Pesticide-Induced Diseases: Alzheimer’s Disease
According to the Alzheimer’s Association, Alzheimer’s disease (AD), the most common form of dementia, is a progressive and fatal brain disease. As many as 5.3 million Americans are living with Alzheimer’s disease. Alzheimer’s destroys brain cells, causing memory loss and problems with thinking and behavior severe enough to affect work, lifelong hobbies or social life. Alzheimer’s gets worse over time, it is fatal, and has no current cure.
- 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.]
- 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.]
- 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. ]
- 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.
This study examined the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. A total of 17,429 hospital records were collected 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. This study supports and extends previous findings 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., et al. 2011. Toxicol Appl Pharmacol. Epub ahead of print]
- Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2.
This study investigated the effects of paraquat pesticide exposure on wild-type mice and β-amyloid precursor protein (APP) transgenic mice. Results show 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. Results demonstrate that mitochondrial damage is a key mechanism underlying cognitive impairment and elevated amyloidogenesis induced by paraquat.
[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]