neurodegenerative diseases (e.g., Parkinson's disease) is weak, at best.
  [Costa LG. 2015. Handb Clin Neurol. 131:135-48]
• Gestational/perinatal chlorpyrifos exposure is not associated with autistic-like behaviors in rodents
  Although animal models cannot exactly replicate human psychiatric disorders, they may be useful to investigate whether the behaviors associated with certain exposures in animals parallel those observed in people. According to the most current version of the Diagnostic and Statistical Manual of Mental Disorders, autism is diagnosed based on (1) persistent deficits in social communication and social interaction; and (2) the presence of restricted, repetitive patterns of behavior, interests and activities. To address whether developmental chlorpyrifos (CPF) exposure was associated with the development of autistic behaviors, a literature search was conducted to identify studies in rats and mice involving gestational or early postnatal exposure to CPF or CPF oxon (CPO, the active metabolite of CPF) and subsequent behavioral testing to assess behaviors related to autism. A total of 13 studies conducted in six different laboratories were identified. Analysis of these studies found that perinatal CPF exposure was generally associated with (1) no effect or increased social communications; (2) no effect or increased social encounters; (3) no effect, reduced stereotypies, or conflicting findings on stereotypic behaviors; and (4) no effect or increased preference for novelty and reduced anxiety in novel environments. These behavioral findings are generally inconsistent with the types of behaviors that would be expected in children with clinical autism. Based on the results of this analysis of rodent model studies involving CPF/CPO exposure, it cannot be concluded that gestational and/or perinatal CPF exposure is likely to be associated with the development of autism-like behaviors in humans.
  [Williams AL, DeSesso JM. 2014. Crit Rev Toxicol. 44(6):523-34]
• Environmental toxic and its effect on neurodevelopment
  Neurodevelopmental disorders are the result of a disturbance of brain function. They are frequent, with varied symptomatology, manifest themselves at different times of life and tend to be persistent with impact at the individual, family and social level. The association of these disorders with genetic entities is low. Although the research supports a mode of genetic inheritance, epigenetic factors and environmental factors can play an important role. In recent years there was a striking increase of these disorders especially attention deficit hyperactivity disorders and pervasive development disorder. Environmental factors such as the intoxication of the fetus by especially heavy metals lead and mercury are to blame in some children, of these disorders. Other substances of wide use, little degradation and maintenance in the food chain as pesticides, polychlorinated biphenyls and now the recycling of electronic waste put especially infants and children at risk, and even more so in the developing countries.
  [Arroyo HA, Fernández MC. 2013. Medicina (B Aires). 73 Suppl 1:93-102.]
• Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders
  Even though high doses of organic pollutants are toxic, relatively low concentrations have been reported to cause long-term alterations in functioning of individual organisms, populations and even next generations. Among these pollutants are dioxins, polychlorinated biphenyls, pesticides, brominated flame retardants, plasticizers (bisphenol A, nonylphenol, and phthalates) as well as personal care products and drugs. In addition to toxic effects, they are able to interfere with hormone receptors, hormone synthesis or hormone conversion. Because these chemicals alter hormone-dependent processes and disrupt functioning of the endocrine glands, they have been classified as endocrine-disrupting chemicals (EDCs). Because certain EDCs are able to alter neural transmission and the formation of neural networks, the term neural-disrupting chemicals has been introduced, thus implicating EDCs in the etiology of neurological disorders. Recently, public concern has been focused on the effects of EDCs on brain function, concomitantly with an increase in neuropsychiatric disorders, including autism, attention deficit and hyperactivity disorder as well as learning disabilities and aggressiveness. Several lines of evidence suggest that exposure to EDCs is associated with depression and could result in neural degeneration. EDCs act via several classes of receptors with the best documented mechanisms being reported for nuclear steroid and xenobiotic receptors. Low doses of EDCs have been postulated to cause incomplete methylation of specific gene regions in the young brain and to impair neural development and brain functions across generations. Efforts are needed to develop systematic epidemiological studies and to investigate the mechanisms of action of EDCs in order to fully understand their effects on wildlife and humans.
  [Kajta M, Wójtowicz AK. 2013. Pharmacol Rep. 65(6):1632-9.]
• Prenatal exposure to environmental contaminants and behavioural problems at age 7-8years
  Animal studies showed that the developing brain is particularly sensitive to chemical exposure. Human studies carried out in areas with high exposures have proven neurodevelopmental disorders in relation to e.g. lead and PCBs. Whether these chemicals are associated with behavioural problems in childhood at current environmental levels is not well known. Therefore, we assessed the association between prenatal exposure to lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE and behavioural problems in 7-8year old children. Prenatal exposure data were obtained from the Flemish mother-new-born cohort. Lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE were analysed in cord blood. When the child reached 7-8years, 270 mothers completed the Strengths and Difficulties Questionnaire assessing their children's behavioural health. We found that doubling the prenatal lead exposure (cord blood lead levels) was associated with a 3.43 times higher risk for hyperactivity in both boys and girls. In addition, total difficulties were 5.08 times more likely in the highest tertile for prenatal lead exposure compared to the lowest tertile. In girls, total difficulties were 4.92 more likely when doubling cord blood p,p'-DDE, whereas no significant association was found in boys. Further, we noted in boys a 1.53 times higher risk for emotional problems when doubling cord blood cadmium, whereas no significant association was found in girls. These results indicate that the presence of environmental contaminants influences the mental health of the next generation.
  [Sioen I, Den Hond E, Nelen V, Van de Mieroop E, et al. 2013. Environ Int. 59:225-31.]
• A Research Strategy to Discover the Environmental Causes of Autism and Neurodevelopmental Disabilities
  This editorial explores the ongoing research, both genetic and environmental studies,to identify the potentially preventable causes of neuro-develop-mental disorders (NDDs). Genetic research has demonstrated that austism spectrum disorder (ASD) and certain other NDDs have a strong hereditary component. Exploration of the environmental causes of autism and other NDDs has been catalyzed by growing recognition of the exquisite sensitivity of the developing human brain to toxic chemicals. This susceptibility is greatest during unique “windows of vulnerability” that open only in embryonic and fetal life and have no later counter-part. Additional prospective studies have linked loss of cognition (IQ), dyslexia, and ADHD to lead, methyl-mercury, organophosphate insecticides, organo-chlorine insecticides, polychlorinated biphenyls, arsenic and others.A major unanswered question is whether there are still undiscovered environ-mental causes of autism or other NDDs among the thousands of chemicals currently in wide use in the United States. The significance of early chemical exposures for children’s health is not yet fully understood. A great concern is that a large number of the chemicals in widest use have not undergone even minimal assessment of potential toxicity, and only about 20% have been screened for potential toxicity during early development. Unless studies specifically examine develop-mental consequences of early exposures to untested chemicals, sub-clinical dysfunction caused by these exposures can go unrecognized for years.
  [Landrigan P.J., Lambertini,L and Birnbaum, L.S. 2012. Environ Health Perspect. 120(7): a258-a260]
• Organophosphate pesticide levels in blood and urine of women and newborns living in an agricultural community
  Organophosphate pesticides are widely used and recent studies suggest associations of in utero exposures with adverse birth outcomes and neurodevelopment. Few studies have characterized organophosphate pesticides in human plasma or established how these levels correlate to urinary measurements. We measured organophosphate pesticide metabolites in maternal urine and chlorpyrifos and diazinon in maternal and cord plasma of subjects living in an agricultural area to compare levels in two different biological matrices. We also determined paraoxonase 1 (PON1) genotypes (PON1192 and PON1−108) and PON1 substrate-specific activities in mothers and their newborns to examine whether PON1 may affect organophosphate pesticide measurements in blood and urine.
  Chlorpyrifos levels in plasma ranged from 0–1726 ng/mL and non-zero levels were measured in 70.5% and 87.5% of maternal and cord samples, respectively. Diazinon levels were lower (0–0.5 ng/mL); non-zero levels were found in 33.3% of maternal plasma and 47.3% of cord plasma. Significant associations between organophosphate pesticide levels in blood and metabolite levels in urine were limited to models adjusting for PON1 levels. Increased maternal PON1 levels were associated with decreased odds of chlorpyrifos and diazinon detection (odds ratio(OR): 0.56 and 0.75, respectively). Blood organophosphate pesticide levels of study participants were similar in mothers and newborns and slightly higher than those reported in other populations. However, compared to their mothers, newborns have much lower quantities of the detoxifying PON1 enzyme suggesting that infants may be especially vulnerable to organophosphate pesticide exposures.
  [Huen, K. et al. (2012) Organophosphate pesticide levels in blood and urine of women and newborns living in an agricultural community, Environmental Research. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0013935112001740.]
• Neurotoxicity of pesticides: a brief review
  Pesticides are substances widely used to control unwanted pests such as insects, weeds, fungi and rodents. Most pesticides are not highly selective, and are also toxic to nontarget species, including humans. A number of pesticides can cause neurotoxicity. Insecticides, which kill insects by targeting their nervous system, have neurotoxic effect in mammals as well. This family of chemicals comprises the organophosphates, the carbamates, the pyrethroids, the organochlorines, and other compounds. Insecticides interfere with chemical neurotransmission or ion channels, and usually cause reversible neurotoxic effects, that could nevertheless be lethal. Some herbicides and fungicides have also been shown to possess neurotoxic properties. The effects of pesticides on the nervous system may be involved in their acute toxicity, as in case of most insecticides, or may contribute to chronic neurodegenerative disorders, most notably Parkinson's disease. This brief review highlights some of the main neurotoxic pesticides, their effects, and mechanisms of action.
  [Costa, L.G. et al. (2008) Neurotoxicity of pesticides: A brief review, Frontiers in Bioscience-Landmark. Available at: https://www.imrpress.com/journal/FBL/13/4/10.2741/2758. ]

• A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration
  Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stages, studies that comprehensively evaluate both males and females are limited. Therefore, in this study we utilized murine models to compare the sex-specific differences in behavioral effects following CLO exposure at different developmental stages. We orally administered CLO to male and female mice as a single high-dose solution (80 mg/kg) during the postnatal period (2-week-old), adolescence (6-week-old), or maturity (10-week-old), and subsequently evaluated higher brain function. The behavioral battery test consisted of open field, light/dark transition, and contextual/cued fear conditioning tests conducted at three and seven months of age. After the behavioral test, the brains were dissected and prepared for immunohistochemical staining. We observed behavioral abnormalities in anxiety, spatial memory, and cued memory only in female mice. Moreover, the immunohistochemical analysis showed a reduction in astrocytes within the hippocampus of female mice with behavioral abnormalities. The behavioral abnormalities observed in female CLO-treated mice were consistent with the typical behavioral abnormalities associated with hippocampal astrocyte dysfunction. It is therefore possible that the CLO-induced behavioral abnormalities are at least in part related to a reduction in astrocyte numbers. The results of this study highlight the differences in behavioral effects following CLO exposure between sexes and developmental stages.
  [Kaku, K. et al. (2024) A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration, The Journal of Toxicological Sciences. Available at: https://www.jstage.jst.go.jp/article/jts/49/7/49_301/_article. ]
• Embryotoxicity Induced by Triclopyr in Zebrafish (Danio rerio) Early Life Stage
  Triclopyr, an auxin-like herbicide that is widely employed for managing weeds in food crops and pastures, has been identified in various environmental settings, particularly aquatic ecosystems. Limited understanding of the environmental fate of this herbicide, its potential repercussions for both the environment and human health, and its insufficient monitoring in diverse environmental compartments has caused it to be recognized as an emerging contaminant of concern. In this study, we have investigated how triclopyr affects zebrafish, considering a new alternative methodology. We focused on the endpoints of developmental toxicity, neurotoxicity, and behavior of zebrafish embryos and larvae. We determined that triclopyr has a 96 h median lethal concentration of 87.46 mg/L (341.01 µM). When we exposed zebrafish embryos to sublethal triclopyr concentrations (0.5, 1, 5, 10, and 50 μM) for up to 144 h, we found that 50 µM triclopyr delayed zebrafish egg hatchability. Yolk sac malabsorption was significant at 0.5, 1, 5, and 10 µM triclopyr. In zebrafish larvae, uninflated swim bladder was significant only at 50 µM triclopyr. Furthermore, zebrafish larvae had altered swimming activity after exposure to 10 µM triclopyr for 144 h. In summary, these comprehensive results indicate that even low triclopyr concentrations can elicit adverse effects during early zebrafish development.
  [Bertoni, Í. et al. (2024) Embryotoxicity Induced by Triclopyr in Zebrafish (Danio rerio) Early Life Stage, Toxics. Available at: https://www.mdpi.com/2305-6304/12/4/255. ]
• Genotoxic and neurotoxic potential of intracellular nanoplastics: A review
  

  Abstract

  Plastic waste comprises polymers of different chemicals that disintegrate into nanoplastic particles (NPLs) of 1–100-nm size, thereby littering the environment and posing a threat to wildlife and human health. Research on NPL contamination has up to now focused on the ecotoxicology effects of the pollution rather than the health risks. This review aimed to speculate about the possible properties of carcinogenic and neurotoxic NPL as pollutants. Given their low-dimensional size and high surface size ratio, NPLs can easily penetrate biological membranes to cause functional and structural damage in cells. Once inside the cell, NPLs can interrupt the autophagy flux of cellular debris, alter proteostasis, provoke mitochondrial dysfunctions, and induce endoplasmic reticulum stress. Harmful metabolic and biological processes induced by NPLs include oxidative stress (OS), ROS generation, and pro-inflammatory reactions. Depending on the cell cycle status, NPLs may direct DNA damage, tumorigenesis, and lately carcinogenesis in tissues with high self-renewal capabilities like epithelia. In cells able to live the longest like neurons, NPLs could trigger neurodegeneration by promoting toxic proteinaceous aggregates, OS, and chronic inflammation. NPL genotoxicity and neurotoxicity are discussed based on the gathered evidence, when available, within the context of the intracellular uptake of these newcomer nanoparticles. In summary, this review explains how the risk evaluation of NPL pollution for human health may benefit from accurately monitoring NPL toxicokinetics and toxicodynamics at the intracellular resolution level.

  
  [Casella, C. and Ballaz, S.J. (2024) ‘Genotoxic and neurotoxic potential of intracellular nanoplastics: A Review’, Journal of Applied Toxicology [Preprint]. doi:10.1002/jat.4598. ]
• Neonicotinoid pesticides: evidence of developmental neurotoxicity from regulatory rodent studies
  Neonicotinoids are the most widely used class of insecticides in the United States (U.S.). and the world. Consistent with their high use and persistence, neonicotinoids are often found contaminating drinking water and food. They are also detected in human urine, breast milk, amniotic and cerebrospinal fluids, as well as the brains of treated rodents. Neonicotinoids were once thought to pose little neurotoxic risk to humans, but a growing body of research challenges that assumption. In this study we provide the first comprehensive assessment of unpublished rodent developmental neurotoxicity (DNT) studies on five neonicotinoids that were submitted to the U.S. Environmental Protection Agency (EPA) by neonicotinoid manufacturers. Groups of female rats were administered three different doses of a neonicotinoid during pregnancy and lactation, and their offspring subjected to various neurological tests and brain measurements. We identified nicotine-like effects such as reduced brain size, indicative of neuronal cell loss. Statistically significant shrinkage of brain tissue was observed in high-dose offspring for five neonicotinoids: acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam. Two brain regions reduced in the rodent studies–the corpus callosum and caudate-putamen–tend to be smaller in people diagnosed with attention-deficit hyperactivity disorder (ADHD), and in children of mothers who smoked during pregnancy, suggesting a possible link between perinatal neonicotinoid exposure and ADHD. A decreased auditory startle reflex was reported for acetamiprid at all doses and was statistically significant in the mid- and high-dose offspring, and for clothianidin in juvenile high-dose females. No mid- or low-dose brain morphometric data were submitted for acetamiprid, imidacloprid, or thiacloprid. Thiamethoxam mid- and low-dose brain morphometric data were provided to EPA upon request. Only partial mid-dose brain morphometry data were submitted for clothianidin, but no low-dose data. Yet despite this lack of data, EPA concluded that only the high-dose brain morphometric effects were treatment-related–setting the mid-dose as the study’s No Observed Adverse Effect Level (NOAEL) or failing to find a definitive NOAEL for acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam. We found numerous deficiencies in EPA’s regulatory oversight and data analyses. EPA dismissed statistically significant adverse effects, accepted substandard DNT studies despite lack of valid positive control data, and allowed neonicotinoid registrants to unduly influence agency decision-making. We conclude that perinatal exposure to neonicotinoids and their metabolites induces adverse, nicotine-like neurotoxic effects in rodent bioassays, and that the exposure limits set by EPA for human exposure are either not protective or not supported by available neurotoxicity data. We propose regulatory changes to empower EPA to better protect public health from developmental neurotoxins like neonicotinoids.
  [Sass, J.B., Donley, N. and Freese, W. (2024) Neonicotinoid pesticides: evidence of developmental neurotoxicity from regulatory rodent studies, Frontiers in Toxicology. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1438890/full. ]
• New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project
  In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.
  [Tal, T. et al. (2024) New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project, Frontiers in Toxicology. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1359507/full. ]
• Association between glyphosate exposure and cognitive function, depression, and neurological diseases in a representative sample of US adults: NHANES 2013–2014 analysis
  Glyphosate, the most widely used herbicide globally, has been linked to neurological impairments in some occupational studies. However, the potential neurotoxic effects of glyphosate exposure in the general population are still not fully understood. We conducted analyses on existing data collected from 1532 adults of the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the possible relationship between glyphosate exposure and cognitive function, depressive symptoms, disability, and neurological medical conditions. Our results showed a significant negative association between urinary glyphosate levels and the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD-WLT) trial 3 recall and delayed recall scores in both models, with ß coefficients of -0.288 (S.E. = 0.111, P = 0.021) and -0.426 (S.E. = 0.148, P = 0.011), respectively. Furthermore, the odds ratio did not show a significant increase with the severity of depressive symptoms with a one-unit increase in ln-glyphosate levels. However, the odds ratio for severe depressive symptoms was significantly higher than for no symptoms (odds ratio = 4.148 (95% CI = 1.009-17.133), P = 0.049). Notably, the odds ratio showed a significant increase for individuals with serious hearing difficulty (odds ratio = 1.354 (95% CI = 1.018-1.800), P = 0.039) with a one-unit increase in ln-glyphosate levels, but not for other neurological medical conditions. In conclusion, our findings provide the first evidence that glyphosate exposure may be associated with neurological health outcomes in the US adult population. Additional investigation is necessary to understand the potential mechanisms and clinical significance of these correlations.
  [Hsiao, C.C., Yang, A.M., Wang, C. and Lin, C.Y., 2023. NHANES 2013–2014 analysis. Environmental Research, p.116860.]
• Association of Prenatal Exposure to Organophosphate, Pyrethroid, and Neonicotinoid Insecticides with Child Neurodevelopment at 2 Years of Age: A Prospective Cohort Study.
  Widespread insecticide exposure might be a risk factor for neurodevelopment of our children, but few studies examined the mixture effect of maternal coexposure to organophosphate insecticides (OPPs), pyrethroids (PYRs), and neonicotinoid insecticides (NNIs) during pregnancy on child neurodevelopment, and critical windows of exposure are unknown. We aimed to evaluate the association of prenatal exposure to multiple insecticides with children's neurodevelopment and to identify critical windows of the exposure. Pregnant women were recruited into a prospective birth cohort study in Wuhan, China, from 2014-2017. Eight metabolites of OPPs (mOPPs), three metabolites of PYRs (mPYRs), and nine metabolites of NNIs (mNNIs) were measured in 3,123 urine samples collected at their first, second, and third trimesters. Children's neurodevelopment [mental development index (MDI) and psychomotor development index (PDI)] was assessed using the Bayley Scales of Infant Development at 2 years of age (N=1,041). Multivariate linear regression models, generalized estimating equation models, and weighted quantile sum (WQS) regression were used to estimate the association between the insecticide metabolites and Bayley scores. Potential sex-specific associations were also examined. Single chemical analysis suggested higher urinary concentrations of some insecticide metabolites at the first trimester were significantly associated with lower MDI and PDI scores, and the associations were more prominent among boys. Each 1-unit increase in ln-transformed urinary concentrations of two mOPPs, 3,5,6-trichloro-2-pyridinol and 4-nitrophenol, was associated with a decrease of 3.16 points [95% confidence interval (CI):−5.59,−0.74] and 3.06 points (95% CI:−5.45,−0.68) respectively in boys' MDI scores. Each 1-unit increase in that of trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (trans-DCCA; an mPYR) was significantly associated with a decrease of 2.24 points (95% CI:−3.89,−0.58) in boys' MDI scores and 1.90 points (95% CI:−3.16,−0.64) in boys' PDI scores, respectively. Significantly positive associations of maternal urinary biomarker concentrations [e.g., dimethyl phosphate (a nonspecific mOPP) and desmethyl-clothianidin (a relatively specific mNNI)] with child neurodevelopment were also observed. Using repeated holdout validation, a 1-quartile increase in the WQS index of the insecticide mixture (in the negative direction) at the first trimester was significantly associated with a decrease of 3.02 points (95% CI:−5.47,−0.57) in MDI scores among the boys, and trans-DCCA contributed the most to the association (18%). Prenatal exposure to higher levels of certain insecticides and their mixture were associated with lower Bayley scores in children, particularly in boys. Early pregnancy may be a sensitive window for such an effect. Future studies are needed to confirm our findings
  [Wang, A., Wan, Y., Mahai, G., Qian, X., Li, Y., Xu, S. and Xia, W., 2023. Environmental Health Perspectives, 131(10), p.107011.]
• Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.
  Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery–replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.
  [Curtis, M.A., Dhamsania, R.K., Branco, R.C., Guo, J.D., Creeden, J., Neifer, K.L., Black, C.A., Winokur, E.J., Andari, E., Dias, B.G. and Liu, R.C., 2023.PNAS nexus, 2(4), p.pgad085.]
• Disparities in Toxic Chemical Exposures and Associated Neurodevelopmental Outcomes: A Scoping Review and Systematic Evidence Map of the Epidemiological Literature.
  Children are routinely exposed to chemicals known or suspected of harming brain development. Targeting Environmental Neuro-Development Risks (Project TENDR), an alliance of more than 50>50 leading scientists, health professionals, and advocates, is working to protect children from these toxic chemicals and pollutants, especially the disproportionate exposures experienced by children from families with low incomes and families of color. This scoping review was initiated to map existing literature on disparities in neurodevelopmental outcomes for U.S. children from population groups who have been historically economically/socially marginalized and exposed to seven exemplar neurotoxicants: combustion-related air pollution (AP), lead (Pb), mercury (Hg), organophosphate pesticides (OPs), phthalates (Phth), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs). Systematic literature searches for the seven exemplar chemicals, informed by the Population, Exposure, Comparator, Outcome (PECO) framework, were conducted through 18 November 2022, using PubMed, CINAHL Plus (EBSCO), GreenFILE (EBSCO), and Web of Science sources. We examined these studies regarding authors’ conceptualization and operationalization of race, ethnicity, and other indicators of sociodemographic and socioeconomic disadvantage; whether studies presented data on exposure and outcome disparities and the patterns of those disparities; and the evidence of effect modification by or interaction with race and ethnicity. Two hundred twelve individual studies met the search criteria and were reviewed, resulting in 218 studies or investigations being included in this review. AP and Pb were the most commonly studied exposures. The most frequently identified neurodevelopmental outcomes were cognitive and behavioral/psychological. Approximately a third (74 studies) reported investigations of interactions or effect modification with 69% (51 of 74 studies) reporting the presence of interactions or effect modification. However, less than half of the studies presented data on disparities in the outcome or the exposure, and fewer conducted formal tests of heterogeneity. Ninety-two percent of the 165 articles that examined race and ethnicity did not provide an explanation of their constructs for these variables, creating an incomplete picture. As a whole, the studies we reviewed indicated a complex story about how racial and ethnic minority and low-income children may be disproportionately harmed by exposures to neurotoxicants, and this has implications for targeting interventions, policy change, and other necessary investments to eliminate these health disparities. We provide recommendations on improving environmental epidemiological studies on environmental health disparities. To achieve environmental justice and health equity, we recommend concomitant strategies to eradicate both neurotoxic chemical exposures and systems that perpetuate social inequities.
  [Payne-Sturges, D.C., Taiwo, T.K., Ellickson, K., Mullen, H., Tchangalova, N., Anderko, L., Chen, A. and Swanson, M., 2023. Environmental Health Perspectives, 131(9), p.096001.]
• Effects of pyrethroids on the cerebellum and related mechanisms: a narrative review
  Pyrethroids (PYRs) are a group of synthetic organic chemicals that mimic natural pyrethrins. Due to their low toxicity and persistence in mammals, they are widely used today. PYRs exhibit higher lipophilicity than other insecticides, which allows them to easily penetrate the blood-brain barrier and directly induce toxic effects on the central nervous system. Several studies have shown that the cerebellum appears to be one of the regions with the largest changes in biomarkers. The cerebellum, which is extremely responsive to PYRs, functions as a crucial region for storing motor learning memories. Exposure to low doses of various types of PYRs during rat development resulted in diverse long-term effects on motor activity and coordination functions. Reduced motor activity may result from developmental exposure to PYRs in rats, as indicated by delayed cerebellar morphogenesis and maturation. PYRs also caused adverse histopathological and biochemical changes in the cerebellum of mothers and their offspring. By some studies, PYRs may affect granule cells and Purkinje cells, causing damage to cerebellar structures. Destruction of cerebellar structures and morphological defects in Purkinje cells are known to be directly related to functional impairment of motor coordination. Although numerous data support that PYRs cause damage to cerebellar structures, function and development, the mechanisms are not completely understood and require further in-depth studies. This paper reviews the available evidence on the relationship between the use of PYRs and cerebellar damage and discusses the mechanisms of PYRs.
  [Hao, F., Bu, Y., Huang, S., Li, W., Feng, H. and Wang, Y., 2023. Critical Reviews in Toxicology, pp.1-15.]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Occupational exposure to pesticides and symptoms of depression in agricultural workers. A systematic review.
  The use of pesticides can result in harm to both the environment and human health. There is a growing concern in the field of occupational health about the impact on the mental health of agricultural workers. The objective of this review was to systematize scientific evidence from the last ten years on the impact of occupational exposure to pesticides on the development of depression symptoms in agricultural workers. We conducted a comprehensive search in the PubMed and Scopus databases from 2011 to September 2022. Our search included studies in English, Spanish, and Portuguese that examined the association between occupational exposure to pesticides and symptoms of depression in agricultural workers, following the guidelines recommended by the PRISMA statement and the PECO strategy (Population, Exposure, Comparison, and Outcomes). Among the 27 articles reviewed, 78% of them indicated a link between exposure to pesticides and the incidence of depression symptoms. The pesticides most frequently reported in the studies were organophosphates (17 studies), herbicides (12 studies), and pyrethroids (11 studies). The majority of the studies were rated as having intermediate to intermediate-high quality, with the use of standardized measures to assess both exposure and effect. The updated evidence presented in our review indicates a clear association between pesticide exposure and the development of depressive symptoms. However, more high-quality longitudinal studies are necessary to control for sociocultural variables and utilize pesticide-specific biomarkers and biomarkers of depression. Given the increased use of these chemicals and the health risks associated with depression, it is crucial to implement more stringent measures to monitor the mental health of agricultural workers regularly exposed to pesticides and to enhance surveillance of companies that apply these chemicals.
  [Cancino, J., Soto, K., Tapia, J., Muñoz-Quezada, M.T., Lucero, B., Contreras, C. and Moreno, J., 2023. Environmental Research, p.116190.]
• Occupational exposure to pesticides as a potential risk factor for epilepsy
  Epilepsy is a chronic neurological disorder in which brain activity becomes abnormal, causing seizures. In a previous study we found that environmental exposure to pesticides was associated with a greater risk of epilepsy. The present study examined possible occupational risk factors that may contribute to the occurrence of epilepsy in farmers and pesticide applicators (sprayers). A case-referent study was conducted on 19,704 individuals over a 17-year study period (2000–2016). Epilepsy cases (n = 5091) were collected from Hospital records and referents (non-epilepsy cases, n = 14.613) from the Centre for Prevention of Occupational Risks, both from Almería (South-Eastern Spain). A significant increased risk of having epilepsy was found in farmers working in intensive agriculture (high-yield greenhouse crops) compared to extensive agriculture (open-air crops). The risk was greater for farmers residing in rural areas with high pesticide use (intensive farming crops in plastic greenhouses) and for those not wearing protective gloves. As for sprayers, the greatest risk of epilepsy was observed in those not wearing face mask, and in those living in areas with high pesticide use (greenhouse intensive agriculture). Overall, this study supports previous findings on the association between epilepsy and pesticide exposure in the general population, and extends the risk to farmers occupationally exposed to pesticides, mainly those engaged in intensive agriculture.
  [Alarcón, R., Giménez, B., Hernández, A.F., López-Villén, A., Parrón, T., García-González, J. and Requena, M., 2023. Neurotoxicology, 96, pp.166-173.]
• Occupational Exposure to Pesticides as a Risk Factor for Sleep Disorders.
  Inadequate sleep has been linked to a variety of impairments in bodily functions, including endocrine, metabolic, higher cortical function, and neurological disorders. For this reason, the aim of this study was to analyze the link between occupational pesticide exposure and sleep health among farmers in Almeria. A cross-sectional study was conducted among a population living on the coast of Almeria (southeastern Spain), where about 33,321 hectares of land are used for intensive agriculture in plastic greenhouses. A total of 380 individuals participated in the study: 189 greenhouse workers and 191 control subjects. The participants were contacted during their annual scheduled occupational health survey. Data on sleep disturbances were collected using the Spanish version of the Oviedo Sleep Questionnaire. Agricultural workers were found to be at a significantly higher risk of insomnia, especially among those who did not wear protective gloves (OR = 3.12; 95% C.I. = 1.93–3.85; p = 0.04) or masks (OR = 2.43; 95% C.I. = 1.19–4.96; p = 0.01). The highest risk of insomnia related to pesticide applicators was observed in those who did not wear a mask (OR = 4.19; 95% C.I. = 1.30–13.50; p = 0.01) or goggles (OR = 4.61; 95% C.I. = 1.38–10.40; p = 0.01). This study supports previous findings indicating an increased risk of sleep disorder in agricultural workers exposed to pesticides at work.
  [Zheng, R., García-González, J., Romero-del Rey, R., López-Villén, A., García-Alvarez, R., Fadul-Calderon, R., Requena-Mullor, M. and Alarcón-Rodríguez, R., 2023. International Journal of Environmental Research and Public Health, 20(4), p.3149.]
• Paraquat and Parkinson’s Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis
  Parkinson’s disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways.
  [WZ, C.S., Naidu, R. and Tang, K.S., 2023. Current Neuropharmacology.]
• Pesticides at brain borders: Impact on the blood-brain barrier, neuroinflammation, and neurological risk trajectories
  Pesticides are omnipresent, and they pose significant environmental and health risks. Translational studies indicate that acute exposure to high pesticide levels is detrimental, and prolonged contact with low concentrations of pesticides, as single and cocktail, could represent a risk factor for multi-organ pathophysiology, including the brain. Within this research template, we focus on pesticides' impact on the blood-brain barrier (BBB) and neuroinflammation, physical and immunological borders for the homeostatic control of the central nervous system (CNS) neuronal networks. We examine the evidence supporting a link between pre- and postnatal pesticide exposure, neuroinflammatory responses, and time-depend vulnerability footprints in the brain. Because of the pathological influence of BBB damage and inflammation on neuronal transmission from early development, varying exposures to pesticides could represent a danger, perhaps accelerating adverse neurological trajectories during aging. Refining our understanding of how pesticides influence brain barriers and borders could enable the implementation of pesticide-specific regulatory measures directly relevant to environmental neuroethics, the exposome, and one-health frameworks.
  [Cresto, N., Forner-Piquer, I., Baig, A., Chatterjee, M., Perroy, J., Goracci, J. and Marchi, N., 2023. Chemosphere, p.138251.]
• Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse
  Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22–1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7–9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition.
  [Jenkins, A. et al. (2023) Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse, Toxicology Reports. Available at: https://www.sciencedirect.com/science/article/pii/S2214750023001099. ]
• Prenatal and childhood chlordecone exposure, cognitive abilities and problem behaviors in 7-year-old children: the TIMOUN mother-child cohort in Guadeloupe
  Background: Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys.

  Objective: To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe.

  Methods: We examined 576 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children's blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child's mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex.

  Results: Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children's blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls.

  Conclusions: These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.
  [Oulhote, Y., Rouget, F., Michineau, L., Monfort, C., Desrochers-Couture, M., Thomé, J.P., Kadhel, P., Multigner, L., Cordier, S. and Muckle, G., 2023. Environmental Health, 22(1), pp.1-13.]

• Prenatal exposure to pesticides and domain-specific neurodevelopment at age 12 and 18 months in Nanjing, China.
  The extensive usage of pesticides has led to a ubiquitous exposure in the Chinese general population. Previous studies have demonstrated developmental neurotoxicity associated with prenatal exposure to pesticides. We aimed to delineate the landscape of internal pesticides exposure levels from pregnant women’s blood serum samples, and to identify the specific pesticides associated with the domain-specific neuropsychological development. Participants included 710 mother-child pairs in a prospective cohort study initiated and maintained in Nanjing Maternity and Child Health Care Hospital. Maternal spot blood samples were collected at enrollment. Leveraging on an accurate, sensitive and reproducible analysis method for 88 pesticides, a total of 49 pesticides were measured simultaneously using gas chromatography-triple quadrupole tandem mass spectrometry (GC–MS/MS). After implementing a strict quality control (QC) management, 29 pesticides were reported. We assessed neuropsychological development in 12-month-old (n = 172) and 18-month-old (n = 138) children using the Ages and Stages Questionnaire (ASQ), Third Edition. Negative binomial regression models were used to investigate the associations between prenatal exposure to pesticides and ASQ domain-specific scores at age 12 and 18 months. Restricted cubic spline (RCS) analysis and generalized additive models (GAMs) were fitted to evaluate non-linear patterns. Longitudinal models with generalized estimating equations (GEE) were conducted to account for correlations among repeated observations. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were applied to examining the joint effect of the mixture of pesticides. Several sensitivity analyses were performed to assess the robustness of the results. We observed that prenatal exposure to chlorpyrifos was significantly associated with a 4 % decrease in the ASQ communication scores both at age 12 months (RR, 0.96; 95 % CI, 0.94–0.98; P < 0.001) and 18 months (RR, 0.96; 95 % CI, 0.93–0.99; P < 0.01). In the ASQ gross motor domain, higher concentrations of mirex (RR, 0.96; 95 % CI, 0.94–0.99, P < 0.01 for 12-month-old children; RR, 0.98; 95 % CI, 0.97–1.00, P = 0.01 for 18-month-old children), and atrazine (RR, 0.97; 95 % CI, 0.95–0.99, P < 0.01 for 12-month-old children; RR, 0.99; 95 % CI, 0.97–1.00, P = 0.03 for 18-month-old children) were associated with decreased scores. In the ASQ fine motor domain, higher concentrations of mirex (RR, 0.98; 95 % CI, 0.96–1.00, P = 0.04 for 12-month-old children; RR, 0.98; 95 % CI, 0.96–0.99, P < 0.01 for 18-month-old children), atrazine (RR, 0.97; 95 % CI, 0.95–0.99, P < 0.001 for 12-month-old children; RR, 0.98; 95 % CI, 0.97–1.00, P = 0.01 for 18-month-old children), and dimethipin (RR, 0.94; 95 % CI, 0.89–1.00, P = 0.04 for 12-month-old children; RR, 0.93; 95 % CI, 0.88–0.98, P < 0.01 for 18-month-old children) were associated with decreased scores. The associations were not modified by child sex. There was no evidence of statistically significant nonlinear relationships between pesticides exposure and RRs of delayed neurodevelopment (P nonlinearity > 0.05). Longitudinal analyses implicated the consistent findings. This study gave an integrated picture of pesticides exposure in Chinese pregnant women. We found significant inverse associations between prenatal exposure to chlorpyrifos, mirex, atrazine, dimethipin and the domain-specific neuropsychological development (i.e., communication, gross motor and fine motor) of children at 12 and 18 months of age. These findings identified specific pesticides with high risk of neurotoxicity, and highlighted the need for priority regulation of them.
  [Wei, H., Zhang, X., Yang, X., Yu, Q., Deng, S., Guan, Q., Chen, D., Zhang, M., Gao, B., Xu, S. and Xia, Y., 2023. Environment International, 173, p.107814.]
• The association of prenatal phthalates, organophosphorous pesticides, and organophosphate esters with early child language ability in Norway
  Prenatal exposure to phthalates, organophosphate esters, and organophosphorous pesticides have been associated with neurodevelopmental deficits including language ability, however, few studies consider the effect of exposure mixtures and the potential longitudinal detriments over time. This study examines the influence of prenatal exposure to phthalates, organophosphate esters, and organophosphorous pesticides, on children's language ability from toddlerhood to the preschool period. This study includes 299 mother-child dyads from Norway in the Norwegian Mother, Father and Child Cohort Study (MoBa). Prenatal exposure to chemicals were assessed at 17 weeks’ gestation, and child language skills were assessed at 18 months using the Ages and Stages Questionnaire communication subscale and at preschool age using the Child Development Inventory. We ran two structural equation models to examine the simultaneous influences of chemical exposures on parent-reported and teacher-reported child language ability. Prenatal organophosphorous pesticides were negatively associated with preschool language ability through language ability at 18 months. Additionally, there was a negative association between low molecular weight phthalates and teacher-reported preschool language ability. There was no effect of prenatal organophosphate esters on child language ability at either 18 months or preschool age. This study adds to the literature on prenatal exposure to chemicals and neurodevelopment and highlights the importance of developmental pathways in early childhood.
  [Ramos, A.M., Herring, A.H., Villanger, G.D., Thomsen, C., Sakhi, A.K., Cequier, E., Aase, H. and Engel, S.M., 2023. Environmental Research, 225, p.115508.]
• Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus
  Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.
  [Bernardino, P.N., Hobson, B.A., Huddleston, S.L., Andrew, P.M., MacMahon, J.A., Saito, N.H., Porter, V.A., Bruun, D.A., Harvey, D.J., Garbow, J.R. and Gelli, A., 2023. Neurobiology of Disease, 187, p.106316.]
• Urinary Glyphosate, 2,4-D and DEET Biomarkers in Relation to Neurobehavioral Performance in Ecuadorian Adolescents in the ESPINA Cohort
  

  Abstract

  Background:

  Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents.

  Methods:

  We assessed 519 participants (11–17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, β17β-estradiol, and testosterone was assessed using structural equation modeling.

  Results:

  The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0–2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration β(β)=−0.19 95% confidence interval (CI): −0.31, −0.07], language [ββ=−0.12 (95% CI: −0.23, −0.01)], and memory/learning [ββ=−0.11 (95% CI: −0.22, 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ββ=−0.08 (95% CI: −0.14, −0.01)]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed.

  Conclusion:

  This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383
  
  [Chronister, B.N.C. et al. (2023) ‘Urinary glyphosate, 2,4-D and DEET biomarkers in relation to neurobehavioral performance in Ecuadorian adolescents in the Espina cohort’, Environmental Health Perspectives, 131(10). doi:10.1289/ehp11383. ]
• Advances and future prospects of pyrethroids: Toxicity and microbial degradation
  Pyrethroids are a class of insecticides structurally similar to that of natural pyrethrins. The application of pyrethrins in agriculture and pest control lead to many kinds of environmental pollution affecting human health and loss of soil microbial population that affect soil fertility and health. Natural pyrethrins have been used since ancient times as insect repellers, and their synthetic versions especially type 2 pyrethroids could be highly toxic to humans. PBO (Piperonyl butoxide) is known to enhance the toxicity of prallethrin in humans due to the resistance in its metabolic degradation. Pyrethroids are also known to cause plasma biochemical profile changes in humans and they also lead to the production of high levels of reactive oxygen species. Further they are also known to increase SGPT activity in humans. Due to the toxicity of pyrethrins in water bodies, soils, and food products, there is an urgent need to develop sustainable approaches to reduce their levels in the respective fields, which are eco-friendly, economically viable, and socially acceptable for on-site remediation. Keeping this in view, an attempt has been made to analyse the advances and prospects in using pyrethrins and possible technologies to control their harmful effects. The pyrethroid types, composition and biochemistry of necessary pyrethroid insecticides have been discussed in detail, in the research paper, along with their effect on insects and humans. It also covers the impact of pyrethroids on different plants and soil microbial flora. The second part deals with the microbial degradation of the pyrethroids through different modes, i.e., bioaugmentation and biostimulation. Many microbes such as Acremonium, Aspergillus, Microsphaeropsis, Westerdykella, Pseudomonas, Staphylococcus have been used in the individual form for the degradation of pyrethroids, while some of them such as Bacillus are even used in the form of consortia.
  [Singh, S. et al. (2022) Advances and future prospects of pyrethroids: Toxicity and microbial degradation, Science of The Total Environment. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0048969722016540. ]
• Environmental Neurotoxic Pesticide Exposure Induces Gut Inflammation and Enteric Neuronal Degeneration by Impairing Enteric Glial Mitochondrial Function in Pesticide Models of Parkinson’s Disease: Potential Relevance to Gut-Brain Axis Inflammation in Parki
  Despite the growing recognition that gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD) and occurs as a major prodromal symptom of PD, its cellular and molecular mechanisms remain largely unknown. Among the various types of GI cells, enteric glial cells (EGCs), which resemble astrocytes in structure and function, play a critical role in the pathophysiology of many GI diseases including PD. Thus, we investigated how EGCs respond to the environmental pesticides rotenone (Rot) and tebufenpyrad (Tebu) in cell and animal models to better understand the mechanism underlying GI abnormalities. Both Rot and Tebu induce dopaminergic neuronal cell death through complex 1 inhibition of the mitochondrial respiratory chain. We report that exposing a rat enteric glial cell model (CRL-2690 cells) to these pesticides increased mitochondrial fission and reduced mitochondrial fusion by impairing MFN2 function. Furthermore, they also increased mitochondrial superoxide generation and impaired mitochondrial ATP levels and basal respiratory rate. Measurement of LC3, p62 and lysosomal assays revealed impaired autolysosomal function in ECGs during mitochondrial stress. Consistent with our recent findings that mitochondrial dysfunction augments inflammation in astrocytes and microglia, we found that neurotoxic pesticide exposure also enhanced the production of pro-inflammatory factors in EGCs in direct correlation with the loss in mitochondrial mass. Finally, we show that pesticide-induced mitochondrial defects functionally impaired smooth muscle velocity, acceleration, and total kinetic energy in a mixed primary culture of the enteric nervous system (ENS). Collectively, our studies demonstrate for the first time that exposure to environmental neurotoxic pesticides impairs mitochondrial bioenergetics and activates inflammatory pathways in EGCs, further augmenting mitochondrial dysfunction and pro-inflammatory events to induce gut dysfunction. Our findings have major implications in understanding the GI-related pathogenesis and progression of environmentally linked PD.
  [Palanisamy, B.N., Sarkar, S., Malovic, E., Samidurai, M., Charli, A., Zenitsky, G., Jin, H., Anantharam, V., Kanthasamy, A. and Kanthasamy, A. The International Journal of Biochemistry & Cell Biology, p.106225.]
• Evaluation of a gene–environment interaction of PON1 and low-level nerve agent exposure with Gulf War illness: a prevalence case–control study drawn from the US military health survey’s national population sample.
  Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias. We investigated a prestated hypothesis of the association of GWI with a gene–environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure. A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment. The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18; 95% CI: 0.81, 1.73; p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine. Given gene–environment independence and monotonicity, the unconfounded aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI.
  [Haley, R.W., Kramer, G., Xiao, J., Dever, J.A. and Teiber, J.F. Environmental health perspectives, 130(5), p.057001.]
• Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders
  Background
  Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer’s disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood–brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα.

  Methods
  Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC–MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aβ40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome.

  Results
  Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aβ40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development.

  Conclusions
  Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aβ, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.
  [Winstone, J.K. et al. (2022) Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFΑ: Implications for neurodegenerative disorders, Journal of Neuroinflammation. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331154/. ]

• Insecticidal Activity, Toxicity, Resistance and Metabolism of Pyrethroids: a Review
  Pyrethroids are synthetic or man-made versions of natural pyrethrins discovered in the flowers of a plant species of the Compositae family called "Chrysanthemum cinerariaefolium". The plant was transported into Europe and America after it was discovered in the Near East. Commercial insecticides such as pyrethrin and synthetic pyrethroid are available. These are used to control agricultural pests as well as non-agricultural insects. They are also commercially used in personal care items such as shampoo and as a scent in insect repellent to boost efficacy and persistence in the environment, these insecticides are frequently combined with additional chemicals in diverse formulations, known as synergists. Nerve toxins, known as pyrethroids, although their chemical mechanism of action is unknown. Pyrethroids are neurotoxins, which interfere with the messages sent along nerves by maintaining sodium and chloride channels in an open position. This review presents perspectives, commercial uses and other useful characteristics features of pyrethroids based on human benefits and environmental friendly...
  [Singh, A. ., Singh, A. ., Singh, P. ., Chakravarty, A. ., Singh , A., Singh, P. ., Mishra, M. K. ., Singh, . V. ., Srivastava, A. K. ., Aggarwal, H. ., & Sagadevan, S. (2022). Insecticidal Activity, Toxicity, Resistance and Metabolism of Pyrethroids: a Review. Science and Technology Indonesia, 7(2), 238–250. https://doi.org/10.26554/sti.2022.7.2.238-250]
• Roundup and glyphosate’s impact on GABA to elicit extended proconvulsant behavior in Caenorhabditis elegans
  As 3 billion pounds of herbicides are sprayed over farmlands every year, it is essential to advance our understanding how pesticides may influence neurological health and physiology of both humans and other animals. Studies are often one-dimensional as the majority examine glyphosate by itself. Farmers and the public use commercial products, like Roundup, containing a myriad of chemicals in addition to glyphosate. Currently, there are no neurological targets proposed for glyphosate and little comparison to Roundup. To investigate this, we compared how glyphosate and Roundup affect convulsant behavior in C. elegans and found that glyphosate and Roundup increased seizure-like behavior. Key to our initial hypothesis, we found that treatment with an antiepileptic drug rescued the prolonged convulsions. We also discovered over a third of nematodes exposed to Roundup did not recover from their convulsions, but drug treatment resulted in full recovery. Notably, these effects were found at concentrations that are 1,000-fold dilutions of previous findings of neurotoxicity, using over 300-fold less herbicide than the lowest concentration recommended for consumer use. Exploring mechanisms behind our observations, we found significant evidence that glyphosate targets GABA-A receptors. Pharmacological experiments which paired subeffective dosages of glyphosate and a GABA-A antagonist yielded a 24% increase in non-recovery compared to the antagonist alone. GABA mutant strain experiments showed no effect in a GABA-A depleted strain, but a significant, increased effect in a glutamic acid decarboxylase depleted strain. Our findings characterize glyphosate’s exacerbation of convulsions and propose the GABA-A receptor as a neurological target for the observed physiological changes. It also highlights glyphosate’s potential to dysregulate inhibitory neurological circuits.
  [Naraine, A.S., Aker, R., Sweeney, I., Kalvey, M., Surtel, A., Shanbhag, V. and Dawson-Scully, K. Scientific Reports, 12(1), pp.1-11.]
• Sex-specific behavioral effects of acute exposure to the neonicotinoid clothianidin in mice
  Although neonicotinoids are among the major classes of pesticides that affect mammalian nervous systems, little is known about sex differences in their effects. This study aimed to examine whether the neurobehavioral effects of a neonicotinoid, clothianidin (CLO), differed between sexes. Male and female C57BL/6N mice were orally administered CLO (5 or 50 mg/kg) at or below the chronic no-observed-adverse-effect-level (NOAEL) and subjected to behavioral tests of emotional and learning functions. Changes in neuroactivity in several brain regions and the concentrations of CLO and its metabolites in blood and urine were measured. Acute CLO exposure caused sex-related behavioral effects; decreases in locomotor activities and elevation of anxiety-like behaviors were more apparent in males than in females. In addition, male-specific impairment of short- and long-term learning memory by CLO exposure was observed in both the novel recognition test and the Barnes maze test. Male-dominant increases in the number of c-fos positive cells were observed in the paraventricular thalamic nucleus in the thalamus and in the dentate gyrus in the hippocampus, which are related to the stress response and learning function, respectively. The concentrations of CLO and most metabolites in blood and urine were higher in males. These results support the notion that male mice are more vulnerable than females to the neurobehavioral effects of CLO and provide novel insights into the risk assessment of neonicotinoids in mammalian neuronal function.
  [Kubo, S. et al. (2022) Sex-specific behavioral effects of acute exposure to the neonicotinoid clothianidin in mice, Toxicology and Applied Pharmacology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0041008X22004288?via%3Dihub. ]
• Atrazine Inhalation Worsen Pulmonary Fibrosis Regulating the Nuclear Factor Erythroid 2-Related Factor (Nrf2) Pathways Inducing Brain Comorbidities
  Pulmonary fibrosis can be caused by genetic abnormalities, autoimmune disorders or exposure to environmental pollutants. All these causes have in common the excessive production of oxidative stress species that initiate a cascade of molecular mechanism underlying fibrosis in a variety of organs, including lungs. The chemical name of Atrazine (ATR) is 6-chloro-N-ethyl-N′-(1-methylethyl)-1,3,5-triazine-2,4-diamine, and it is the most commonly used broad-spectrum herbicide in agricultural crops. Additionally, Bleomycin is a chemotherapeutic agent often used for different lymphoma with a seriously pulmonary complication. The most accredited hypothesis that may explain the mechanism of toxicity induced by ATR or bleomycin is exactly the production of reactive oxygen species (ROS) that leads to an unbalance in the physiological anti-oxidant system. However, until today, nobody has investigated the effect of ATR exposure during pulmonary fibrosis. Methods: Mice were subject to ATR exposure, to bleomycin injection or to both. At the end of experiment, the lungs and blood were collected. Additionally, we analyzed by different test such as open field, pole and rotarod test or other we investigated the effects of ATR or bleomycin exposure on behavior. Results: Following ATR or bleomycin induction, we found a significant increase in lung damage, fibrosis, and oxidative stress. This condition was significantly worsened when the animals injected with bleomycin were also exposed to ATR. Additionally, we observed significant motor and non-motor impairment in animals exposed to ATR. Conclusion: Our study demonstrates that ATR exposure, decrease nuclear factor-erythroid 2-related factor (Nrf2) pathways in both lung and brain.
  [D’Amico, R., Monaco, F., Fusco, R., Siracusa, R., Impellizzeri, D., Peritore, A.F., Crupi, R., Gugliandolo, E., Cuzzocrea, S., Di Paola, R. and Genovese, T. Cell. Physiol. Biochem, 55, pp.704-725.]
• Atrazine Inhalation Worsen Pulmonary Fibrosis Regulating the Nuclear Factor-Erythroid 2-Related Factor (Nrf2) Pathways Inducing Brain Comorbidities
  Pulmonary fibrosis can be caused by genetic abnormalities, autoimmune disorders or exposure to environmental pollutants. All these causes have in common the excessive production of oxidative stress species that initiate a cascade of molecular mechanism underlying fibrosis in a variety of organs, including lungs. The chemical name of Atrazine (ATR) is 6-chloro-N-ethyl-N′-(1-methylethyl)-1,3,5-triazine-2,4-diamine, and it is the most commonly used broad-spectrum herbicide in agricultural crops. Additionally, Bleomycin is a chemotherapeutic agent often used for different lymphoma with a seriously pulmonary complication. The most accredited hypothesis that may explain the mechanism of toxicity induced by ATR or bleomycin is exactly the production of reactive oxygen species (ROS) that leads to an unbalance in the physiological anti-oxidant system. However, until today, nobody has investigated the effect of ATR exposure during pulmonary fibrosis. Mice were subject to ATR exposure, to bleomycin injection or to both. At the end of experiment, the lungs and blood were collected. Additionally, we analyzed by different test such as open field, pole and rotarod test or other we investigated the effects of ATR or bleomycin exposure on behavior. Following ATR or bleomycin induction, we found a significant increase in lung damage, fibrosis, and oxidative stress. This condition was significantly worsened when the animals injected with bleomycin were also exposed to ATR. Additionally, we observed significant motor and non-motor impairment in animals exposed to ATR. Our study demonstrates that ATR exposure, decrease nuclear factor-erythroid 2-related factor (Nrf2) pathways in both lung and brain.  
  [D'Amico, R., Monaco, F., Fusco, R., Siracusa, R., Impellizzeri, D., Peritore, A.F., Crupi, R., Gugliandolo, E., Cuzzocrea, S., Di Paola, R. and Genovese, T. Cell Physiol Biochem, 55, pp.704-725.]
• Endocrine disruptors also function as nervous disruptors and can be renamed endocrine and nervous disruptors (ENDs)
  Endocrine disruption (ED) and endocrine disruptors (EDs) emerged as scientific concepts in 1995, after numerous chemical pollutants were found to be responsible for reproductive dysfunction. The World Health Organization established in the United Nations Environment Programme a list of materials, plasticizers, pesticides, and various pollutants synthesized from petrochemistry that impact not only reproduction, but also hormonal functions, directly or indirectly. Cells communicate via either chemical or electrical signals transmitted within the endocrine or nervous systems. To investigate whether hormone disruptors may also interfere directly or indirectly with the development or functioning of the nervous system through either a neuroendocrine or a more general mechanism, we examined the scientific literature to ascertain the effects of EDs on the nervous system, specifically in the categories of neurotoxicity, cognition, and behaviour. To date, we demonstrated that all of the 177 EDs identified internationally by WHO are known to have an impact on the nervous system. Furthermore, the precise mechanisms underlying this neurodisruption have also been established. It was previously believed that EDs primarily function via the thyroid. However, this study presents substantial evidence that approximately 80 % of EDs operate via other mechanisms. It thus outlines a novel concept: EDs are also neurodisruptors (NDs) and can be collectively termed endocrine and nervous disruptors (ENDs). Most of ENDs are derived from petroleum residues, and their various mechanisms of action are similar to those of “spam” in electronic communications technologies. Therefore, ENDs can be considered as an instance of spam in a biological context.
  [Seralini, G.E. and Jungers, G. Toxicology Reports, 8, pp.1538-1557.]
• Household pesticide exposures and infant gross motor development in the MADRES cohort
  The development of motor skills in infancy is a vital neurodevelopmental milestone. Although previous studies have explored the neurotoxic effects of agricultural pesticides on infants’ motor development, limited research has examined early postnatal household pesticide use on infants’ motor development, particularly among urban communities. This study examined the association between early postnatal household pesticide use and infants’ gross and fine motor development at 6 months of age. Questionnaires were administered via telephone to 296 mother–infant dyads in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort. Early life household pesticide use was assessed via questionnaire administered when infants turned 3 months old and gross and fine motor development was assessed by the Ages and Stages Questionnaire (ASQ-3) at 6 months old. Infant gross motor scores were reverse coded so that higher scores indicated lower gross motor performance. Negative binomial regressions were performed to assess the relationship between household pesticide use and infant gross motor development. Infants were predominantly Hispanic (78.7%) and full term (gestational age at birth: 39.0 ± 1.9 weeks), with 22.3% of maternal participants reporting household use of rodent and insect pesticides. Adjusting for recruitment site, maternal age, ethnicity, household income, education, infant corrected age, infant sex, and home type, infants with maternal-reported household use of rodent and insect pesticides had 1.30 times higher expected gross motor scores (95% confiidence interval 1.05, 1.61) than infants with no reported use of household pesticides, with higher scores indicating reduced gross motor performance. Our results suggest household use of rodent and insect pesticides may harm infants’ gross motor development in early childhood. Future research should evaluate the impact of specific household chemicals in infant biospecimens and their associations with infant motor development to confirm these findings.
  [Hernandez‐Castro, I., Eckel, S.P., Chavez, T., Johnson, M., Lerner, D., Grubbs, B., Toledo‐Corral, C.M., Farzan, S.F., Habre, R., Dunton, G.F. and Breton, C.V. Paediatric and perinatal epidemiology.]
• Mechanisms of organophosphate neurotoxicity
  The canonical mechanism of organophosphate (OP) neurotoxicity is the inhibition of acetylcholinesterase (AChE). However, multiple lines of evidence suggest that mechanisms in addition to or other than AChE inhibition contribute to the neurotoxic effects associated with acute and chronic OP exposures. Characterizing the role(s) of AChE inhibition versus noncholinergic mechanisms in OP neurotoxicity remains an active area of research with significant diagnostic and therapeutic implications. Here, we review recently published studies that provide mechanistic insights regarding (1) OP-induced status epilepticus, (2) long-term neurologic consequences of acute OP exposures, and (3) neurotoxic effects associated with repeated low-level OP exposures. Key data gaps and challenges are also discussed.
  [Tsai, Y.-H. and Lein, P.J. (2021) Mechanisms of organophosphate neurotoxicity, Current opinion in toxicology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302047/. ]
• Pre-differentiation exposure to low-dose of atrazine results in persistent phenotypic changes in human neuronal cell lines
  Exposures to organic pesticides, particularly during a developmental window, have been associated with various neurodegenerative diseases later in life. Atrazine (ATZ), one of the most used pesticides in the U.S., is suspected to be associated with increased neurodegeneration later in life but few studies assessed the neurotoxicity of developmental ATZ exposure using human neuronal cells. Here, we exposed human SH-SY5Y cells to 0.3, 3, and 30 ppb of ATZ prior to differentiating them into dopaminergic-like neurons in ATZ-free medium to mimic developmental exposure. The differentiated neurons exhibit altered neurite outgrowth and SNCA pathology depending on the ATZ treatment doses. Epigenome changes, such as decreases in 5mC (for 0.3 ppb only), H3K9me3, and H3K27me3 were observed immediately after exposure. These alterations persist in a compensatory manner in differentiated neurons. Specifically, we observed significant reductions in 5mC and H3K9me3, as well as, an increase in H3K27me3 in ATZ-exposed cells after differentiation, suggesting substantial chromatin rearrangements after developmental ATZ exposure. Transcriptional changes of relevant epigenetic enzymes were also quantified but found to only partially explain the observed epigenome alteration. Our results thus collectively suggest that exposure to low-dose of ATZ prior to differentiation can result in long-lasting changes in epigenome and increase risks of SNCA-related Parkinson's Disease.
  [Xie, J., Lin, L., Sánchez, O.F., Bryan, C., Freeman, J.L. and Yuan, C., 2021. Environmental Pollution, 271, p.116379.]
• The pyriproxyfen metabolite, 4′–OH–PPF, disrupts thyroid hormone signaling in neural stem cells, modifying neurodevelopmental genes affected by ZIKA virus infection
  North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by the Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. Thyroid hormone (TH) represses MSI1. PPF is a suspected TH disruptor. We hypothesized that co-exposure to the main metabolite of PPF, 4′–OH–PPF, could exacerbate ZIKV effects through increased MSI1 expression. Exposing an in vivo reporter model, Xenopus laevis, to 4′–OH–PPF decreased TH signaling and increased msi1 mRNA and protein, confirming TH-antagonistic properties. Next, we investigated the metabolite's effects on mouse subventricular zone-derived neural stem cells (NSCs). Exposure to 4′–OH–PPF dose-dependently reduced neuroprogenitor proliferation and dysregulated genes implicated in neurogliogenesis. The highest dose induced Msi1 mRNA and protein, increasing cell apoptosis and the ratio of neurons to glial cells. Given these effects of the metabolite alone, we considered if combined infection with ZIKV worsened neurogenic events. Only at the fourth and last day of incubation did co-exposure of 4′–OH–PPF and ZIKV decrease viral replication, but viral RNA copies stayed within the same order of magnitude. Intracellular RNA content of NSCs was decreased in the combined presence of 4′–OH–PPF and ZIKV, suggesting a synergistic block of transcriptional machinery. Seven out of 12 tested key genes in TH signaling and neuroglial commitment were dysregulated by co-exposure, of which four were unaltered when exposed to 4′–OH–PPF alone. We conclude that 4′–OH–PPF is an active TH-antagonist, altering NSC processes known to underlie correct cortical development. A combination of the TH-disrupting metabolite and ZIKV could aggravate the microcephaly phenotype.
  [Vancamp, P., Spirhanzlova, P., Sébillot, A., Butruille, L., Gothié, J.D., Le Mével, S., Leemans, M., Wejaphikul, K., Meima, M., Mughal, B.B. and Roques, P. Environmental Pollution, 285, p.117654.]
• Toxicant-induced loss of tolerance for chemicals, foods, and drugs: assessing patterns of exposure behind a global phenomenon
  Despite 15–36% of the U.S. population reporting Chemical Intolerances (CI) or sensitivity, the condition has been overlooked in medicine and public health. CI is characterized by multisystem symptoms and new-onset intolerances that develop in a subset of individuals following a major chemical exposure event or repeated low-level exposures. While Toxicant-Induced Loss of Tolerance (TILT) is a two-stage disease mechanism proposed to explain CI, less is known about the exposures that initiate the disease, than about the intolerances that have been documented. We reviewed eight major exposure events that preceded onset of chemical intolerance in groups of individuals sharing the same exposure. Our goal was to identify the chemicals and/or groups of chemicals that were most pervasive during each exposure event as well as identify the concentrations of key chemicals involved in each exposure event and the proportions of exposed individuals who ultimately developed TILT following exposure. Case studies we selected for review included (1) workers at U.S. Environmental Protection Agency (EPA) headquarters during renovations; (2) Gulf War veterans; (3) pesticide exposure among casino workers; (4) exposure to aircraft oil fumes; (5) the World Trade Center tragedy; (6) surgical implants; (7) moldy environments; and (8) tunnel workers exposed to solvents. Mixed volatile and semi-volatile organic compounds (VOCs and SVOCs), followed by pesticides and combustion products were most prevalent across TILT initiation events. As a broader category, synthetic organic chemicals and their combustion products were the primary exposures associated with chemical intolerance. Such chemicals included pesticides, peroxides, nerve agents, anti-nerve agent drugs, lubricants and additives, xylene, benzene, and acetone. A select group of exposures were predominant in several major initiating events, suggesting their potential role in TILT initiation. Such insights are useful to public health scientists, physicians, and policymakers seeking to minimize harmful exposures and prevent future disease.
  [Masri, S., Miller, C.S., Palmer, R.F. and Ashford, N. Environmental Sciences Europe, 33(1), pp.1-19.]
• Glyphosate exposure exacerbates the dopaminergic neurotoxicity in the mouse brain after repeated administration of MPTP
  Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. Epidemiological studies suggest that the exposure of the herbicide glyphosate may influence the development of PD in humans. In this study, we examined whether the exposure of glyphosate can affect the reduction of dopamine transporter (DAT) in the striatum and tyrosine hydroxylase (TH) in the substantial nigra (SNr) of mouse brain after repeated administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Repeated injections of MPTP (10 mg/kg × 3, 2-h interval) significantly decreased the density of DAT-immunoreactivity in the striatum and the number of TH-immunoreactivity in the SNr. Glyphosate exposure for 14 days significantly potentiated MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of mouse brain. This study suggests that glyphosate exposure might exacerbate MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of adult mice. It is likely that exposure of glyphosate may be an environmental risk factor for PD since glyphosate has been used widely in the world.
  [Pu, Y., Chang, L., Qu, Y., Wang, S., Tan, Y., Wang, X., Zhang, J. and Hashimoto, K., 2020. Neuroscience Letters, p.135032.]
• The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity
  Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp®, has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as “probably carcinogenic” in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries’ authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.
  [Peillex, C. and Pelletier, M. (2020) The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity, Journal of Immunotoxicology. Available at: https://www.tandfonline.com/doi/full/10.1080/1547691X.2020.1804492.]
• Pollution and children's health
  Findings
  The Lancet Commission on Pollution and Health found that pollution – air, water, soil, and chemical pollution - was responsible in 2016 for 940,000 deaths in children worldwide, two-thirds of them in children under the age of 5. Pollution is inequitably distributed, and the overwhelming majority of pollution-related deaths in children occurred in low- and middle-income countries (LMICs). Most were due to respiratory and gastrointestinal diseases caused by polluted air and water.

  Pollution is linked also to multiple non-communicable diseases (NCDs) in children including low birth weight, asthma, cancer and neurodevelopmental disorders, and these diseases are on the rise. The full impact of pollution, especially chemical pollution on the global burden of pediatric disease is not yet known, but almost certainly is undercounted because patterns of chemical exposure are not well charted and the potential toxicity of many chemical pollutants has not been characterized. The list of pediatric NCDs attributed to pollution will likely expand as the health effects of newer chemical pollutants are better defined and additional associations between pollution and disease are discovered.

  Conclusion
  Pollution prevention presents a major, largely unexploited opportunity to improve children's health and prevent NCDs, especially in LMICs. Failure to incorporate pollution prevention into NCD control programs is a major missed opportunity for disease prevention.
  [Landrigan, P. et al. (2019) ‘Pollution and children’s health’, Science of The Total Environment, 650, pp. 2389–2394. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0048969718338543?via%3Dihub. ]

• Neurochemical and Behavioral Dysfunctions in Pesticide Exposed Farm Workers: A Clinical Outcome
  The problem of pesticides is not new and its exposure to human due to indiscriminate use is largely associated with the health related problems including neurotoxicological alterations. High levels of pesticide residues and their metabolites in the dietary constituents, food materials, maternal blood, cord blood, placenta breast milk have been reported and linked to alterations in birth weight, crown heel length, head circumference, mid-arm circumference and ponderal index of the neonates. Epidemiological studies have suggested that exposure of pesticide to human could be a significant risk factor for neurological disorders, including Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. Cholinergic and non-cholinergic dysfunctions in pesticide exposed population, especially in children have also been frequently reported in recent years. Developmental neurotoxicity is another concern in the area where pregnant are more prone towards its exposure and which results in the abnormalities in the fetus. In view of the increasing risk of human health through pesticide exposure, the present review has been focused on the studies pertaining to pesticide induced neurochemical alterations and associated behavioral abnormalities in farm workers which could establish a possible link between the its exposure and associated health hazards.
  [Kori, R.K., Singh, M.K., Jain, A.K. and Yadav, R.S., 2018. Indian Journal of Clinical Biochemistry, 33, pp.372-381.]
• The Organophosphorus Pesticide Chlorpyrifos Induces Sex-Specific Airway Hyperreactivity in Adult Rats.
  Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. While the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans. Additionally, sex differences in asthma incidence have been demonstrated in the human population, but whether OP-induced AHR is sex-dependent has not been systematically studied in a preclinical model. In this study, eight-week old male and female Sprague Dawley rats were administered CPF at doses causing comparable AChE inhibition in whole lung homogenate (30 mg/kg in males, 7 mg/kg in females, sc) prior to assessing pulmonary mechanics in response to electrical stimulation of the vagus nerves at 24 h, 48 h, 72 h, 7 d or 14 d post-exposure in males, and 24 h or 7 d post-exposure in females. CPF significantly potentiated vagally-induced airway resistance and tissue elastance at 7 d post-exposure in males, and at 24 h and 7 d post-exposure in females. These effects occurred independent of significant AChE inhibition in cerebellum, blood, trachealis, or isolated airway, suggesting that AChE-independent OP-induced airway hyperreactivity is a cross-species phenomenon. These findings have significant implications for assessing the risk posed by CPF, and potentially other OPs, to human health and safety.
  [Shaffo FC, Grodzki AC, Schelegle ES, Lein PJ. 2018. Toxicol Sci. doi: 10.1093/toxsci/kfy158.]
• Association between Pesticide Profiles Used on Agricultural Fields near Maternal Residences during Pregnancy and IQ at Age 7 Years.
  We previously showed that potential prenatal exposure to agricultural pesticides was associated with adverse neurodevelopmental outcomes in children, yet the effects of joint exposure to multiple pesticides is poorly understood. In this paper, we investigate associations between the joint distribution of agricultural use patterns of multiple pesticides (denoted as "pesticide profiles") applied near maternal residences during pregnancy and Full-Scale Intelligence Quotient (FSIQ) at 7 years of age. Among a cohort of children residing in California's Salinas Valley, we used Pesticide Use Report (PUR) data to characterize potential exposure from use within 1 km of maternal residences during pregnancy for 15 potentially neurotoxic pesticides from five different chemical classes. We used Bayesian profile regression (BPR) to examine associations between clustered pesticide profiles and deficits in childhood FSIQ. BPR identified eight distinct clusters of prenatal pesticide profiles. Two of the pesticide profile clusters exhibited some of the highest cumulative pesticide use levels and were associated with deficits in adjusted FSIQ of -6.9 (95% credible interval: -11.3, -2.2) and -6.4 (95% credible interval: -13.1, 0.49), respectively, when compared with the pesticide profile cluster that showed the lowest level of pesticides use. Although maternal residence during pregnancy near high agricultural use of multiple neurotoxic pesticides was associated with FSIQ deficit, the magnitude of the associations showed potential for sub-additive effects. Epidemiologic analysis of pesticides and their potential health effects can benefit from a multi-pollutant approach to analysis.
  [Coker E, Gunier R, Bradman A, et al. 2017. Int J Environ Res Public Health. 14(5). pii: E506.]
• Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort.
  The potential impact of environmental exposure to pyrethroid insecticides on child neurodevelopment has only just started to receive attention despite their widespread use. We investigated the associations between prenatal and childhood exposure to pyrethroid insecticides and behavioural skills in 6-year-olds.The PELAGIE cohort enrolled 3421 pregnant women from Brittany, France between 2002 and 2006. 428 mothers were randomly selected for the study when their children turned 6, and 287 (67%) agreed to participate. Children's behaviour was assessed using the Strengths and Difficulties Questionnaire (SDQ). Three subscales (prosocial behaviour, internalising disorders and externalising disorders) were considered. Five pyrethroid metabolites were measured in maternal and child urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Increased prenatal cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA) concentrations were associated with internalising difficulties (Cox p value=0.05). For childhood 3-phenoxybenzoic acid (PBA) concentrations, a positive association was observed with externalising difficulties (Cox p value=0.04) and high ORs were found for abnormal or borderline social behaviour (OR 2.93, 95% CI 1.27 to 6.78, and OR 1.91, 95% CI 0.80 to 4.57, for the intermediate and highest metabolite categories, respectively). High childhood trans-DCCA concentrations were associated with reduced externalising disorders (Cox p value=0.03).The present study suggests that exposure to certain pyrethroids, at environmental levels, may negatively affect neurobehavioral development by 6 years of age.
  [Viel JF, Rouget F, Warembourg C, Monfort C, et al. 2017. Occup Environ Med. 74(4):275-281.]
• Bifenthrin-induced neurotoxicity in rats: involvement of oxidative stress.
  Extensive use of synthetic pyrethroids has resulted in serious human health issues. Induction of oxidative stress is an important mechanism of action of most pesticides including pyrethroids. In the present study, we have elucidated the possible role of oxidative stress in bifenthrin-induced neurotoxicity. Adult male Wistar rats were administered bifenthrin (3.5 and 7 mg per kg body weight p.o.) for 30 days. Behavioral studies were conducted on a set of randomly selected rats from each treatment group after completion of treatment. Neurochemical parameters were assessed 24 h after the last dose was administered. The selected behavioral and neurochemical endpoints were also assessed 15 days after cessation of exposure to reveal whether the neurobehavioral changes produced by bifenthrin were temporary or permanent. Deficits in motor activity, motor incoordination, and cognitive impairment were observed after exposure to bifenthrin. Levels of biogenic amines viz. dopamine (DA) and its metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), epinephrine (EPN), norepinephrine (NE), and serotonin (5-HT) altered in the frontal cortex, corpus striatum, and hippocampus of bifenthrin-treated rats. A decrease in the activity of acetylcholinesterase (AChE) occurred in all regions of the brain. Both doses of bifenthrin significantly induced lipid peroxidation (LPO) and increased protein carbonyl levels in the frontal cortex, corpus striatum, and hippocampus of rats. The activities of antioxidant enzymes, i.e. catalase, superoxide dismutase, and glutathione peroxidase, were also suppressed in all selected regions of the brain. A trend of recovery was, however, observed in all the behavioral and neurochemical endpoints 15 days after withdrawal of exposure. Oxidative stress seems to play an important role in bifenthrin-induced neurotoxicity. Our study suggests that long-term exposure to these compounds can produce detrimental effects.
  [Syed F, Awasthi KK, Chandravanshi LP, et al 2017. Toxicol Res (Camb). 7(1):48-58.]
• Developmental neurotoxicity of different pesticides in PC-12 cells in vitro.
  The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals.
  [Christen V, Rusconi M, Crettaz P, Fent K. 2017. Toxicol Appl Pharmacol. 325:25-36]
• Diazinon and parathion diverge in their effects on development of noradrenergic systems
  Organophosphate pesticides elicit developmental neurotoxicity through mechanisms over and above their shared property as cholinesterase inhibitors. We compared the consequences of neonatal exposure (postnatal days PN1-4) to diazinon or parathion on development of norepinephrine systems in rat brain, using treatments designed to produce equivalent effects on cholinesterase, straddling the threshold for barely-detectable inhibition. Norepinephrine levels were measured throughout development from the immediate posttreatment period (PN5), to early adolescence (PN30), young adulthood (PN60) and full adulthood (PN100); we assessed multiple brain regions containing all the major noradrenergic synaptic projections. Diazinon elicited a significant overall deficit of norepinephrine, whereas parathion produced a net increase. The effects were not immediately apparent (PN5) but rather emerged over the course of development, indicating that the organophosphate effects represent alteration of the trajectory of development, not just continuance of an initial injury. There were no comparable effects on β-adrenergic receptors, indicating that the presynaptic changes were not an adaptation to an underlying, primary effect on postsynaptic receptor signaling. Because we used the cholinesterase inhibition benchmark, the absolute dose of diazinon was much higher than that of parathion, since the latter is a more potent cholinesterase inhibitor. Our results are consistent with the growing evidence that the various organophosphates can differ in their impact on brain development and that consequently, the cholinesterase benchmark is an inadequate predictor of adverse neurodevelopmental effects.
  [Slotkin TA, Skavicus S, Seidler FJ. 2017. Brain Res Bull. 130:268-273.]
• Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat.
  Attention deficit hyperactivity disorder (ADHD) is characterized by behavioral and cognitive symptoms. Longitudinal studies demonstrated that the symptoms remains clinically significant for the majority of ADHD children into adulthood. Furthermore, a population-based birth cohort provided the initial evidence of adult ADHD that lacks a history of childhood ADHD. We previously demonstrated that neonatal exposure to bisphenol A, an environmental chemical caused hyperactivity in the juvenile. Here, we extend to examine other chemical such as rotenone, a dopaminergic toxins. Oral administration of rotenone (3mg/kg) into 5-day-old male Wistar rats significantly caused hyperactivity at adulthood (8∼11 weeks old; p<0.05). It was about 1.3∼1.4-fold more active in the nocturnal phase after administration of rotenone than control rats. Higher dose (16mg/kg) or repeated lower dose of rotenone (1mg/kg/day for 4days) caused hyperactivity in the juvenile. Furthermore, DNA array analyses showed that neonatal exposure to rotenone altered the levels of gene expression of several molecules related to apoptosis/cell cycle, ATPase, skeletal molecule, and glioma. Bivariate normal distribution analysis indicates no correlation in gene expression between a hyperactivity disorder model and a Parkinson's disease model by rotenone. Thus, we demonstrate a rotenone models of ADHD whose onset varies during juvenile and adulthood.
  [Ishido M, Suzuki J, Masuo Y. 2017. Toxicol Lett. 266:42-48]
• Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum
  Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children's health. Here we examined the effects of longterm (14 days) and low dose (1 μM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, ≥1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain.
  [Kimura-Kuroda J, Nishito Y, Yanagisawa H, Kuroda Y, et al. 2017. Int J Environ Res Public Health. 13(10). pii: E987.]
• Neurodevelopmental disorders and pesticide exposure: the northeastern Italian experience.
  Endocrine disruptors are chemical substances that can interfere with the endocrine system. They include pesticides, metals, additives or contaminants in food, and personal care products. Pesticides are the only substances intentionally released into our environment to kill living things (herbicides, insecticides, fungicides, rodenticides). There is scientific evidence that exposure to pesticides produces a growing number of human pathological conditions; among these, stillbirth is an emerging issue.
  [Roncati L, Pusiol T, Piscioli F, Lavezzi AM. Arch Toxicol. 91(2):603-604.]
• Neurological Deficits After Long-term Pyrethroid Exposure.
  Pyrethroid pesticides have been suggested to be a cause of Parkinson's disease and other neurodegenerative diseases. To investigate this, a cross-sectional study was conducted among 120 Bolivian public health vector program spray men, primarily exposed to pyrethroids. Pesticide exposure and central nervous system (CNS) symptoms were determined by a structured interview, whereas neuromotor and neurocognitive performance was assessed using the computerized Behavioral Assessment and Research System and CATSYS system. Individuals exposed to higher levels reported significantly more CNS symptoms (adjusted odds ratio per quintile of cumulative exposure = 2.01 [1.22-3.31]). There was no association seen between pyrethroid exposure and neuromotor performance. Higher spraying intensity was associated with significantly worse neurocognitive performance in structural equation models (adjusted β per quintile = -0.405 [-0.660 to -0.150]), and workers only exposed to pyrethroids performed worse than workers also exposed to other pesticides (adjusted β = -1.344 [-2.224 to -0.464]). Chronic pyrethroid exposure may cause deterioration in neurocognitive performance, and exposure control is recommended.
  [Hansen MRH, Jørs E, Lander F, Condarco G, et al. 2017. Environ Health Insights. 11:1178630217700628.]
• Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds
  Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, the experimental models of occupational OP exposure currently used in the field. Animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.
  [Voorhees JR, Rohlman DS, Lein PJ, Pieper AA. 2017. Front Neurosci. 10:590]
• Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.
  Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.
  [Voorhees JR, Rohlman DS, Lein PJ, Pieper AA. 2017. Front Neurosci. 10:590.]
• Prenatal and postnatal exposure to organophosphate pesticides and childhood neurodevelopment in Shandong, China.
  Although studies in laboratory animals demonstrate neurodevelopmental deficits caused by prenatal or postnatal organophosphate pesticide (OP) exposure, there is limited evidence on effects induced by not only prenatal but also postnatal exposure of children to OPs. We measured diethylphosphate (DE), dimethylphosphate (DM), and total dialkylphosphate (DAP) metabolites in maternal and child urine at 12 and 24months of age and examined their relationship with developmental quotients (DQs) in 12-month-old infants and 24-month-old children in Shandong, China.The median concentrations of total DAP metabolites (DAPs) in child urine [371.97nmol/g creatinine (12-month-old infants), 538.64nmol/g creatinine (24-month-old children)] were higher than those in maternal urine (352.67nmol/g creatinine). Prenatal OP exposure was negatively associated with 24-month-old children's DQs, especially among boys. A 10-fold increase in prenatal DEs and DAPs was associated with a 2.59- and 2.49-point decrease in social domain DQ scores in 24-month-old children (n=262), respectively. However, positive association of postnatal exposure to OPs and 24-month-old children's DQs was observed (n=237). Neither prenatal nor postnatal exposure to OPs was related to 12-month-old infants' DQs.These data suggested that prenatal OP exposure could adversely affect children's neurodevelopment at 24months of age, especially among boys. The prenatal period might be a critical window of OP exposure. In view of the positive association with postnatal OP exposure, it is necessary to interpret findings with caution.
  [Wang Y, Zhang Y, Ji L, Hu Y, et al. 2017. Environ Int. 108:119-126.]
• Prenatal exposure to lambda-cyhalothrin alters brain dopaminergic signaling in developing rats
  The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats.
  [Dhuriya YK, Srivastava P2, Shukla RK, et al. 2017. Toxicology. 386:49-59.]
• Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes.
  Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6-9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ - 0.13, 95% CI - 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ - 0.17, 95% CI - 0.33, - 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision.
  [Furlong MA, Herring A, Buckley JP, Goldman BD, et al. 2017. Environ Res.158:737-747. ]
• Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning.
  Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β -4.50, 95% CI -8.05, -0.95), Depression (β -3.21, 95% CI -6.38, -0.05), Somatization (β -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (β -3.59, 95% CI -6.97, -0.21), Emotional Control (β -3.35, 95% CI -6.58, -0.12), Shifting (β -3.42, 95% CI -6.73, -0.11), and Monitoring (β -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β -4.74, 95% CI -9.37, -0.10), Conduct Problems (β -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (β -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (β -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits.
  [Furlong MA, Barr DB, Wolff MS, Engel SM. 2017. Neurotoxicology. 62:231-238.]
• Sex-dependent effects of developmental exposure to different pesticides on spatial learning. The role of induced neuroinflammation in the hippocampus.
  The use of pesticides has been associated with impaired neurodevelopment in children. The aims of this work were to assess: 1) the effects on spatial learning of developmental exposure to pesticides 2) if the effects are sex-dependent and 3) if hippocampal neuroinflammation is associated with the impairment of spatial learning. We analyzed the effects of developmental exposure to four pesticides: chlorpyrifos, carbaryl, endosulfan and cypermethrin. Exposure was from gestational day 7 to post-natal day 21 and spatial learning and memory was assessed when the rats were young adults. The effects of pesticides on spatial learning were pesticide and gender-dependent. Carbaryl did not affect spatial learning in males or females. Endosulfan and chlorpyrifos impaired learning in males but not in females. Cypermethrin improved spatial learning in the Morris water maze both in males and females while impaired learning in the radial maze only in males. Spatial learning ability was lower in control female rats than in males. All pesticides induced neuroinflammation, increasing IL-1b content in the hippocampus and there is a negative correlation between IL-1b levels in the hippocampus and spatial learning. Neuroinflammation would contribute to the effects of pesticides on spatial learning.
  [Gómez-Giménez B, Llansola M, Hernández-Rabaza V, et al. 2017. Food Chem Toxicol. 99:135-148. ]
• The Impact of Prenatal Organophosphate Pesticide Exposures on Thai Infant Neurodevelopment.
  A birth cohort was begun to investigate the levels and sources of pesticide exposure in pregnant women living in Thailand, and to examine the effects of pesticide exposure on infant neurodevelopment at five months of age. Subjects were interviewed using questionnaires regarding their demographic characteristics, educational background, and work and home activities related to pesticide exposures. Spot urine samples were collected at 28 weeks gestation and analyzed by gas chromatography-mass spectrometry to determine maternal metabolite levels of organophosphate pesticides including dimethyl phosphate (DMP); total DEP (diethyl phosphate (DEP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP), and total DAP (the sum of all metabolite levels). At five months of age, infant development was evaluated using the Bayley Scales of Infant and Toddler Development-III (Bayley-III). Higher total DEP and total DAP metabolite levels from the mother at 28 weeks' gestation were significantly associated with reduced motor composite scores on the Bayley-III at five months of age. The total DEP levels were also significantly associated with reduced cognitive composite scores. Prenatal concentrations of maternal urinary metabolites were associated with infant cognitive and motor development. The results of several studies now suggest the need for public health intervention to reduce prenatal pesticide exposures from both agricultural and domestic use.
  [Kongtip P, Techasaensiri B, Nankongnab N, et al. 2017. Int J Environ Res Public Health. 14(6). pii: E570.]
• Adverse Associations of both Prenatal and Postnatal Exposure to Organophosphorous Pesticides with Infant Neurodevelopment in an Agricultural Area of Jiangsu Province, China.
  Prenatal exposure to organophosphorous (OP) pesticides has been found to be associated with adverse effects on child neurodevelopment, but evidence on potential effects induced by both prenatal and postnatal OP exposure in infants is limited.Our aim was to investigate the associations of both prenatal and postnatal OP exposure with birth outcomes and infant neurodevelopment.Exposure to OP in 310 mother-infant pairs was assessed by measuring dimethylphosphate (DM), diethylphosphate (DE), and total dialkylphosphate (DAP) metabolites in urines from pregnant women and their children at 2 years of age. The Gesell Developmental Schedules was administered to examine neurodevelopment of 2-year-old children.Based on the Gesell Developmental Schedules, the proportions of children with developmental delays were < 6%. Adverse associations between head circumference at birth and prenatal OP exposure were demonstrated. Both prenatal and postnatal OP exposure was significantly associated with increased risk of being developmentally delayed. Specifically, odds ratio (OR) value for prenatal DEs was 9.75 (95% CI: 1.28, 73.98, p = 0.028) in the adaptive area, whereas in the social area, OR values for postnatal DEs and DAPs were 9.56 (95% CI: 1.59, 57.57, p = 0.014) and 12.00 (95% CI: 1.23, 117.37, p = 0.033), respectively. Adverse associations were observed only in boys, not in girls.Both prenatal and postnatal OP exposure may adversely affect the neurodevelopment of infants living in the agricultural area. The present study adds to the accumulating evidence on associations of prenatal and postnatal OP exposure with infant neurodevelopment.
  [Liu P, Wu C, Chang X, Qi X, Zheng M, Zhou Z. 2016. Environ Health Perspect. 124(10):1637-1643.]
• An Observational Study to Evaluate Associations Between Low-Level Gestational Exposure to Organophosphate Pesticides and Cognition During Early Childhood.
  Prenatal exposure to organophosphate pesticides, which is ubiquitous, may be detrimental to neurological development. We examined 327 mother/infant pairs in Cincinnati, Ohio, between 2003 and 2006 to determine associations between prenatal exposure to organophosphate pesticides and neurodevelopment. Twice during pregnancy urinary concentrations of 6 common dialkylphosphates, nonspecific metabolites of organophosphate pesticides, were measured. Aggregate concentrations of diethylphosphates, dimethylphosphates, and total dialkylphosphates were calculated. Bayley Scales of Infant Development, Second Edition-Mental and Psychomotor Developmental indices were administered at ages 1, 2, and 3 years, the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, at age 4, and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at age 5. Mothers with higher urinary total dialkylphosphate concentrations reported higher levels of socioeconomic status and increased fresh fruit and vegetable intake. We found no associations between prenatal exposure to organophosphate pesticides and cognition at 1-5 years of age. In our cohort, exposure to organophosphate pesticides during pregnancy was not associated with cognition during early childhood. It is possible that a higher socioeconomic status and healthier diet may protect the fetus from potential adverse associations with gestational organophosphate pesticide exposure, or that dietary exposure to the metabolites is innocuous and not an ideal measure of exposure to the parent compound.
  [Donauer S, Altaye M, Xu Y, Sucharew H, et al. 2016. Am J Epidemiol. 184(5):410-8. ]
• Association between background exposure to organochlorine pesticides and the risk of cognitive impairment: A prospective study that accounts for weight change
  Background exposure to organochlorine (OC) pesticides was recently linked to cognitive impairment and dementia in cross-sectional and case–control studies. This prospective study was performed to evaluate if OC pesticides at baseline are associated with the future risk of cognitive impairment in elderly, with particular focus on weight change. Plasma concentrations of 3 OC pesticides (p,p′-DDE, trans-nonachlor, and hexachlorobenzene) were measured among 989 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Cognitive impairment was validated by reviewing medical records. During the ten year follow-up, cognitive impairment was developed in 75 subjects. When weight change from age 70 to 75 was considered in analyses, elderly with incident cases before age 75 were excluded to keep the prospective perspective, leaving 795 study subjects and 44 incident cases. The summary measure of 3 OC pesticides predicted the development of cognitive impairment after adjusting for covariates, including weight change. Compared to subjects with OC pesticides < 25th percentile, adjusted hazard ratios (HRs) in those with 25th–
  [Lee, D.H., Lind, P.M., Jacobs Jr, D.R., Salihovic, S., van Bavel, B. and Lind, L., 2016. Association between background exposure to organochlorine pesticides and the risk of cognitive impairment: a prospective study that accounts for weight change. Environment international, 89, pp.179-184.]
• Cytotoxicity induced by cypermethrin in Human Neuroblastoma Cell Line SH-SY5Y.
  The purpose of this study was to evaluate the cytotoxic potential of Cypermethrin (CM) on cultured human Neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with CM at 0-200µM for 24, 48, and 72 h, in vitro. It was found that CM induced the cell death of Neuroblastoma cells in a dose- and time-dependent manner, as shown by LDH assays. Next, some aspects of the process of cell death triggered by CM in the human SH-SY5Y cell line were investigated. It was revealed that the pan-caspase inhibitor Q-VD-OPh, sensitizes SH-SY5Y cells to necroptosis caused by CM. Furthermore, signal transduction inhibitors PD98059, SL-327, SB202190, SP600125 failed to attenuate the effect of the pesticide. Finally, it was shown that inhibition of TNF-a by Pomalidomide (PLD) caused statistically significant reduction in CM-induced cytotoxicity. Overall, the data obtained suggest that CM induces neurotoxicity in SH-SY5Y cells by necroptosis.
  [Raszewski G, Lemieszek MK, Łukawski K. 2016. Ann Agric Environ Med. 23(1):106-10.]
• Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes.
  The large number of compounds that needs to be tested for developmental neurotoxicity drives the need to establish in vitro models to evaluate specific neurotoxic endpoints. We used neural stem cells derived from rat neuroepithelium on embryonic day 14 to evaluate the impact of diverse toxicants on their ability to differentiate into glia and neurons: a glucocorticoid (dexamethasone), organophosphate insecticides (chlorpyrifos, diazinon, parathion), insecticides targeting the GABAA receptor (dieldrin, fipronil), heavy metals (Ni2+, Ag+), nicotine and tobacco smoke extract. We found three broad groupings of effects. One diverse set of compounds, dexamethasone, the organophosphate pesticides, Ni2+ and nicotine, suppressed expression of the glial phenotype while having little or no effect on the neuronal phenotype. The second pattern was restricted to the pesticides acting on GABAA receptors. These compounds promoted the glial phenotype and suppressed the neuronal phenotype. Notably, the actions of compounds eliciting either of these differentiation patterns were clearly unrelated to deficits in cell numbers: dexamethasone, dieldrin and fipronil all reduced cell numbers, whereas organophosphates and Ni2+ had no effect. The third pattern, shared by Ag+ and tobacco smoke extract, clearly delineated cytotoxicity, characterized by major cell loss with suppression of differentiation into both glial and neuronal phenotypes; but here again, there was some selectivity in that glia were suppressed more than neurons. Our results, from this survey with diverse compounds, point to convergence of neurotoxicant effects on a specific "decision node" that controls the emergence of neurons and glia from neural stem cells.
  [Slotkin TA, Skavicus S, Card J, et al. 2016. Toxicology. 372:42-51]
• Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies
  The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.
  [Tartaglione AM, Venerosi A, Calamandrei G. 2016. Curr Top Behav Neurosci. 29:231-64]
• Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study
  The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors. This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals. Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree. We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. 
  [Litvan I, Lees PS, Cunningham CR, Rai SN, et al. 2016. Mov Disord. 31(5):644-52. ]
• Lambda-cyhalothrin disrupts the up-regulation effect of 17β-estradiol on post-synaptic density 95 protein expression via estrogen receptor α-dependent Akt pathway.
  Lambda-cyhalothrin (LCT), one of the type II pyrethroids, has been widely used throughout the world. The estrogenic effect of LCT to increase cell proliferation has been well established. However, whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated. In addition, 17β-Estradiol (E2) plays a crucial role in neurodevelopment and induces an increase in synaptic proteins. The post-synaptic density 95 (PSD95) protein, which is involved in the development of the structure and function of new spines and localized with estrogen receptor α (ERα) at the post-synaptic density (PSD), was detected in our study by using hippocampal neuron cell line HT22. We found that LCT up-regulated PSD95 and ERα expression, estrogen receptor (ER) antagonist ICI182,780 and phosphatidylinositol-4; 5-bisphosphate 3-kinase (PI3K) inhibitor LY294,002 blocked this effect. In addition, LCT disrupted the promotion effect of E2 on PSD95. To investigate whether the observed changes are caused by ERα-dependent signaling activation, we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B (PKB/Akt)-eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) pathway. There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment. In addition, LCT could disrupt the activation effect of E2 on the Akt pathway. However, no changes in cAMP response element-binding protein (CREB) activation and PSD95 messenger ribonucleic acid (mRNA) were observed. Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway, and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
  [Wang Q, Xia X, Deng X, Li N, et al. 2016. J Environ Sci (China). 41:252-60.]
• Negative Role of the Environmental Endocrine Disruptors in the Human Neurodevelopment
  The endocrine disruptors (EDs) are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS) the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected by centralization in the last year (2015). More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs), chlorpyrifos and chlorfenvinfos, have been found in seven and three samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers but simply time-deferral mechanisms of absorption.
  [Roncati L, Termopoli V, Pusiol T. 2016. Front Neurol. 7:143.]
• Pesticide exposure and neurodevelopment in children aged 6-9 years from Talamanca, Costa Rica.
  Certain pesticides may affect children's neurodevelopment. We assessed whether pesticide exposure was associated with impaired neurobehavioral outcomes in children aged 6-9 years. We conducted a cross-sectional study in 140 children living near banana plantations and plantain farms in the Talamanca County, Costa Rica and assessed their neurobehavioral performance. Exposure was determined by analyzing urinary metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol, TCPy), mancozeb (ethylenethiourea, ETU), and pyrethroids (3-phenoxybenzoic acid, 3-PBA). Repeated urine samples were obtained for 36 children. We estimated associations of pesticide concentrations with neurobehavioral outcomes using multivariable linear and logistic regression models. Median (25th-75th percentiles) TCPy, ETU, and 3-PBA concentrations were 1.4 (.7-3.1), 1.2 (.7-3.0), and .8 (.5-1.5) μg/L, respectively. Intraclass correlation coefficients (ICC) ranged between .32 and .67. After adjustment for potential confounders, higher urinary TCPy concentrations were associated with poorer working memory in boys (n = 59) (β per 10-fold increase in TCPy concentrations = -7.5, 95% CI: -14.4, -.7); poorer visual motor coordination (β = -1.4, 95% CI: -2.7, -.1); increased prevalence of parent-reported cognitive problems/inattention (adjusted OR per 10-fold increase in urinary concentrations = 5.8, 95% CI: 1.6, 22.9), oppositional disorders (aOR = 3.9, 95% CI: 1.0, 16.0), and ADHD (aOR = 6.8, 95% CI: 1.8, 28.6), and; decreased ability to discriminate colors (aOR = 6.6, 95% CI: 1.6, 30.3; the higher the score the worse). Higher ETU concentrations were associated with poorer verbal learning outcomes (β = -7.0, 95% CI: -12.7, -1.3). Higher 3-PBA concentrations were associated with poorer processing speed scores, particularly in girls (β = -8.8, 95% CI: -16.1, -1.4). Our findings indicate that children living near banana and plantain plantations are exposed to pesticides that may affect their neurodevelopment, which for certain domains may differ between boys and girls. We recommend the implementation of measures to reduce pesticide exposure in children living nearby banana plantations.
  [van Wendel de Joode B, Mora AM, Lindh CH, et al. 2016. Cortex. 85:137-150. ]
• Pesticides, Neurodevelopmental Disagreement, and Bradford Hill's Guidelines
  Neurodevelopmental disorders such as autism affect one-eighth of all U.S. newborns. Yet scientists, accessing the same data and using Bradford-Hill guidelines, draw different conclusions about the causes of these disorders. They disagree about the pesticide-harm hypothesis, that typical United States prenatal pesticide exposure can cause neurodevelopmental damage. This article aims to discover whether apparent scientific disagreement about this hypothesis might be partly attributable to questionable interpretations of the Bradford-Hill causal guidelines. Key scientists, who claim to employ Bradford-Hill causal guidelines, yet fail to accept the pesticide-harm hypothesis, fall into errors of trimming the guidelines, requiring statistically-significant data, and ignoring semi-experimental evidence. However, the main scientists who accept the hypothesis appear to commit none of these errors. Although settling disagreement over the pesticide-harm hypothesis requires extensive analysis, this article suggests that at least some conflicts may arise because of questionable interpretations of the guidelines.
  [Shrader-Frechette K, ChoGlueck C. 2016. Account Res. 1-13]
• Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
  Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
  [Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64.]
• Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
  Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
  [Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64]
• Prenatal exposure to multiple pesticides is associated with auditory brainstem response at 9months in a cohort study of Chinese infants
  Pesticides are associated with poorer neurodevelopmental outcomes, but little is known about the effects on sensory functioning.Auditory brainstem response (ABR) and pesticide data were available for 27 healthy, full-term 9-month-old infants participating in a larger study of early iron deficiency and neurodevelopment. Cord blood was analyzed by gas chromatography-mass spectrometry for levels of 20 common pesticides. The ABR forward-masking condition consisted of a click stimulus (masker) delivered via ear canal transducers followed by an identical stimulus delayed by 8, 16, or 64 milliseconds (ms). ABR peak latencies were evaluated as a function of masker-stimulus time interval. Shorter wave latencies reflect faster neural conduction, more mature auditory pathways, and greater degree of myelination. Linear regression models were used to evaluate associations between total number of pesticides detected and ABR outcomes. We considered an additive or synergistic effect of poor iron status by stratifying our analysis by newborn ferritin (based on median split).Infants in the sample were highly exposed to pesticides; a mean of 4.1 pesticides were detected (range 0-9). ABR Wave V latency and central conduction time (CCT) were associated with the number of pesticides detected in cord blood for the 64ms and non-masker conditions. A similar pattern seen for CCT from the 8ms and 16ms conditions, although statistical significance was not reached. Increased pesticide exposure was associated with longer latency. The relation between number of pesticides detected in cord blood and CCT depended on the infant's cord blood ferritin level. Specifically, the relation was present in the lower cord blood ferritin group but not the higher cord blood ferritin group.ABR processing was slower in infants with greater prenatal pesticide exposure, indicating impaired neuromaturation. Infants with lower cord blood ferritin appeared to be more sensitive to the effects of prenatal pesticide exposure on ABR latency delay, suggesting an additive or multiplicative effect.
  [Sturza J, Silver MK, Xu L, Li M, et al. 2016. Environ Int.92-93:478-85.]
• Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.
  Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile.Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70).At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21.These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long-lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.
  [De Felice A, Greco A, Calamandrei G, Minghetti L. 2016. J Neuroinflammation. 13(1):149]
• Prenatal Triclosan Exposure and Anthropometric Measures Including Anogenital Distance in Danish Infants.
  Prenatal triclosan exposure is associated with reduced head circumference, a trait linked to cognitive impairment.
  [Lassen et al. 2016. Environmental Health Perspectives doi: 10.1289/ehp.1409637.]
• Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects.
  Environmental exposures play a critical role in the genesis of some child mental health problems.We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function.We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice.Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value.
  [Rauh VA, Margolis AE. 2016. J Child Psychol Psychiatry. 57(7):775-93.]
• Residential proximity to organophosphate and carbamate pesticide use during pregnancy, poverty during childhood, and cognitive functioning in 10-year-old children.
  Low-income communities and communities of color have been shown to experience disproportionate exposure to agricultural pesticides, which have been linked to poorer neurobehavioral outcomes in infants and children. Few studies have assessed health impacts of pesticide mixtures in the context of socioeconomic adversity.We evaluated associations between both nearby agricultural pesticide use and poverty measures and cognitive abilities in 10-year-old children (n = 501) using data from a longitudinal birth cohort study linked with data from the California Pesticide Use Reporting system and the American Community Survey. Associations were assessed using multivariable linear regression.Children of mothers in the highest quartile compared to the lowest quartile of proximal pesticide use had lower performance on Full Scale IQ [β = -3.0; 95% Confidence Interval (CI) = (-5.6, -0.3)], Perceptual Reasoning [β = -4.0; (-7.6, -0.4)], and Working Memory [β = -2.8; (-5.6, -0.1)]. Belonging to a household earning an income at or below the poverty threshold was associated with approximately two point lower scores on Full Scale IQ, Verbal Comprehension, and Working Memory. Living in the highest quartile of neighborhood poverty at age 10 was associated with approximately four point lower performance on Full Scale IQ, Verbal Comprehension, Perceptual Reasoning, and Working memory.Residential proximity to OP and carbamate pesticide use during pregnancy and both household- and neighborhood-level poverty during childhood were independently associated with poorer cognitive functioning in children at 10 years of age.
  [Rowe C, Gunier R, Bradman A, Harley KG, et al. 2016. Environ Res.150:128-37.]
• Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment.
  Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.
  [Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M. 2016. Environ Int. 92-93:657-79. ]
• The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.
  Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism in recent decades, in the absence of any known changes in the human gene pool suggests a strong environmental influence. Numerous pollutants have been implicated in epidemiological studies, including pesticides, heavy metals, industrial solvents, air pollutants, particulate matter, bisphenol A, phthalates and flame retardants. Many genes have been implicated in autism, some of which are directly related to detoxification processes. Many are also expressed prenatally in the frontal cortex when the effects of such toxins on neurodevelopment are most relevant. To gain access to the foetal brain, toxins must pass placental and blood/brain barriers and access to maternal or children's blood necessitates passage across skin, airway and intestinal barriers. Literature survey of a subset of 206 genes, defined as prime autism susceptibility candidates from an Autworks/Genotator analysis, revealed that most could be related to barrier function at blood/brain, skin, intestinal, placental or other interfaces. These genes were highly enriched in proteome datasets from blood/brain and placental trophoblast barriers and many localised to skin, intestinal, lung, umbilical and placental compartments. Many were also components of the exosomal/transcytosis pathway that is involved in the transfer of compounds across cells themselves, rather than between them. Several are involved in the control of respiratory cilia that sweep mucus and noxious particles from the airways. A key role of autism susceptibility genes may thus relate to their ability to modulate the access of numerous toxins to children, and adults and, during gestation, to the developing foetal brain.
  [Carter CJ. 2016. Neurochem Int. 99:42-51]
• ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before pregnancy
  The aim of this study was to investigate how chronic low-dose chlorpyrifos exposure of female Wistar rats before and during pregnancy affects behavioural parameters in their offspring. Four months before pregnancy, we exposed three groups of rats to chlorpyrifos doses of 5, 10, and 15 mg kg-1 body weight every day for 30 days, whereas one group received a single 30 mg kg-1 dose on gestational day 6. When the offspring of the exposed rats grew up, we studied their anxiety rate, motor activity, and cognitive abilities using the respective behavioural tests: open field test, dark/light box, and the extrapolation escape test. The offspring of rats exposed before pregnancy had significantly higher activity rate than controls, and even showed motor agitation and hyperactivity signs. The offspring of rats exposed to the single dose had difficulties solving the extrapolation escape test and showed poorer short- and long-term memory performance. This confirmed that even pre-pregnancy chlorpyrifos exposure can cause neurobehavioral consequences in offspring. Even though the mechanisms of the observed changes remain unclear and need further investigation, these data seem alarming and may serve as an important argument for revising the terms of safe pesticide use.
  [Grabovska S, Salyha Y. 2015. Arh Hig Rada Toksikol. 66(2):121-7]
• Assessment of learning, memory, and attention in developmental neurotoxicity regulatory studies: synthesis, commentary, and recommendations
  Cognitive tests of learning and memory (L&M) have been required by U.S. Environmental Protection Agency (EPA) developmental neurotoxicity test (DNT) guidelines for more than two decades. To evaluate the utility of these guidelines, the EPA reviewed 69 pesticide DNT studies. This review found that the DNT provided or could provide the point-of-departure for risk assessment by showing the Lowest Observable Adverse Effect Level (LOAEL) in 28 of these studies in relation to other reported end points. Among the behavioral tests, locomotor activity and auditory/acoustic startle provided the most LOAELs, and tests of cognitive function and the Functional Observational Battery (FOB) the fewest. Two issues arose from the review: (1) what is the relative utility of cognitive tests versus tests of unconditioned behavior, and (2) how might cognitive tests be improved? The EPA sponsored a symposium to address this. Bushnell reviewed studies in which both screening (locomotor activity, FOB, reflex ontogeny, etc.) and complex tests (those requiring training) were used within the same study; he found relatively little evidence that complex tests provided a LOAEL lower than screening tests (with exceptions). Levin reviewed reasons for including cognitive tests in regulatory studies and methods and evidence for the radial arm maze and its place in developmental neurotoxicity assessments. Driscoll and Strupp reviewed the value of serial reaction time operant methods for assessing executive function in developmental neurotoxicity studies. Vorhees and Williams reviewed the value of allocentric (spatial) and egocentric cognitive tests and presented methods for using the Morris water maze for spatial and the Cincinnati water maze for egocentric cognitive assessment. They also reviewed the possible use of water radial mazes. The relatively lower impact of cognitive tests in previous DNT studies in the face of the frequency of human complaints of chemical-induced cognitive dysfunction indicates that animal cognitive tests need improvement. The contributors to this symposium suggest that if the guidelines are updated, they be made more specific by recommending preferred tests and providing greater detail on key characteristics of such tests. Additionally, it is recommended that guidance be developed to address important issues with cognitive tests and to provide the information needed to improve the design, conduct, and interpretation of tests of higher function within a regulatory context. These steps will maximize the value of cognitive tests for use in hazard evaluation and risk assessment.
  [Vorhees, C. and Makris, S. (2015) Assessment of learning, memory, and attention in developmental neurotoxicity regulatory studies: synthesis, commentary, and recommendations, Neurotoxicology and Teratology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0892036215300386. ]
• Associations of maternal organophosphate pesticide exposure and PON1 activity with birth outcomes in SAWASDEE birth cohort, Thailand.
  Prenatal organophosphate (OP) pesticide exposure has been reported to be associated with adverse birth outcomes and neurodevelopment. However, the mechanisms of toxicity of OP pesticides on human fetal development have not yet been elucidated. Our pilot study birth cohort, the Study of Asian Women and Offspring's Development and Environmental Exposures (SAWASDEE cohort) aimed to evaluate environmental chemical exposures and their relation to birth outcomes and infant neurodevelopment in 52 pregnant farmworkers in Fang district, Chiang Mai province, Thailand. A large array of data was collected multiple times during pregnancy including approximately monthly urine samples for evaluation of pesticide exposure, three blood samples for pesticide-related enzyme measurements and questionnaire data. This study investigated the changes in maternal acetylcholinesterase (AChE) and paraoxonase 1 (PON1) activities and their relation to urinary diakylphosphates (DAPs), class-related metabolites of OP pesticides, during pregnancy. Maternal AChE, butyrylcholinesterase (BChE) and PON1 activities were measured three times during pregnancy and urinary DAP concentrations were measured, on average, 8 times from enrollment during pregnancy until delivery. Among the individuals in the group with low maternal PON1 activity (n=23), newborn head circumference was negatively correlated with log10 maternal ∑DEAP and ∑DAP at enrollment (gestational age=12±3 weeks; β=-1.0 cm, p=0.03 and β=-1.8 cm, p<0.01, respectively) and at 32 weeks pregnancy (β=-1.1cm, p=0.04 and β=-2.6 cm, p=0.01, respectively). Furthermore, among these mothers, newborn birthweight was also negatively associated with log10 maternal ∑DEAP and ∑DAP at enrollment (β=-219.7 g, p=0.05 and β=-371.3g, p=0.02, respectively). Associations between maternal DAP levels and newborn outcomes were not observed in the group of participants with high maternal PON1 activity. Our results support previous findings from US birth cohort studies. This is the first study to report the associations between prenatal OP pesticide exposure and birth outcomes in Thailand.
  [Naksen W, Prapamontol T, Mangklabruks A, Chantara S, et al. 2015. Environ Res. 142:288-96.]
• Changes in neuronal dopamine homeostasis following 1-methyl-4-phenylpyridinium (MPP+) exposure.
  1-Methyl-4-phenylpyridinium (MPP(+)), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, selectively kills dopaminergic neurons in vivo and in vitro via a variety of toxic mechanisms, including mitochondrial dysfunction, generation of peroxynitrite, induction of apoptosis, and oxidative stress due to disruption of vesicular dopamine (DA) storage. To investigate the effects of acute MPP(+) exposure on neuronal DA homeostasis, we measured stimulation-dependent DA release and non-exocytotic DA efflux from mouse striatal slices and extracellular, intracellular, and cytosolic DA (DAcyt) levels in cultured mouse ventral midbrain neurons. In acute striatal slices, MPP(+) exposure gradually decreased stimulation-dependent DA release, followed by massive DA efflux that was dependent on MPP(+) concentration, temperature, and DA uptake transporter activity. Similarly, in mouse midbrain neuronal cultures, MPP(+) depleted vesicular DA storage accompanied by an elevation of cytosolic and extracellular DA levels. In neuronal cell bodies, increased DAcyt was not due to transmitter leakage from synaptic vesicles but rather to competitive MPP(+)-dependent inhibition of monoamine oxidase activity. Accordingly, monoamine oxidase blockers pargyline and l-deprenyl had no effect on DAcyt levels in MPP(+)-treated cells and produced only a moderate effect on the survival of dopaminergic neurons treated with the toxin. In contrast, depletion of intracellular DA by blocking neurotransmitter synthesis resulted in ∼30% reduction of MPP(+)-mediated toxicity, whereas overexpression of VMAT2 completely rescued dopaminergic neurons. These results demonstrate the utility of comprehensive analysis of DA metabolism using various electrochemical methods and reveal the complexity of the effects of MPP(+) on neuronal DA homeostasis and neurotoxicity.
  [Choi SJ, Panhelainen A, Schmitz Y, et al. 2015. J Biol Chem.290(11):6799-809.]
• Chronic adverse effects of long-term exposure of children to dichlorodiphenyltrichloroethane (DDT) through indoor residual spraying: A systematic review.
  Malaria remains a significant public health problem in endemic regions of the world, most especially in sub-Saharan Africa. As part of the global efforts to control malaria, dichlorodiphenyltrichloroethane (DDT), a cheap and effective chemical, was endorsed by the World Health Organization for use in indoor residual spraying (IRS). However, in the light of evidence on the acute toxicity of DDT, concerns have grown about the safety or the possible chronic health effects from the continued use of this persistent chemical, generating much debate and research efforts over the years. The purpose of this study was to identify, appraise and synthesise evidence about the chronic adverse effects of long-term exposure to DDT in children, 0-18 years, in zones where IRS is practised, in order to contribute to informing policy decisions.Twenty-seven electronic databases were systematically searched using pre-defined inclusion/exclusion criteria. Two were trial registers while 25 others indexed studies of various designs. Only nine studies met the inclusion/exclusion criteria out of 3281 hits generated. Five of the studies are of high quality while four are of moderate quality. For the three studies on neurodevelopment, evidence suggestive of negative impact of DDT was found. For the three studies on endocrine/congenital disorders, ambivalent evidence existed. In the case of the immunity-related outcome, there was growing but insufficient evidence of negative effect. The only study on survival outcome was inconclusive. Empirically, insufficient evidence exists with regard to the chronic adverse effects of long-term exposure of children to DDT through IRS. Considering the dearth of studies and the fact that many adverse effects might take much longer time to manifest, inferences drawn are weak. It would therefore require a series of well-coordinated observational studies done in the context of IRS to adequately address this evidence gap in the future.
  [Osunkentan AO, Evans D. 2015. Rural Remote Health.15(2):2889.]
• Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin.
  Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.
  [Lee I, Eriksson P, et al. 2015. Toxicology. 335:1-10.]
• Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome.
  Organohalogens are persistent organic pollutants that have a wide range of chemical application. There is growing evidence that several of these chemical compounds interfere with human development in various ways. The aim of this review is to provide an update on the relationship between various persistent organic pollutants and childhood neurodevelopmental outcome from studies from the past 10 years. This review focuses on exposure to polychlorinated biphenyls (PCBs), hydroxylated PCBs (OH-PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyldichloroethylene (DDE), and in addition on exposure to phthalates, bisphenol A, and perfluorinated compounds and their associations with neurodevelopmental outcome in childhood, up to 18 years of age. This review shows that exposure to environmental chemicals affects neurodevelopmental outcome in children. Regarding exposure to PCBs and OH-PCBs, most studies report no or inverse associations with neurodevelopmental outcomes. Regarding exposure to PBDEs, lower mental development, psychomotor development and IQ were found at preschool age, and poorer attention at school age. Regarding exposure to DDE, most studies reported inverse associations with outcome, while others found no associations. Significant relations were particularly found at early infancy on psychomotor development, on attention and ADHD, whereas at school age, no adverse relationships were described. Additionally, several studies report gender-related vulnerability. Future research should focus on the long-term effects of prenatal and childhood exposure to these environmental chemicals, on sex-specific and combined exposure effects of environmental chemicals, and on possible mechanisms by which these chemicals have their effects on neurodevelopmental and behavioral outcomes.
  [Berghuis SA, Bos AF, Sauer PJ, Roze E. 2015. Arch Toxicol. 89(5):687-709]
• Occupational exposures and parkinsonism
  In recent years, the contribution of exposure to environmental toxicants has been recognized as a significant contributor to the etiopathogenesis of parkinsonism. Of these toxicants, exposure to pesticides, metals, solvents used in manufacturing processes, as well as flame-retardant chemicals used in consumer and commercial products, has received the greatest attention as possible risk factors. Related to this, individuals who are exposed to these compounds at high concentrations or for prolonged periods of time in an occupational setting appear to be one of the more vulnerable populations to these effects. Our understanding of which compounds are involved and the potential molecular pathways that are susceptible to these chemicals and may underlie the pathogenesis has greatly improved. However, there are still hundreds of chemicals that we are exposed to in the environment for which we do not have any information on their potential neurotoxicity on the nigrostriatal dopamine system. Thus, using our past accomplishments as a blueprint, future endeavors should focus on elaborating upon these initial findings in order to identify specific and relevant chemical toxicants in our environment that can impact the risk of parkinsonism and work towards a means to attenuate or abolish their effects on the human population.
  [Caudle WM. 2015. Handb Clin Neurol. 131:225-39.]
• Pre- and postnatal exposures to pesticides and neurodevelopmental effects in children living in agricultural communities from South-Eastern Spain.
  Childrens exposure to neurotoxic compounds poses a major problem to public health because oftheir actively developing brain that makes them highly vulnerable. However, limited information is available on neuropsychological effects in children associated with pre- and postnatal exposures to pesticides.Study's aim was to evaluate the association between current and pre- and postnatal exposures to pesticides and their effects on neurodevelopment in children aged 6–11 years living in agricultural communities from South-Eastern Spain.An ambispective study was conducted on 305 children aged 6–11 years randomly selected from public schools of the study area. Current exposure to organophosphate pesticides was assessed measuring children's urinary levels of dialkylphosphates (DAPs). Both prenatal and postnatal residential exposure to pesticides was estimated by developing a geographical information system (GIS) technology-based index that integrated distance-weighted measure of agricultural surface, time-series of crop areas per municipality and year, and land-use maps. Neuropsychological performance was evaluated with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV).Greater urinary DAP levels were associated with a poorer performance on intelligence quotient and verbal comprehension domain, with effects being more prominent in boys than in girls. The influence of an increase in 10 ha per year in crop surface around the child's residence during the postnatal period was associated with decreased intelligence quotient, processing speed and verbal comprehension scores. As regards prenatal exposure to pesticides, a poor processing speed performance was observed. These effects were also more prominent in boys than in girls.Our results suggest that postnatal exposure to pesticides can negatively affect children's neuropsychological performance. Prenatal exposure was weakly associated to neurodevelopment impairment.
  [González-Alzaga B, Hernández AF, Rodríguez-Barranco M, et al. 2015. Environ Int. 85:229-37. ]
• Prenatal exposure to the organophosphate pesticide chlorpyrifos and childhood tremor.
  The organophosphate insecticide chlorpyrifos (CPF), widely used for agricultural purposes, has been linked to neurodevelopmental deficits. Possible motor effects at low to moderate levels of exposure have not been evaluated.Prenatal exposure to CPF was measured in umbilical cord blood in a sample of 263 inner-city minority children, who were followed prospectively. At approximately 11 years of age (mean age 10.9 ± 0.85 years, range=9.0-13.9), during a neuropsychological assessment, children were asked to draw Archimedes spirals. These were rated by a senior neurologist specializing in movement disorders who was blind to CPF exposure level.Compared to all other children, those with prenatal CPF exposure in the upper quartile range (n=43) were more likely to exhibit mild or mild to moderate tremor (≥ 1) in either arm (p=0.03), both arms (p=0.02), the dominant arm (p=0.01), and the non-dominant arm (p=0.055). Logistic regression analyses showed significant CPF effects on tremor in both arms, either arm, the dominant arm (p-values <0.05), and the non-dominant arm (p=0.06), after adjustment for sex, age at testing, ethnicity, and medication. Prenatal CPF exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.
  [Rauh VA, Garcia WE, Whyatt RM, Horton MK, et al. 2015. Neurotoxicology. 51:80-6. ]
• Pyrethroid insecticide exposure and cognitive developmental disabilities in children: The PELAGIE mother-child cohort.
  Pyrethroid insecticides are widely used in agriculture and in homes. Despite the neurotoxicity of these insecticides at high doses, few studies have examined whether lower-level exposures could adversely affect children's neurodevelopment. The PELAGIE cohort included 3421 pregnant women from Brittany, France between 2002 and 2006. When their children reached their sixth birthday, 428 mothers from the cohort were randomly selected, successfully contacted and found eligible. A total of 287 (67%) mothers agreed to participate with their children in the neuropsychological follow-up. Two cognitive domains were assessed by the Wechsler Intelligence Scale for Children: verbal comprehension and working memory. Five pyrethroid and two organophosphate insecticide metabolites were measured in maternal and child first-void urine samples collected between 6 and 19 gestational weeks and at 6years of age, respectively. Linear regression models were used to estimate associations between cognitive scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Maternal prenatal pyrethroid metabolite concentrations were not consistently associated with any children's cognitive scores. By contrast, childhood 3-PBA and cis-DBCA concentrations were both negatively associated with verbal comprehension scores (P-trend=0.04 and P-trend<0.01, respectively) and with working memory scores (P-trend=0.05 and P-trend<0.01, respectively). No associations were observed for the three other childhood pyrethroid metabolite concentrations (4-F-3-PBA, cis-DCCA, and trans-DCCA). Low-level childhood exposures to deltamethrin (as cis-DBCA is its principal and selective metabolite), in particular, and to pyrethroid insecticides, in general (as reflected in levels of the 3-PBA metabolite) may negatively affect neurocognitive development by 6years of age. Whatever their etiology, these cognitive deficits may be of importance educationally, because cognitive impairments in children interfere with learning and social development. Potential causes that can be prevented are of paramount public health importance.
  [Viel JF, Warembourg C, Le Maner-Idrissi G, Lacroix A, et al. 2015. Environ Int. 82:69-75.]
• The neurotoxicity of organochlorine and pyrethroid pesticides
  Organochlorine and pyrethroid compounds represent an old and a new class, respectively, of insecticides. Organochlorines such as DDT, dieldrin, or chlordecone, have been banned, primarily because of environmental issues. DDT is still used in certain countries to fight malaria-bearing mosquitoes, while lindane still finds some limited used against head lice. In contrast, pyrethroids find widespread use because of their efficacy, low environmental persistence, and relatively low mammalian toxicity. Like all insecticides, organochlorines and pyrethroids target the nervous system of insects and of nontarget species. All pyrethroids and DDT interact with the sodium channel; by keeping it open longer, they increase the likelihood of action potentials developing, thus creating a condition of hyperexcitability, whose main clinical sign is tremors. Most other organochlorines (except chlordecone), as well as certain (type II) pyrethroids, block the chloride channels of the GABA-A receptor, and cause seizures. Evidence of an association between exposure to organochlorine and pyrethroid insecticides and neurodegenerative diseases (e.g., Parkinson's disease) is weak, at best.
  [Costa LG. 2015. Handb Clin Neurol. 131:135-48]
• Effects of occupational exposure to chlorpyrifos on neuropsychological function: a prospective longitudinal study
  Exposure to chlorpyrifos (CPF), an organophosphorus (OP) anticholinesterase insecticide, occurs typically in settings where multiple agents are present (e.g., agriculture) and quantitative dose measures may be absent (e.g., pesticide application). Such exposures allow few opportunities to study potential neurobehavioral effects of CPF alone. We studied the relationship between CPF exposure and behavioral function among CPF manufacturing workers, which allowed identification, measurement, and estimation of exposure and important non-exposure variables that potentially could affect study findings. A prospective longitudinal study design was used to compare neurobehavioral function over a one-year period among 53 CPF workers and 60 referent workers. Quantitative and qualitative measures were used, and potential confounders were identified and tested for possible inclusion in our statistical models. Neurobehavioral function was assessed by neuropsychological tests covering various behavioral domains that may be adversely affected by exposure to CPF in sufficient amount. CPF workers had significantly greater CPF exposures during the study period than did referents at levels where physiologic effects on plasma butyrylcholinesterase (BuChE) activity were apparent and with higher 3,5,6-trichloro-2-pyridinol (TCPy/Cr) urinary excretion (p<0.0001) and lower average BuChE activity (p<0.01). No evidence for impaired neurobehavioral domains by either group of workers was observed at baseline, on repeat examination, or between examinations. CPF workers scored higher than referent workers on the verbal memory domain score (p=0.03) at baseline, but there were no significant changes in verbal memory over time and no significant group-by-time interactions.The study provides important information about CPF exposure in the workplace by not supporting our working hypothesis that CPF exposure associated with various aspects of the manufacturing process would be accompanied by adverse neurobehavioral effects detectable by quantitative neurobehavioral testing. Some aspects making this workplace site attractive for study and also present limitations for the generalization of results to other situations that might have exposures that vary widely between and within different facilities and locations. For example, these results might not apply to occupations such as applicators with higher exposure or to workers with low educational levels.
  [Berent S, Giordani B, Albers JW, Garabrant DH, et al. 2014. Neurotoxicology. 41:44-53]
• Acetylcholinesterase activity and neurodevelopment in boys and girls.
  Organophosphate exposures can affect children's neurodevelopment, possibly due to neurotoxicity induced by acetylcholinesterase (AChE) inhibition, and may affect boys more than girls. Authors tested the hypothesis that lower AChE activity is associated with lower neurobehavioral development among children living in Ecuadorian floricultural communities. In 2008, authors examined 307 children (age: 4-9 years; 52% male) and quantified AChE activity and neurodevelopment in 5 domains: attention/executive functioning, language, memory/learning, visuospatial processing, and sensorimotor (NEPSY-II test). Mean ± standard deviation AChE activity was 3.14 ± 0.49 U/mL (similar for both genders). The range of scores among neurodevelopment subtests was 5.9 to 10.7 U. Girls had a greater mean attention/executive functioning domain score than boys. In boys only, there were increased odds ratios of low neurodevelopment among those in the lowest tertile versus the highest tertile of AChE activity after adjustment for socioeconomic and demographic factors, height-for-age, and hemoglobin. Within these domains, attention, inhibition and long-term memory subtests were most affected.Overall, low AChE activity was associated with deficits in neurodevelopment, particularly in attention, inhibition, and memory in boys but not in girls. These critical cognitive skills affect learning and academic performance. Added precautions regarding secondary occupational pesticide exposure would be prudent.
  [Suarez-Lopez JR1, Himes JH, et al. 2013. Pediatrics.132(6):e1649-58.]
• Clinical and radiological findings in chlorfenapyr poisoning
  This is a case report of suicidal ingestion of chlorfenapyr, presenting with neurological complications after a latent period of more than a week, and rapidly progressing to death within days of symptoms. Chlorfenapyr is a moderately hazardous pesticide according to World Health Organization toxicity classification, and kills target organism by depriving it of energy through interference with oxidative phosphorylation at mitochondrial level. A pro-pesticide, chlorfenapyr takes time to convert to its active form and either this active form or a toxic metabolite causes delayed neurological symptoms. It causes significant neurotoxicity in rat models. This case report provides for the first time from India (second worldwide), clinical and “radiological evidence” (magnetic resonance imaging showing demyelinating/oedematous changes) of “chlorfenapyr neurotoxicity in humans.” It also highlights the “latent period” between ingestion and onset of fatal manifestations. Earlier, similar case reports of human deaths with delayed onset neurological symptoms, due to chlorfenapyr poisoning have been reported, from Japan, Columbia, and Korea.
  [Tharaknath, V.R. et al. (2013) Clinical and radiological findings in chlorfenapyr poisoning, Annals of Indian Academy of Neurology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724086/. ]
• Environmental toxic and its effect on neurodevelopment
  Neurodevelopmental disorders are the result of a disturbance of brain function. They are frequent, with varied symptomatology, manifest themselves at different times of life and tend to be persistent with impact at the individual, family and social level. The association of these disorders with genetic entities is low. Although the research supports a mode of genetic inheritance, epigenetic factors and environmental factors can play an important role. In recent years there was a striking increase of these disorders especially attention deficit hyperactivity disorders and pervasive development disorder. Environmental factors such as the intoxication of the fetus by especially heavy metals lead and mercury are to blame in some children, of these disorders. Other substances of wide use, little degradation and maintenance in the food chain as pesticides, polychlorinated biphenyls and now the recycling of electronic waste put especially infants and children at risk, and even more so in the developing countries.
  [Arroyo HA, Fernández MC. 2013. Medicina (B Aires). 73 Suppl 1:93-102.]
• Brain and nervous system damaged by low-level exposure to organophosphate pesticides
  

  Abstract

  Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed.
  [Ross, S.M. et al. (2012) ‘Neurobehavioral problems following low-level exposure to organophosphate pesticides: A systematic and meta-analytic review’, Critical Reviews in Toxicology, 43(1), pp. 21–44. doi:10.3109/10408444.2012.738645. ]

• 7-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide
  This is a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health) to estimate the relationship between prenatal chlorpyrifos (CPF) exposure and neurodevelopment among cohort children at age 7 years. 265 children were sampled and researchers measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma), and 7-year neurodevelopment. On average, for each standard deviation increase in exposure (4.61 pg/g), Full-Scale IQ declined by 1.4%, and Working Memory declined by 2.8%. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.
  [Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. 2011. Environ Health Perspect. doi:10.1289/ehp.1003160]
• Assessing Children's Dietary Pesticide Exposure: Direct Measurement of Pesticide Residues in 24-hr Duplicate Food Samples
  Researchers measured pesticide residues in 24-hr duplicate food samples collected from a group of 46 young children participating in the Children's Pesticide Exposure Study (CPES). Samples of all conventional fruits, vegetables, and fruit juices equal to the quantity consumed by their children, similarly prewashed/ prepared, and from the same source or batch. Individual or composite food items were analyzed for organophosphate (OP) and pyrethroid insecticide residues. Auhors found 14% or 5% of those food samples contained at least one OP or pyrethroid insecticide, respectively. We measured a total of 11 OP insecticides, at levels ranging from 1 to 387 ng/g, and three pyrethroid insecticides, at levels ranging from 2 to 1,133 ng/g, in children's food samples. The frequent consumption of food commodities with episodic presence of pesticide residues that are suspected to cause developmental and neurological effects in young children supports the need for further mitigation.
  [Lu C, Schenck FJ, Pearson MA, Wong JW.2010. Environ Health Perspect.118(11):1625-30.]
• Neonatal exposure to chlorpyrifos affects maternal responses and maternal aggression of female mice in adulthood
  CD-1 mice were exposed to the organophosphate pesticide chlorpyrifos (CPF) throughout postnatal days (PND) 11–14 at the subtoxic dose of 3 mg/kg. At adolescent age, females and males underwent a sociability test in which level of sociability and social preference were measured. At adulthood only females' behavior was analyzed. Maternal behavior of CPF-exposed females was assessed on postpartum day 1 after removal of the pups for 1 h, while anxiety levels were measured in a 5 min dark–light test on postpartum day 2. Nest defense response to an unfamiliar male intruder was assessed on postpartum day 7. In addition, from birth to postpartum day 7 a detailed analysis of nest building activity was carried out. Neonatal CPF exposure does not interfere with social behavior and social preferences at adolescence, whereas at adulthood it induces significant behavioral alterations in lactating females. Motivation to build and defend the nest was decreased in CPF females that were also less anxious than controls in the dark–light paradigm. These results confirm that developmental exposure to CPF induces long-lasting alterations in selected sexual-dimorphic responses of the adult social repertoire, and suggest that early exposure to CPF might interfere with hypothalamic neuroendocrine mechanisms regulating social responses.
  [Venerosi, A., Cutuli, D., Colonnello, V., Cardona, D., Ricceri, L. and Calamandrei, G., 2008. Neurotoxicology and teratology, 30(6), pp.468-474.]
• Developmental neurotoxicity of industrial chemicals.
  Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.
  [Grandjean P and Landrigan PJ.2006. Lancet.368(9553):2167-78]
• Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs.
  Pyrethroid insecticides have been used for more than 40 years and account for 25% of the worldwide insecticide market. Although their acute neurotoxicity to adults has been well characterized, information regarding the potential developmental neurotoxicity of this class of compounds is limited. There is a large age dependence to the acute toxicity of pyrethroids in which neonatal rats are at least an order of magnitude more sensitive than adults to two pyrethroids. There is no information on age-dependent toxicity for most pyrethroids. In the present review authors examine the scientific data related to potential for age-dependent and developmental neurotoxicity of pyrethroids. As a basis for understanding this neurotoxicity, authors discuss the heterogeneity and ontogeny of voltage-sensitive sodium channels, a primary neuronal target of pyrethroids. Authors also summarize 22 studies of the developmental neurotoxicity of pyrethroids and review the strengths and limitations of these studies. These studies examined numerous end points, with changes in motor activity and muscarinic acetylcholine receptor density the most common. Many of the developmental neurotoxicity studies suffer from inadequate study design, problematic statistical analyses, use of formulated products, and/or inadequate controls. These factors confound interpretation of results. To better understand the potential for developmental exposure to pyrethroids to cause neurotoxicity, additional, well-designed and well-executed developmental neurotoxicity studies are needed. These studies should employ state-of-the-science methods to promote a greater understanding of the mode of action of pyrethroids in the developing nervous system.
  [Shafer TJ, Meyer DA, Crofton KM.2005. Environ Health Perspect. 113(2):123-36.]
• Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype.
  Study tested exposed C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
  [Thiruchelvam, M., et al. 2003. Eur J Neurosci 18(3):589-600]
• An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico
  In a comparative study in Mexico, children exposed to pesticides demonstrated decreases in stamina, coordination, memory, and the ability to draw familiar subjects.
  [Guillette, E., et al. 1998. Environmental Health Perspectives, 106(6):347-353.]

• Background exposure to persistent organic pollutants predicts stroke in the elderly
  Background exposure to persistent organic pollutants (POPs), lipophilic xenobiotics that accumulate mainly in adipose tissue, has recently emerged as a new risk factor for cardiovascular diseases. This prospective study was performed to evaluate if plasma concentrations of selected POPs predict incident stroke among the elderly. Twenty‐one POPs (including 16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured in plasma collected at baseline in 898 participants aged 70 years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Stroke diagnosis was validated by hospital records. During the five year follow-up, 35 subjects developed hospital-treated stroke. After adjusting for known stroke risk factors, most PCBs with 4, 5, or 6 chlorine atoms, p,p′-DDE, trans-nonachlor, and octachlorodibenzo-p-dioxin significantly predicted the risk of stroke. Across quartiles of summary measures of PCBs and OC pesticides, the adjusted ORs were 1.0, 0.8 (95% confidence interval: 0.2–2.5), 1.2 (0.4–3.4), and 2.1 (0.7–6.2) for PCBs and 1.0, 1.2 (0.3–4.2), 2.3 (0.7–6.9), and 3.0 (1.0–9.4) for OC pesticides (P for trend = 0.11 and 0.03, respectively). The adjusted ORs among participants ≥ 90th percentile of the summary measures were 5.5 (1.7–18.1) for PCBs and 4.0 (1.1–14.6) for OC pesticides; corresponding ORs for those ≥ 95th percentile were 7.8 (2.1–29.6) and 9.5 (2.3–38.9). Background exposure to POPs may play an important role in development or progression of stroke in the elderly.
  [Lee, D.H., Lind, P.M., Jacobs Jr, D.R., Salihovic, S., van Bavel, B. and Lind, L., 2012. Environment international, 47, pp.115-120.]