- 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. ] - An update of the impact of pesticide exposure on memory and learning
The dependence on the use of pesticides in agribusiness leads to an increase in human exposure to these chemical compounds through occupational activity, contamination of the environment, food and water. The nervous system is the target of most insecticidal pesticides and when these are poorly selective, they can harm non-target species, including humans. This work aimed to investigate the effects of pesticide exposure on memory and learning. Articles published in PubMed database between 2015 and 2024 were reviewed. One hundred and sixty-one articles were included in this review, of which one hundred and thirty two were preclinical studies and twenty-nine were human studies. Among preclinical studies, exposure to organophosphates, pyrethroids, neonicotinoids, carbamates, in addition to herbicides, fungicides and mixed exposures was associated with learning and memory deficits in animals such as bees, mosquitoes, fishes, mice, rats, and bats. Olfactory, associative and aversive learning, as well as memory capacity were affected by the exposure to pesticides. Most human studies evaluated the environmental and occupational exposure to organophosphate pesticides, pyrethroids and carbamates associated with the outcomes of interest. Living close to pesticide application areas and having parents working in agriculture were associated with worse learning and memory scores in childhood and adolescence. Prenatal exposure to insecticides has already been associated with poorer attention skills and attention-deficit/hyperactivity disorder (ADHD) symptoms, intellectual disability, autism spectrum disorder, motor delays, and attention problems. In adults, exposure during occupational activity was also associated with poorer memory and learning performance. The evidence found in this review suggests that pesticides with different mechanisms of action were able to cause some cognitive impairment. Developmental exposure, as well as chronic environmental and occupational exposure, can contribute to poorer cognitive performance, especially in learning and memory.
[Honatel, K.F. et al. (2024) An update of the impact of pesticide exposure on memory and learning, Discover Toxicology. Available at: https://link.springer.com/article/10.1007/s44339-024-00011-9.] - Cyfluthrin exposure during pregnancy causes neurotoxicity in offspring—Ca2+ overload via IP3R-GRP75-VDAC1 pathway
Cyfluthrin (Cy) is a widely used pyrethroid insecticide. There is growing evidence that Cy can cause damage to the nervous, reproductive, and immune systems, but there is limited evidence on the potential effects of maternal Cy exposure on offspring. A model of maternal Cy exposure was used to assess its neurobehavioral effects on young-adult offspring. We found that gestational Cy exposure affected pregnancy outcomes and fetal development, and that offspring showed impairments in anxiety as well as learning and memory, accompanied by impairments in hippocampal synaptic ultrastructure and synaptic plasticity. In addition, the IP3R-GRP75-VDAC1 apoptogenic pathway was also upregulated, and in vitro models showed that inhibition of this pathway alleviated neuronal apoptosis as well as synaptic plasticity damage. In conclusion, maternal Cy exposure during pregnancy can cause neurobehavioral abnormalities and synaptic damage in offspring, which may be related to neuronal apoptosis induced by activation of the IP3R-GRP75-VDAC1 pathway in the hippocampus of offspring. Our findings provide clues to understand the neurotoxicity mechanism of maternal Cy exposure to offspring during pregnancy.
[Haoxuan Gao, Mi Tian, Xiaozhe Geng, Ji Zhao, Yanan Song, Bing Wu, Xueyan Tian, Yong Yang, Wensi Ni, Huifang Yang, Cyfluthrin exposure during pregnancy causes neurotoxicity in offspring—Ca2+ overload via IP3R-GRP75-VDAC1 pathway, Ecotoxicology and Environmental Safety, Volume 274, 2024, 116218, ISSN 0147-6513, https://doi.org/10.1016/j.ecoenv.2024.116218.] - 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. ] - Lambda-cyhalothrin alters locomotion, mood and memory abilities in Swiss mice
Lambda-cyhalothrin (LCT) is a type II pyrethroid widely used in agriculture for plant protection against pests. However, pyrethroids represents a risk for rural female farmworkers, and few studies addressed LCT-behavioural alterations in mice. The present study evaluates the effect of LCT on behaviour of eight weeks aged female mice. Mice were divided into three groups including treated mice that received through gavage (i) 0.5 mg/kg bw and (ii) 2 mg/kg of LCT dissolved in corn oil, and (iii) the vehicle controls. Behavioural tests assess the locomotor activity using open field test, the anxiety by the dark-light box test, the learning memory with novel object recognition test, the memory retention by the elevated plus maze test, and the spatial working memory using the Y-maze test. Subacute treatment with low doses of LCT decreases total distance travelled, induces anxiogenic effect by reducing the time spent in the enlightened compartment, alters memory retention by increasing the latency time, and also affects learning memory by reducing the recognition index parameter. However, LCT does not significantly alter spatial working memory. In conclusion, LCT-treated female mice show an alteration in locomotor activity, mood state and memory abilities probably related to oxidative stress and altered neurotransmission.
[Assmaa Tali, Nadra Lekouch, Samir Ahboucha, Lambda-cyhalothrin alters locomotion, mood and memory abilities in Swiss mice, Food and Chemical Toxicology, Volume 188, 2024, 114680, ISSN 0278-6915, https://doi.org/10.1016/j.fct.2024.114680.] - Long-term behavioral and neurochemical paradoxical alterations elicited following intranasal application of a chlorpyrifos formulation in mice
The intranasal (IN) administration route represents a pathway for xenobiotics to reach the brain. The present study aimed to address the long-term consequences of IN administration of a chlorpyrifos (CPF) commercial formulation (fCPF) in mice. For this purpose, adult male CF-1 mice were intranasally administered with fCPF (10 mg/kg/day) three days a week, for 2 and 4 weeks, respectively. Behavioral and biochemical analyses were conducted 3–7, and 7.5 months after the last IN fCPF administration, respectively. Following a 6-month fCPF-free washout period, fur appearance and body injuries scores improved in the fCPF-treated groups. Notably, spatial learning and memory enhancement was observed 4 and 7 months after the last IN fCPF administration. Changes in oxidative stress markers and the activities of enzymes involved in cholinergic and glutamatergic pathways were observed in different brain areas from fCPF-treated mice, still after 7.5 months from fCPF application. Altogether, these neurochemical disturbances could be responsible for the described behavioral observations.
[Cristina Eugenia Gallegos, Fernanda Gumilar, Mariana Bartos, Carlos Javier Baier,
Long-term behavioral and neurochemical paradoxical alterations elicited following intranasal application of a chlorpyrifos formulation in mice, Pesticide Biochemistry and Physiology, Volume 198, 2024, 105717, ISSN 0048-3575, https://doi.org/10.1016/j.pestbp.2023.105717.
] - 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. ] - Olfactory Learning Behavior and Mortality of the Honey Bee Apis mellifera jemenitica in Response to Pyrethroid Insecticide (Deltamethrin)
Honey bees are constantly threatened due to the wide use of pesticides. This study presents the effects of deltamethrin on the mortality, olfactory learning, and memory formation of the native Saudi bee Apis mellifera jemenitica. Topical and oral application of realistic field and serial dilutions of deltamethrin (250, 125, 62.5, and 25 ppm) caused significant mortality at 4, 12, 24, and 48 h posttreatment. Bee mortality increased with the increasing concentration of insecticide at all tested posttreatment times. Highest mortality was observed at 24 h and 48 h after both exposure routes. Food consumption gradually decreased with increasing concentration of deltamethrin during oral exposure. The LC50 of deltamethrin was determined at 12, 24, and 48 h for topical (86.28 ppm, 36.16 ppm, and 29.19 ppm, respectively) and oral (35.77 ppm, 32.53 ppm, and 30.78 ppm, respectively) exposure. Oral exposure led to significantly higher bee mortality than topical exposure of deltamethrin at 4 h and 12 h, but both exposure routes were equally toxic to bees at 24 h and 48 h. The sublethal concentrations (LC10, LC20, and LC30) of deltamethrin significantly impaired the learning during conditioning trials, as well as the memory formation of bees at 2, 12, and 24 h after topical and oral exposure. Thus, deltamethrin inhibits learning, and bees were unable to memorize the learned task.
[Abuagla, M. I. B., Iqbal, J., Raweh, H. S. A., & Alqarni, A. S. (2024). Olfactory Learning Behavior and Mortality of the Honey Bee Apis mellifera jemenitica in Response to Pyrethroid Insecticide (Deltamethrin). Toxics, 12(1), 25. https://doi.org/10.3390/toxics12010025] - Persistent diazinon induced neurotoxicity: The effect on inhibitory avoidance memory performance, amyloid precursor proteins, and TNF-α levels in the prefrontal cortex of rats
Introduction
Organophosphate pesticides (Ops) like diazinon (DZN) have well-known neurotoxic effects and low-level chronic exposure has been linked to detrimental neurobehavioral impairments and memory deficits. However, it’s not entirely clear how DZN-induced biological changes, particularly in the prefrontal cortex (PFC) contribute to these effects. The purpose of this study is to investigate the impact of DZN exposure on inhibitory avoidance (IA) memory function, amyloid precursor expression (APP), and proinflammatory tumor necrosis factor-α (TNF-α) levels in the rat cortex.
Materials and Methods
Rats were divided into 4 groups and recived 2 mg/kg DZN for 5-days or 12-weeks and two control groups recived the same volume of vehicle. IA memory was assesed using the shuttle box apparatus. Rats were sacrificed and the prefrontal cortex PFC were removed. Real-time PCR and Western blotting were used to messure TNF-α, and amyloid protein precursors gene expression and protein levels.
Results
Our findings indicated that DZN caused body weight loss and a notable decline in performance on the IA memory. Additionally, 5-days exposure increased APP and APLP2 protein levels in the PFC, while 12-weeks exposure decreased these levels. Furthermore, expression of APP and APLP2 gens were decreased in PFC. TNF-α levels increased as a result of 5-days exposure to DZN, but these levels dropped to normal after 12-weeks administration, and this observation was significant.
Conclusion
Taken together, exposure to low doses of DZN leads to disturbances in IA memory performance and also alternations in amyloid beta precursors that can be related to increased risk of Alzheimer’s disease.
[Afshari S, Sarailoo M, Asghariazar V, Safarzadeh E, Dadkhah M. Persistent diazinon induced neurotoxicity: The effect on inhibitory avoidance memory performance, amyloid precursor proteins, and TNF-α levels in the prefrontal cortex of rats. Human & Experimental Toxicology. 2024;43. doi:10.1177/09603271241235408] - 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.] - Behavioral and neurochemical impairments after intranasal administration of chlorpyrifos formulation in mice
Among the most relevant environmental factors associated with the etiology of neurodegenerative disorders are pesticides. Spray drift or volatilization generates pesticide dispersion after its application. In addition, inhalation or intranasal (IN) administration of xenobiotics constitutes a feasible route for substance delivery to the brain. This study investigates the behavioral and neurochemical effects of IN exposure to a commercial formulation of chlorpyrifos (fCPF). Adult male CF-1 mice were intranasally administered with fCPF (3–10 mg/kg/day) three days a week, for 2 weeks. Behavioral and biochemical analyses were conducted 20 and 30 days after the last IN fCPF administration, respectively. No significant behavioral or biochemical effects were observed in the 3 mg/kg fCPF IN exposure group. However, animals exposed to 10 mg/kg fCPF showed anxiogenic behavior and recognition memory impairment, with no effects on locomotor activity. In addition, the IN administration of 10 mg/kg fCPF altered the redox balance, modified the activity of enzymes belonging to the cholinergic and glutamatergic pathways, and affected glucose metabolism, and cholesterol levels in different brain areas. Taken together, these observations suggest that these biochemical imbalances could be responsible for the neurobehavioral disturbances observed after IN administration of fCPF in mice.
[Cristina Eugenia Gallegos, Mariana Bartos, Fernanda Gumilar, Alejandra Minetti, Carlos Javier Baier,
Behavioral and neurochemical impairments after intranasal administration of chlorpyrifos formulation in mice, Pesticide Biochemistry and Physiology, Volume 189, 2023, 105315, ISSN 0048-3575, https://doi.org/10.1016/j.pestbp.2022.105315.] - Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts
Background
During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community.
Methods
The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI.
Results
Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans.
Conclusions
This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.
[Keating, D., Krengel, M., Dugas, J. et al. Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts. Environ Health 22, 68 (2023). https://doi.org/10.1186/s12940-023-01018-2]
- 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. ] - Neuroprotective effect of piracetam-loaded magnetic chitosan nanoparticles against thiacloprid-induced neurotoxicity in albino rats
Thiacloprid (TH) is a neurotoxic agricultural insecticide and potential food contaminant. The purpose of this study was to investigate the relationship between TH exposure and memory dysfunction in rats, as well as the potential protective effect of piracetam and piracetam-loaded magnetic chitosan nanoparticles (PMC NPs). Rats were divided into five equal groups (six rats/group). The control group received saline. Group II was treated with PMC NPs at a dose level of 200 mg/kg body weight (Bwt); Group III was treated with 1/10 LD50 of TH (65 mg/kg Bwt); Group IV was treated with TH (65 mg/kg Bwt) and piracetam (200 mg/kg Bwt); Group V was co-treated with TH (65 mg/kg Bwt) and PMC NPs (200 mg/kg Bwt). All animal groups were dosed daily for 6 weeks by oral gavage. Footprint analysis, hanging wire test, open field test, and Y-maze test were employed to assess behavioral deficits. Animals were euthanized, and brain tissues were analyzed for oxidative stress biomarkers, proinflammatory cytokines, and gene expression levels of glial fibrillary acidic protein (GFAP), amyloid-beta precursor protein (APP), B-cell lymphoma 2 (Bcl-2), and caspase-3. Brain and sciatic nerve tissues were used for the evaluation of histopathological changes and immunohistochemical expression of tau protein and nuclear factor kappa B (NF-κB), respectively. The results revealed that TH-treated rats suffered from oxidative damage and inflammatory effect on the central and peripheral nerves. The administration of PMC NPs considerably protected against TH-induced neuronal damage, increased antioxidant enzyme activity, decreased inflammatory markers, and improved behavioral performance than the group treated with piracetam. The neuroprotective effect of PMC NPs was mediated through the inhibition of GFAP, APP, caspase-3, Tau, and NF-κB gene expression with induction of Bcl-2 expression. In conclusion, TH could induce oxidative stress, inflammatory and neurobehavior impairment in rats. However, PMC NPs administration markedly mitigated TH-induced brain toxicity, possibly via oxidative and inflammatory modulation rather than using piracetam alone.
[Abomosallam, M., Hendam, B.M., Abdallah, A.A. et al. Neuroprotective effect of piracetam-loaded magnetic chitosan nanoparticles against thiacloprid-induced neurotoxicity in albino rats. Inflammopharmacol 31, 943–965 (2023). https://doi.org/10.1007/s10787-023-01151-x] - 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.] - Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders
Increasing evidence from animal and epidemiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity and may increase the risk for psychiatric disorders such as autism and intellectual disability. However, the underlying pathogenic mechanisms remain largely elusive. This work was aimed at testing the hypothesis that developmental exposure to different classes of pesticides hijacks intracellular neuronal signaling contributing to synaptic and behavioral alterations associated with neurodevelopmental disorders (NDD). Low concentrations of organochlorine (dieldrin, endosulfan, and chlordane) and organophosphate (chlorpyrifos and its oxon metabolite) pesticides were chronically dosed ex vivo (organotypic rat hippocampal slices) or in vivo (perinatal exposure in rats), and then biochemical, electrophysiological, behavioral, and proteomic studies were performed. All the pesticides tested caused prolonged activation of MAPK/ERK pathway in a concentration-dependent manner. Additionally, some of them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In the case of the pesticide chlordane, the effect was attributed to chronic modulation of MAPK/ERK signaling. These synaptic alterations were reproduced following developmental in vivo exposure to chlordane and chlorpyrifos-oxon, and were also associated with prototypical behavioral phenotypes of NDD, including impaired motor development, increased anxiety, and social and memory deficits. Lastly, proteomic analysis revealed that these pesticides differentially regulate the expression of proteins in the hippocampus with pivotal roles in brain development and synaptic signaling, some of which are associated with NDD. Based on these results, we propose a novel mechanism of synaptic dysfunction, involving chronic overactivation of MAPK and impaired mGluR-LTD, shared by different pesticides which may have important implications for NDD.
[López-Merino, E., Cuartero, M.I., Esteban, J.A. et al. Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders. Cell Biol Toxicol 39, 2089–2111 (2023). https://doi.org/10.1007/s10565-022-09697-2] - 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. ] - Association of Gulf War Illness-Related Symptoms with Military Exposures among 1990–1991 Gulf War Veterans Evaluated at the War-Related Illness and Injury Study Center (WRIISC)
Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990–1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans’ reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans’ severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78–9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02–5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01–5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war.
[Ahmed, S. T., Steele, L., Richardson, P., Nadkarni, S., Bandi, S., Rowneki, M., Sims, K. J., Vahey, J., Gifford, E. J., Boyle, S. H., Nguyen, T. H., Nono Djotsa, A., White, D. L., Hauser, E. R., Chandler, H., Yamal, J. -M., & Helmer, D. A. (2022). Association of Gulf War Illness-Related Symptoms with Military Exposures among 1990–1991 Gulf War Veterans Evaluated at the War-Related Illness and Injury Study Center (WRIISC). Brain Sciences, 12(3), 321. https://doi.org/10.3390/brainsci12030321] - 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] - Motor, memory, and anxiety-like behavioral impairments associated with brain-derived neurotrophic factor and dopaminergic imbalance after inhalational exposure to deltamethrin
Believed to cause damage to the nervous system and possibly being associated with neurodegenerative diseases, deltamethrin (DM) is a type II pyrethroid used in pest control, public health, home environment, and vector control. The objective of this study was to evaluate the motor, cognitive and emotional changes associated with dopaminergic and BDNF imbalance after DM exposure in rats. Sixty Wistar rats (9–10 months-old) were used, under Ethics Committee on Animal Research license (ID 19/2017). The animals were randomly divided into four groups: control (CTL, 0.9% saline), DM2 (2 mg DM in 1.6 mL 0.9% saline), DM4 (4 mg of DM in 1.6 mL of 0.9% saline), and DM8 (8 mg of DM in 1.6 mL of 0.9% saline). DM groups were submitted to 9 or 15 inhalations, one every 48 h. Half of the animals from each group were randomly selected and perfused 24 h after the 9th or 15th inhalation. Throughout the experiment, the animal’s behavior were evaluated using catalepsy test, open field, hole-board test, Modified Elevated Plus Maze, and social interaction. At the end of the experiments, the rats were perfused transcardially and their brains were processed for Tyrosine Hydroxylase (TH) and Brain derived neurotrophic factor (BDNF) immunohistochemistries. The animals submitted to 9 inhalations of DM showed a reduction in immunoreactivity for TH in the Substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and dorsal striatum (DS) areas, and an increase in BDNF in the DS and CA1, CA3 and dentate gyrus (DG) hippocampal areas. Conversely, the animals submitted to 15 inhalations of DM showed immunoreactivity reduced for TH in the SNpc and VTA, and an increase in BDNF in the hippocampal areas (CA3 and DG). Our results indicate that the DM inhalation at different periods induce motor and cognitive impairments in rats. Such alterations were accompanied by dopaminergic system damage and a possible dysfunction on synaptic plasticity.
[Marina F. Souza, Katty A.A.L. Medeiros, Lívia C.R.F. Lins, José M.M. Bispo, Auderlan M. Gois, Edson R. Santos, Thiago H. Almeida-Souza, João E.C. Melo, Heitor S. Franco, Rodolfo S. Silva, Eduardo A. Pereira-Filho, Marco Aurelio M. Freire, José R. Santos, Motor, memory, and anxiety-like behavioral impairments associated with brain-derived neurotrophic factor and dopaminergic imbalance after inhalational exposure to deltamethrin, Brain Research Bulletin, Volume 181, 2022, Pages 55-64, ISSN 0361-9230, https://doi.org/10.1016/j.brainresbull.2022.01.004.] - Persistent neurobehavioral and neurochemical anomalies in middle-aged rats after maternal diazinon exposure
Diazinon is an organophosphate pesticide that has a history of wide use. Developmental exposures to organophosphates lead to neurobehavioral changes that emerge early in life and can persist into adulthood. However, preclinical studies have generally evaluated changes through young adulthood, whereas the persistence or progression of deficits into middle age remain poorly understood. The current study evaluated the effects of maternal diazinon exposure on behavior and neurochemistry in middle age, at 1 year postpartum, comparing the results to our previous studies of outcomes at adolescence and in young adulthood (4 months of age) (Hawkey 2020). Female rats received 0, 0.5 or 1.0 mg/kg/day of diazinon via osmotic minipump throughout gestation and into the postpartum period. The offspring were tested on a battery of locomotor, affective, and cognitive tests at young adulthood and during middle age. Some of the neurobehavioral consequences of developmental DZN seen during adolescence and young adulthood faded with continued aging, whereas other neurobehavioral effects emerged with aging. At middle age, the rats showed few locomotor effects, in contrast to the locomotor hyperactivity that had been observed in adolescence. Notably, though, DZN exposure during development impaired reference memory performance in middle-aged males, an effect that had not been seen in the younger animals. Likewise, middle-aged females exposed to DZN showed deficient attentional accuracy, an effect not seen in young adults. Across adulthood, the continued potential for behavioral defects was associated with altered dopaminergic function, characterized by enhanced dopamine utilization that was regionally-selective (striatum but not frontal/parietal cortex). This study shows that the neurobehavioral impairments from maternal low dose exposure to diazinon not only persist, but may continue to evolve as animals enter middle age.
[Andrew B. Hawkey, Erica Pippen, Bruny Kenou, Zade Holloway, Theodore A. Slotkin, Frederic J. Seidler, Edward D. Levin, Persistent neurobehavioral and neurochemical anomalies in middle-aged rats after maternal diazinon exposure, Toxicology, Volume 472, 2022, 153189, ISSN 0300-483X, https://doi.org/10.1016/j.tox.2022.153189.] - Pesticide exposure and cortical brain activation among farmworkers in Costa Rica
Background: Previous epidemiological studies have reported associations of pesticide exposure with poor cognitive function and behavioral problems. However, these findings have relied primarily on neuropsychological assessments. Questions remain about the neurobiological effects of pesticide exposure, specifically where in the brain pesticides exert their effects and whether compensatory mechanisms in the brain may have masked pesticide-related associations in studies that relied purely on neuropsychological measures.
Methods: We conducted a functional neuroimaging study in 48 farmworkers from Zarcero County, Costa Rica, in 2016. We measured concentrations of 13 insecticide, fungicide, or herbicide metabolites or parent compounds in urine samples collected during two study visits (approximately 3-5 weeks apart). We assessed cortical brain activation in the prefrontal cortex during tasks of working memory, attention, and cognitive flexibility using functional near-infrared spectroscopy (fNIRS). We estimated associations of pesticide exposure with cortical brain activation using multivariable linear regression models adjusted for age and education level.
Results: We found that higher concentrations of insecticide metabolites were associated with reduced activation in the prefrontal cortex during a working memory task. For example, 3,5,6-trichloro-2-pyridinol (TCPy; a metabolite of the organophosphate chlorpyrifos) was associated with reduced activation in the left dorsolateral prefrontal cortex (β = -2.3; 95% CI: -3.9, -0.7 per two-fold increase in TCPy). Similarly, 3-phenoxybenzoic acid (3-PBA; a metabolite of pyrethroid insecticides) was associated with bilateral reduced activation in the dorsolateral prefrontal cortices (β = -3.1; 95% CI: -5.0, -1.2 and -2.3; 95% CI: -4.5, -0.2 per two-fold increase in 3-PBA for left and right cortices, respectively). These associations were similar, though weaker, for the attention and cognitive flexibility tasks. We observed null associations of fungicide and herbicide biomarker concentrations with cortical brain activation during the three tasks that were administered.
Conclusion: Our findings suggest that organophosphate and pyrethroid insecticides may impact cortical brain activation in the prefrontal cortex - neural dynamics that could potentially underlie previously reported associations with cognitive and behavioral function. Furthermore, our study demonstrates the feasibility and utility of fNIRS in epidemiological field studies.
[Mora, A. M., Baker, J. M., Hyland, C., Rodríguez-Zamora, M. G., Rojas-Valverde, D., Winkler, M. S., Staudacher, P., Palzes, V. A., Gutiérrez-Vargas, R., Lindh, C., Reiss, A. L., Eskenazi, B., Fuhrimann, S., & Sagiv, S. K. (2022). Pesticide exposure and cortical brain activation among farmworkers in Costa Rica. Neurotoxicology, 93, 200–210. https://doi.org/10.1016/j.neuro.2022.10.004]
- 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. ] - The negative effect of flumethrin stress on honey bee (Apis mellifera) worker from larvae to adults
Flumethrin is a highly effective acaricide, but its lipophilic characteristic has some negative effects, such as accumulation in bee hives and bee products. However, studies on the survival stress of honey bees subsequent to chronic flumethrin exposure are limited. To answer this question, a study was carried out on the stress to honey bee (Apis mellifera) workers from larvae to adults by chronic exposure to sublethal concentrations of flumethrin. Three flumethrin treatment groups (1, 0.1, 0.01 mg/L) and one control group (with no added flumethrin) were established and divided the worker larvae into four groups. Then, starting with 2-day-old larvae, larvae and subsequent emerged worker bees of the four groups were orally fed with the corresponding concentrations of flumethrin until all the adult worker bees died, respectively. When the concentration was at 0.01 mg/L of flumethrin, the lifespan of adult worker bees decreased, and a down-regulation of detoxification-related genes (CYP450,GSTS) was induced in 1-day-old pupae. When it is at 0.1 mg/L flumethrin, the lifespan of adult worker bees was again shortened, and down-regulation of memory-related genes (GluRA1, Nmdar1, Tyr1) in 1-day-old pupae and gene Tyr1 in 1-day-old worker bees, detoxification-related genes (CYP450,GSTS) in 1-day-old pupae, and immunity genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees were observed. When the concentration is at 1 mg/L flumethrin, lighter birth weight of newly emerged honeybee was found and deficiencies in olfactory learning and memory were observed in 7-day-old worker bees. Memory-related genes (GluRA1, Nmdar1, Tyr1) were down-regulated in 1-day-old pupae and genes (Nmdar1,Tyr1)in 1-day-old worker bees, as were detoxification-related genes (CYP450,GSTS) in 1-day-old pupae and gene CPY450 in 7-day-old worker bees, and immune genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees. There was no significant difference in pupal weight, capping rate, emergence rate, expression of immune-related genes of 1-day-old pupae, expression of immune-related genes and detoxification-related genes of 1-day-old worker bees, expression of memory-related genes and detoxification-related gene GSTS of 7-day-old worker bees. These data provide an ominous warning about the unintended consequences on apiaries, and underscore the need for careful control of flumethrin residues in bee hives.
[Zhen Li, Heyan Yang, Longtao Yu, Chen Liu, Xiaobo Wu, The negative effect of flumethrin stress on honey bee (Apis mellifera) worker from larvae to adults, Pesticide Biochemistry and Physiology, Volume 188, 2022, 105289, ISSN 0048-3575, https://doi.org/10.1016/j.pestbp.2022.105289.] - 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.] - Exposure to multiple pesticides and neurobehavioral outcomes among smallholder farmers in Uganda
Background
Multiple epidemiological studies have shown that exposure to single pesticide active ingredients or chemical groups is associated with adverse neurobehavioral outcomes in farmers. In agriculture, exposure to multiple pesticide active ingredients is the rule, rather than exception. Therefore, occupational studies on neurobehavioral effects of pesticides should account for potential co-exposure confounding.
Methods
We conducted a cross-sectional study of 288 Ugandan smallholder farmers between September and December 2017. We collected data on self-reported use of pesticide products during the 12 months prior to survey and estimated yearly exposure-intensity scores for 14 pesticide active ingredients using a semi-quantitative exposure algorithm. We administered 11 neurobehavioral tests to assess five neurobehavioral domains. We implemented a Bayesian Model-Averaging (BMA) approach to examine the association between exposure to multiple pesticides and neurobehavioral outcomes, while accounting for multiple testing. We applied two levels of inference to determine (1) which neurobehavioral outcomes were associated with overall pesticide exposure (marginal inclusion probability (MIP) for covariate-only models <0.5) and (2) which specific pesticide active ingredients were associated with these outcomes (MIP for models where active ingredient was included >0.5).
Results
Seventy-two percent of farmers reported use of pesticide products that contained at least one of 14 active ingredients, while the applicators used in median three different active ingredients (interquartile range (IQR) 4) in the 12 months prior to the study. The most widely used active ingredients were glyphosate (79%), cypermethrin (60%), and mancozeb (55%). We found that overall pesticide exposure was associated with impaired visual memory (Benton Visual Retention Test (BVRT)), language (semantic verbal fluency test), perceptual-motor function (Finger tapping test), and complex attention problems (Trail making A test and digit symbol test). However, when we looked at the associations for individual active ingredients, we only observed a positive association between glyphosate exposure and impaired visual memory (-0.103 [95% Bayesian Credible Interval (BCI)] [-0.24, 0] units in BVRT scores per interquartile range (IQR) increase in annual exposure to glyphosate, relative to a median [IQR] of 6 [3] units in BVRT across the entire study population).
Conclusions
We found that overall pesticide exposure was associated with several neurobehavioral outcome variables. However, when we examined individual pesticide active ingredients, we observed predominantly null associations, except for a positive association between glyphosate exposure and impaired visual memory. Additional epidemiologic studies are needed to evaluate glyphosate’s neurotoxicity, while accounting for co-pollutant confounding.
[Samuel Fuhrimann, Andrea Farnham, Philipp Staudacher, Aggrey Atuhaire, Tiziana Manfioletti, Charles B. Niwagaba, Sarah Namirembe, Jonathan Mugweri, Mirko S. Winkler, Lutzen Portengen, Hans Kromhout, Ana M. Mora, Exposure to multiple pesticides and neurobehavioral outcomes among smallholder farmers in Uganda, Environment International, Volume 152, 2021, 106477, ISSN 0160-4120, https://doi.org/10.1016/j.envint.2021.106477.] - 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.] - Assessment of lethal and sublethal effects of imidacloprid, ethion, and glyphosate on aversive conditioning, motility, and lifespan in honey bees (Apis mellifera L.)
Honeybees (Apis mellifera) play an important role in agriculture worldwide. Several factors including agrochemicals can affect honey bee health including habitat fragmentation, pesticide application, and pests. The growing human population and subsequent increasing crop production have led to widespread use of agrochemicals and there is growing concern that pollinators are being negatively impacted by these pesticides. The present study compares acute exposure to imidacloprid (0.2 and 0.4 mgL−1), ethion (80 and 106.7 mgL−1) or glyphosate (0.12 and 0.24 mgL−1) on aversive learning and movement, to chronic exposure at these and higher concentrations on movement, circadian rhythms, and survival in honey bee foragers. For acute learning studies, a blue/yellow shuttle box experiment was conducted; we observed honey bee choice following aversive and neutral stimuli. In learning studies, control bees spent >50% of the time on yellow which is not consistent with previous color bias literature in the subspecies or region of the study. The learning apparatus was also used to estimate mobility effects within 20 min of exposure. Chronic exposure (up to 2 weeks) with the above metrics was recorded by an automated monitoring system. In chronic exposure experiments, RoundUp®, was also tested to compare to its active ingredient, glyphosate. We found that imidacloprid and ethion have negative impacts on aversive learning and movement following a single-dose and that chronic exposure effects were dose-dependent for these two insecticides. In contrast, glyphosate had no effect on learning and less of an effect on movement; RoundUp® showed dose-dependent results on circadian rhythmicity. Overall, the results suggest that short-term exposure to imidacloprid and ethion adversely affect honey bee foragers and chronic exposure to glyphosate may affect pollination success.
[Sahar Delkash-Roudsari, Ana M. Chicas-Mosier, Seyed Hossein Goldansaz, Khalil Talebi-Jahromi, Ahmad Ashouri, Charles I. Abramson, Assessment of lethal and sublethal effects of imidacloprid, ethion, and glyphosate on aversive conditioning, motility, and lifespan in honey bees (Apis mellifera L.), Ecotoxicology and Environmental Safety, Volume 204, 2020, 111108, ISSN 0147-6513, https://doi.org/10.1016/j.ecoenv.2020.111108.] - Association between cholinesterase's inhibition and cognitive impairment: A basis for prevention policies of environmental pollution by organophosphate and carbamate pesticides in Chile
Background
In Chile organophosphate pesticides are widely used in the production of fruits. Pesticides use is regulated for professional practice but there is no regulation regarding exposure to the general population.
Objective
To relate exposure to cholinesterase's inhibitor pesticides during the spray season with neuropsychological impairment in occupationally exposed (OE) and environmentally exposed (EE) groups of people.
Methods
Exposure was assessed through inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity and neuropsychological outcomes were evaluated through a large battery of tests covering general mental status, language, memory, attention, executive function, praxis and psychomotricity. Evaluations were carried out firstly in a period of no/low organophosphate pesticide use and subsequently during the spray season. All parameters were calculated as the relative change from baseline to spray season.
Results
For this study in total 156 participants were recruited divided equally over participants with environmental exposures (EE) and participants with occupational exposure (OE). In the EE, BChE's enzyme activity inhibition ≥30% showed significant association with 10% or more decreased performance in several tests evaluating six of the eight cognitive areas (excepting psychomotricity and mood status); besides, for AChE inhibition in EE, the association was significant in three tests evaluating attention and one of executive function. Whereas, in OE, the inhibition of the BChE ≥30% was associated with a low performance of one attention test and for AChE the exceedance of the standard was associated with diminished performance in one test of memory and attention, respectively. The association between biomarkers of biological effect and cognitive impairment persisted among the EE group after removing confounders. No association was found between biomarkers of biological acute effect and decreased cognitive performance in the OE group.
Conclusions
Increased exposure to pesticides was confirmed by increased inhibition of cholinesterase's in both exposure groups; which was associated with a diminished neuropsychological performance, mainly in the environmentally exposed study group.
[Muriel Ramírez-Santana, Liliana Zúñiga-Venegas, Sebastián Corral, Nel Roeleveld, Hans Groenewoud, Koos van der Velden, Paul T.J. Scheepers, Floria Pancetti, Association between cholinesterase's inhibition and cognitive impairment: A basis for prevention policies of environmental pollution by organophosphate and carbamate pesticides in Chile, Environmental Research, Volume 186, 2020, 109539, ISSN 0013-9351, https://doi.org/10.1016/j.envres.2020.109539.] - 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.] - Imidacloprid impairs performance on a model flower handling task in bumblebees (Bombus impatiens)
Bumblebees exposed to neonicotinoid pesticides collect less pollen on foraging trips. Exposed bumblebees are also slower to learn to handle flowers, which may account for reduced pollen collection. It is unclear, however, why neonicotinoid exposure slows learning to handle flowers. We investigated the effect of imidacloprid, a neonicotinoid pesticide, on bumblebee motor learning using a lab model of flower handling. Bumblebees learned to invert inside a narrow tube and lift a petal-shaped barrier to reach a reward chamber. Imidacloprid-exposed bumblebees showed a dose-dependent delay to solve the task, which resulted from reduced switching between behavioural strategies and a subsequent delay in use of the successful strategy. This effect was consistent in colonies exposed at 10 but not 2.6 ppb, suggesting a variable effect on individuals at lower doses. These results help to explain why exposed bumblebees are slow to learn to handle flowers and collect less pollen on foraging trips.
[Phelps, J.D., Strang, C.G. & Sherry, D.F. Imidacloprid impairs performance on a model flower handling task in bumblebees (Bombus impatiens). Ecotoxicology 29, 359–374 (2020). https://doi.org/10.1007/s10646-020-02182-8] - Insecticide exposure during brood or early-adult development reduces brain growth and impairs adult learning in bumblebees
For social bees, an understudied step in evaluating pesticide risk is how contaminated food entering colonies affects residing offspring development and maturation. For instance, neurotoxic insecticide compounds in food could affect central nervous system development predisposing individuals to become poorer task performers later-in-life. Studying bumblebee colonies provisioned with neonicotinoid spiked nectar substitute, we measured brain volume and learning behaviour of 3 or 12-day old adults that had experienced in-hive exposure during brood and/or early-stage adult development. Micro-computed tomography scanning and segmentation of multiple brain neuropils showed exposure during either of the developmental stages caused reduced mushroom body calycal growth relative to unexposed workers. Associated with this was a lower probability of responding to a sucrose reward and lower learning performance in an olfactory conditioning test. While calycal volume of control workers positively correlated with learning score, this relationship was absent for exposed workers indicating neuropil functional impairment. Comparison of 3- and 12-day adults exposed during brood development showed a similar degree of reduced calycal volume and impaired behaviour highlighting lasting and irrecoverable effects from exposure despite no adult exposure. Our findings help explain how the onset of pesticide exposure to whole colonies can lead to lag-effects on growth and resultant dysfunction.
[Smith DB, Arce AN, Ramos Rodrigues A, Bischoff PH, Burris D, Ahmed F, Gill RJ. Insecticide exposure during brood or early-adult development reduces brain growth and impairs adult learning in bumblebees. Proc Biol Sci. 2020 Mar 11;287(1922):20192442. doi: 10.1098/rspb.2019.2442. Epub 2020 Mar 4. PMID: 32126960; PMCID: PMC7126076.] - Reduced neurobehavioral functioning in agricultural workers and rural inhabitants exposed to pesticides in northern Chile and its association with blood biomarkers inhibition
Background
Previous biomonitoring studies have shown that people in the rural population of Coquimbo, the major agricultural area in northern Chile are being occupationally and environmentally exposed to organophosphate/carbamate (OP/CB) pesticides. Given their harmful effects, this study had two aims; first, to evaluate the effect of cumulative or chronic exposure to OP/CB pesticides on the neurobehavioral performance of agricultural workers and rural inhabitants; second, to determine if changes in the neurobehavioral performance are associated to changes in blood biomarkers of OP/CB pesticides during the spray season, when exposure is higher.
Methods
For the first aim, a cross sectional study of neurobehavioral performance in adult volunteers (men and women, 18–50 years-old, right-handed) was carried out in the pre-spray season. Sampling was done by convenience and a questionnaire was used to categorize participants depending on their level of chronic exposure, as either: occupationally exposed (OE, n = 87), environmentally exposed (EE, n = 81), or non-exposed controls or reference group (RG, n = 100). A neurobehavioral test battery consisting of 21 tests to measure cognitive, motor and emotional state was applied. For the second aim, neurobehavioral measures were taken a second time from EE and OE groups during the spray season, and their exposure corroborated by blood-based biomarker inhibition.
Results
Lower neurobehavioral performance was observed in the pre-spray evaluation of EE and OE groups compared to the non-exposed, OE being the worst performing group. Seasonal exposure impaired performance in both exposure groups on all tests except those on attention and mood. Data modeling of the basal (pre-spray) measurements showed that the level of exposure was the best predictor of performance. During spraying, inhibition of BChE activity in the EE group was the best predictor of low performance in tests measuring logical, auditory and visual memory, inhibitory control of cognitive interference, constructional and planning abilities, executive functions, and motor speed and coordination.
Conclusion
Long-term occupational or environmental exposure to pesticides caused impairment in neurobehavioral functioning, which worsened during the spraying season, mainly in EE. BChE inhibition was the best predictor for seasonal neurobehavioral changes in EE.
[Ramírez-Santana, M., Zúñiga-Venegas, L., Corral, S. et al. Reduced neurobehavioral functioning in agricultural workers and rural inhabitants exposed to pesticides in northern Chile and its association with blood biomarkers inhibition. Environ Health 19, 84 (2020). https://doi.org/10.1186/s12940-020-00634-6]
- Residential proximity to greenhouse agriculture and neurobehavioral performance in Ecuadorian children
Background
Children living near greenhouse agriculture may have an increased risk of pesticide exposure due to drift or direct contact with pesticide-treated areas. However, little is known about whether this increased potential for chronic exposure may impair their neurodevelopment.
Methods
We examined 307 children aged 4–9 years, living in agricultural communities in Ecuador (ESPINA study). The two exposures calculated were residential distance from the nearest flower plantation perimeter and flower plantation surface area within 100 m of homes. Five neurobehavioral domains were assessed: Attention/Inhibitory Control, Memory/Learning, Visuospatial processing and Sensorimotor (higher values reflect better performance). Low scores were defined according to the test's cut-offs. Models were adjusted for demographic, socio-economic and growth variables.
Results
The mean (SD) residential distance to the nearest flower plantation was 446 m (344). Living 100 m closer to crops was associated with increased odds (OR [95% CI]) of low scores in the domains of Memory/Learning (1.24 [1.05, 1.46]) and Language (1.09 [1.00, 1.19]). Associations were strongest among children living within 50 m, having significantly lower scores in Language (−1.28 which is ~50% of a SD [-2.50, −0.06]), Attention/Inhibitory Control (−1.24 units, [-2.45, −0.04]), and Memory/Learning (−0.91, [-1.99, 0.17]), compared to children living farther than 500 m. Analyses of areas of flower crops near homes concurred with these findings.
Conclusions
Close residential proximity to greenhouse floricultural crops was associated with adverse neurobehavioral performance in Attention/Inhibitory Control, Language and Memory/Learning among children. This highlights the importance of reducing pesticide drift from plantations to nearby homes.
[Elizabeth Friedman, Marnie F. Hazlehurst, Christine Loftus, Catherine Karr, Kelsey N. McDonald, Jose Ricardo Suarez-Lopez, Residential proximity to greenhouse agriculture and neurobehavioral performance in Ecuadorian children, International Journal of Hygiene and Environmental Health, Volume 223, Issue 1, 2020, Pages 220-227, ISSN 1438-4639, https://doi.org/10.1016/j.ijheh.2019.08.009.] - 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.] - APOE genetic background and sex confer different vulnerabilities to postnatal chlorpyrifos exposure and modulate the response to cholinergic drugs
Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups.
[Laia Guardia-Escote, Pia Basaure, Fiona Peris-Sampedro, Judit Biosca-Brull, Maria Cabré, Fernando Sánchez-Santed, José L. Domingo, Maria Teresa Colomina, APOE genetic background and sex confer different vulnerabilities to postnatal chlorpyrifos exposure and modulate the response to cholinergic drugs, Behavioural Brain Research, Volume 376, 2019, 112195, ISSN 0166-4328, https://doi.org/10.1016/j.bbr.2019.112195.
] - Brain transcriptome of honey bees (Apis mellifera) exhibiting impaired olfactory learning induced by a sublethal dose of imidacloprid
Declines in honey bee populations represent a worldwide concern. The widespread use of neonicotinoid insecticides has been one of the factors linked to these declines. Sublethal doses of a neonicotinoid insecticide, imidacloprid, has been reported to cause olfactory learning deficits in honey bees via impairment of the target organ, the brain. In the present study, olfactory learning of honey bees was compared between controls and imidacloprid-treated bees. The brains of imidacloprid-treated and control bees were used for comparative transcriptome analysis by RNA-Seq to elucidate the effects of imidacloprid on honey bee learning capacity. The results showed that the learning performance of imidacloprid-treated bees was significantly impaired in comparison with control bees after chronic oral exposure to imidacloprid (0.02 ng/μl) for 11 days. Gene expression profiles between imidacloprid treatment and the control revealed that 131 genes were differentially expressed, of which 130 were downregulated in imidacloprid-treated bees. Validation of the RNA-Seq data using qRT-PCR showed that the results of qRT-PCR and RNA-Seq exhibited a high level of agreement. Gene ontology annotation indicated that the oxidation-reduction imbalance might exist in the brain of honey bees due to oxidative stress induced by imidacloprid exposure. KEGG and ingenuity pathway analysis revealed that transient receptor potential and Arrestin 2 in the phototransduction pathway were significantly downregulated in imidacloprid-treated bees, and that five downregulated genes have causal effects on behavioral response inhibition in imidacloprid-treated bees. Our results suggest that downregulation of brain genes involved in immune, detoxification and chemosensory responses may result in decreased olfactory learning capabilities in imidacloprid-treated bees.
[Zhiguo Li, Tiantian Yu, Yanping Chen, Matthew Heerman, Jingfang He, Jingnan Huang, Hongyi Nie, Songkun Su, Brain transcriptome of honey bees (Apis mellifera) exhibiting impaired olfactory learning induced by a sublethal dose of imidacloprid, Pesticide Biochemistry and Physiology, Volume 156, 2019, Pages 36-43, ISSN 0048-3575, https://doi.org/10.1016/j.pestbp.2019.02.001.] - Crocin-protected malathion-induced spatial memory deficits by inhibiting TAU protein hyperphosphorylation and antiapoptotic effects
Organophosphorus compounds are widely used in agriculture. Epidemiological studies propose that pesticide exposure is a risk factor for Alzheimer’s disease (AD), but the mechanisms are unclear. Here, we investigated the impact of malathion exposure on the cognitive ability and the underlying mechanisms in rats. Moreover, we studied whether crocin reduced malathion-induced cognitive and memory loss in rats. Malathion (100 mg/kg) and crocin (10, 20 and 40 m/kg) were administered into the rats once a day for 14 days via i.p. Also vitamin E was used as positive control. Malathion exhibited spatial memory deficits as assessed by Morris water maze (MWM). Malathion increased the latency to reach the platform and decreased time spent and swimming distance of animals in target quadrant in probe trial. These effects were protected by crocin. Malathion exposure induced spatial learning and memory deficits with a simultaneous decrease of PSD93 and TAU hyperphosphorylation at multiple AD-related phosphorylation sites with activation of glycogen synthase kinase-3β (GSK-3β) and inhibition of protein phosphatase-2A (PP2A). Additionally, the elevation of malondialdehyde (MDA), TNF α and IL-6 levels, amelioration of reduced glutathione (GSH) in the hippocampus and reduction of plasma acetylcholinesterase activity were observed upon administration of the malathion. Also, malathion-induced apoptosis in the hippocampus. Crocin or vitamin E improved memory damages and antagonized the effects of malathion. According to the data of this study, crocin mitigated malathion-induced neurological alterations and cognitive impairment by reducing oxidative stress and inflammation, inhibiting TAU protein hyperphosphorylation and antiapoptotic effects.
[Mohammadzadeh, L. et al. (2019) ‘Crocin-protected malathion-induced spatial memory deficits by inhibiting TAU protein hyperphosphorylation and antiapoptotic effects’, Nutritional Neuroscience, 23(3), pp. 221–236. doi: 10.1080/1028415X.2018.1492772.] - Early-life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice
Permethrin, a pyrethroid chemical, is widely used as a pesticide because of its rapid insecticidal activity. Although permethrin is considered to exert very low toxicity in mammals, the effects of early, low-level, chronic exposure on the adult central nervous system are unclear. In this study, we investigated the effects of low-level, chronic permethrin exposure in early life on the brain functions of adult mice, using environmentally relevant concentrations. We exposed mice to the acceptable daily intake level of permethrin (0.3 ppm) in drinking water during the prenatal and postnatal periods. We then examined the effects on the central nervous system in adult male offspring. In the permethrin group, we detected behavior that displayed incomplete adaptation to a novel environment, as well as an impairment in learning and memory. In addition, immunohistochemical analysis revealed an increase in doublecortin- (an immature neuron marker) positive cells in the hippocampal dentate gyrus in the permethrin exposure group compared with the control group. Additionally, in the permethrin exposure group there was a decrease in astrocyte number in the hilus of the dentate gyrus, and remaining astrocytes were often irregularly shaped. These results suggest that exposure to permethrin at low levels in early life affects the formation of the neural circuit base and behavior after maturation. Therefore, in the central nervous system of male mice, low-level, chronic permethrin exposure during the prenatal and postnatal periods has effects that were not expected based on the known effects of permethrin exposure in mature animals.
[Saito H, Hara K, Tominaga T, Nakashima K, Tanemura K. Early-life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice. J Appl Toxicol. 2019; 39: 1651–1662. https://doi.org/10.1002/jat.3882] - 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. ]
- Protective effects of syringic acid on neurobehavioral deficits and hippocampal tissue damages induced by sub-chronic deltamethrin exposure
Recent developments in the field of insecticide exposure have led to a renewed interest in alternative antioxidant therapy. The present study was to investigate the neuroprotective role of syringic acid (SA, 25 mg/kg/day) on the neurotoxicity and oxidative damage induced by deltamethrin (DTM, 1.28 mg/kg/day during two months) in CA1/3 pyramidal neurons. Animals were divided into 4 groups (n = 16/group) (250–270 g) for control, DTM, SA and DTM + SA. DTM and SA were administered by oral gavage daily. Rats that were given sub-chronic DTM had revealed a significant increase in caspase-3 levels, impaired recognition memory, reduced antioxidant activity and enhanced free radicals in the hippocampus. The results showed that SA ameliorated neurobehavioral alterations, reduced reactive oxygen/nitrogen species, pyknosis in the CA1/3 and increased antioxidant enzyme activity. In conclusion, SA (25 mg/kg/day) had potential neuroprotective and therapeutic impacts against sub-chronic DTM exposure via its antioxidant and antiapoptotic efficacy. Therefore, it can be used as a neuroprotective natural plant-derived agent against DTM-induced neurotoxicity.
[Eren Ogut, Rahime Sekerci, Guven Akcay, Fatos Belgin Yildirim, Narin Derin, Mutay Aslan, Leyla Sati, Protective effects of syringic acid on neurobehavioral deficits and hippocampal tissue damages induced by sub-chronic deltamethrin exposure, Neurotoxicology and Teratology, Volume 76, 2019, 106839, ISSN 0892-0362, https://doi.org/10.1016/j.ntt.2019.106839.] - Impaired associative learning after chronic exposure to pesticides in young adult honey bees
Neonicotinoids are the most widespread insecticides in agriculture, preferred for their low toxicity to mammals and their systemic nature. Nevertheless, there have been increasing concerns regarding their impact on non-target organisms. Glyphosate is also widely used in crops and, therefore, traces of this pesticide are likely to be found together with neonicotinoids. Although glyphosate is considered a herbicide, adverse effects have been found on animal species, including honey bees. Apis mellifera is one of the most important pollinators in agroecosystems and is exposed to both these pesticides. Traces can be found in nectar and pollen of flowers that honey bees visit, but also in honey stores inside the hive. Young workers, which perform in-hive tasks that are crucial for colony maintenance, are potentially exposed to both these contaminated resources. These workers present high plasticity and are susceptible to stimuli that can modulate their behaviour and impact on colony state. Therefore, by performing standardised assays to study sublethal effects of these pesticides, these bees can be used as bioindicators. We studied the effect of chronic joint exposure to field-realistic concentrations of the neonicotinoid imidacloprid and glyphosate on gustatory perception and olfactory learning. Both pesticides reduced sucrose responsiveness and had a negative effect on olfactory learning. Glyphosate also reduced food uptake during rearing. The results indicate differential susceptibility according to honey bee age. The two agrochemicals had adverse effects on different aspects of honey bee appetitive behaviour, which could have repercussions for food distribution, propagation of olfactory information and task coordination within the nest.
[Carolina Mengoni Goñalons, Walter M. Farina; Impaired associative learning after chronic exposure to pesticides in young adult honey bees. J Exp Biol 1 April 2018; 221 (7): jeb176644. doi: https://doi.org/10.1242/jeb.176644] - 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.] - Neuropsychological functioning in military pesticide applicators from the Gulf War: Effects on information processing speed, attention and visual memory
1991 Gulf War (GW) veterans continue to experience debilitating cognitive and mood problems more than two decades following their return from deployment. Suspected causes for these cognitive complaints include additive and/or synergistic effects of the varying combinations of exposures to chemicals in theater, including pesticides and pyridostigmine bromide (PB) pills. This study was undertaken to address one of the key recommendations of the US Department of Defense Environmental Exposure Report on Pesticides, which was to conduct an epidemiological study to further evaluate the role of neurotoxicant exposures in the expression of central nervous system symptoms reported by GW veterans. This study evaluated the role of pesticides and/or PB in the development of chronic neuropsychological dysfunction in GW veterans. We examined the associations between self-reported measures of pesticide and PB exposures and performance on neuropsychological tests in a group of 159 GW-deployed preventative medicine personnel who had varying levels of pesticide exposures during their work as pesticide applicators or other preventative medicine roles. These veterans had a unique knowledge of pesticides and their usage during the war. It was hypothesized that pesticide applicator personnel with higher exposures would perform significantly worse on objective cognitive measures than lower-exposed personnel and that multiple chemical exposures (pesticide and PB) would further diminish cognitive functioning and increase mood complaints. Study results showed that the participants with both high pesticide and high PB exposure performed worse on specific measures than the groups with high single exposures or low exposures to both toxicants. High combined exposure was associated with significantly slower information processing reaction times, attentional errors, worse visual memory functioning, and increased mood complaints. In addition, stepwise regression analyses of individual pesticide exposures found that pest strip exposure was associated with slower reaction times and attentional errors, and that fly bait and delouser exposures predicted greater mood complaints.
[Kimberly Sullivan, Maxine Krengel, William Bradford, Callie Stone, Terri Ann Thompson, Timothy Heeren, Roberta F. White, Neuropsychological functioning in military pesticide applicators from the Gulf War: Effects on information processing speed, attention and visual memory, Neurotoxicology and Teratology, Volume 65, 2018, Pages 1-13, ISSN 0892-0362, https://doi.org/10.1016/j.ntt.2017.11.002.] - Postnatal exposure to chlorpyrifos produces long-term effects on spatial memory and the cholinergic system in mice in a sex- and APOE genotype-dependent manner
Organophosphorus pesticides – and in particular chlorpyrifos (CPF) – are extensively used worldwide. They mainly exert their toxicity by targeting the cholinergic system. Several studies suggested that the gene coding for apolipoprotein E (apoE), which is a risk factor for several diseases, can also confer different vulnerability to toxic insults. This study was aimed at assessing the long-term effects of postnatal exposure to CPF on learning and memory as well as the expression levels of several genes involved in cholinergic neurotransmission in mice. Both male and female apoE4-TR and C57BL/6 mice were exposed to either 0 or 1 mg/kg/day of CPF by oral gavage using a micropipette on postnatal days 10–15. At 9 months, they were tested in a Morris Water Maze (MWM) and the gene expression in the frontal cortex and hippocampus was evaluated. Our results show that, in males, CPF had an effect on the spatial retention, while in females, it altered the expression levels of nicotinic receptors. Furthermore, apoE4-TR mice performed the worst during the MWM retention and presented low expression levels in a considerable number of cholinergic genes. Taken together, the current results reveal long-term effects in mice nine months after postnatal exposure to CPF, which are modulated by sex and apoE4 genotype.
[Laia Guardia-Escote, Pia Basaure, Jordi Blanco, Maria Cabré, Cristian Pérez-Fernández, Fernando Sánchez-Santed, José L. Domingo, Maria Teresa Colomina, Postnatal exposure to chlorpyrifos produces long-term effects on spatial memory and the cholinergic system in mice in a sex- and APOE genotype-dependent manner, Food and Chemical Toxicology, Volume 122, 2018, Pages 1-10, ISSN 0278-6915, https://doi.org/10.1016/j.fct.2018.09.069.] - 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.] - Effects of Deltamethrin on striatum and hippocampus mitochondrial integrity and the protective role of Quercetin in rats
The present work is to evaluate the neurotoxicity induced by pyrethroid insecticide “Deltamethrin” at 0.32 mg/kg/day in two main regions of the Wistar rat brain (hippocampus and striatum) and the protective effects of Quercetin at 10 mg/kg/day on this toxicity after 90 days of exposure. The assay of brain parameters showed that Deltamethrin caused a significant increase of mitochondrial metabolite level (proteins, lipids, and carbohydrates) and enzyme activity (glutathione S-transferase and superoxide dismutase); a decreased amount of mitochondrial glutathione level and catalase and glutathione peroxidase activities; and an increase of malondialdehyde (MDA) acid levels of the two regions. Furthermore, mitochondrial functional testing in the brains of treated rats exhibited a significant increase in permeability followed by a mitochondrial swelling. Instead, a statistically significant decrease in mitochondrial respiration (O2 consumption) was recorded in the striatum and hippocampus. Our study showed that the pesticide caused a significant increase of the cytochrome c amount correlated with activation of neuronal apoptosis mechanisms by the significant increase of caspase-3 of hippocampus and striatum. In particular, the results of behavioral tests (open field, classic maze tests of sucrose, and Morris water maze) have significant changes, namely bad behavior of the treated rats, affecting the level of anxiety, learning, and memory, and general motor activity has mainly been shown in treated rats. In addition, the histological cuts clearly confirm cerebral necrosis in the hippocampus and the striatum caused by the pesticide. They allow us to consider the necrotic areas, black spots, reduction, and denaturation of these brain regions in the treated rats. On the other hand, we have studied the protective effects against the neurotoxicity of Deltamethrin (DLM). In this context, after the gavage of Quercetin at the dose of 10 mg/kg/day, we have noticed an improvement in the entire parameters: mitochondrial enzyme, metabolic, histological, and behavioral parameters. This confirmed the improvement of preventive and curative effect of Quercetin against free radicals induced by the DLM.
[Gasmi, S., Rouabhi, R., Kebieche, M. et al. Effects of Deltamethrin on striatum and hippocampus mitochondrial integrity and the protective role of Quercetin in rats. Environ Sci Pollut Res 24, 16440–16457 (2017). https://doi.org/10.1007/s11356-017-9218-8] - 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.] - Long-term and low-dose malathion exposure causes cognitive impairment in adult mice: evidence of hippocampal mitochondrial dysfunction, astrogliosis and apoptotic events
The organophosphorus (OP) pesticide malathion is a neurotoxic compound whose acute toxicity is primarily caused by the inhibition of acetylcholinesterase (AChE), leading to cholinergic syndrome-related symptoms. Some lines of evidence indicate that long-term exposure to low levels of OP may produce neuropsychiatric and/or neurobehavioral signs that do not necessarily involve the AChE inhibition. This study evaluated the effects of a repeated (15-day period) and low-dose malathion exposure on spatial memory and discrimination (object location task), as well as on biochemical parameters in the hippocampus of mice [AChE and mitochondrial chain complexes activities; levels of proapoptotic proteins (Bax and Bak) and cholinergic neuronal and astroglial markers (ChAT and GFAP, respectively)]. Malathion treatments (30 and 100 mg/kg, s.c.) did not affect the body weight of animals and caused no evident signs of cholinergic toxicity throughout the treatment, although the highest dose (100 mg/kg) was associated with inhibition of AChE activity. Malathion-exposed animals showed a significant impairment on spatial memory and discrimination, which was correlated with a decrease in the mitochondrial complex I activity in the hippocampus. Moreover, malathion increased the levels of proapoptotic proteins and induced astroglial activation. The results show that long-term malathion exposure, at a dose that does not affect hippocampal AChE activity (30 mg/kg), caused impaired spatial memory and discrimination in mice that was related to hippocampal mitochondrial dysfunctional, astrogliosis and apoptosis. When extrapolated to humans, such results shed light on noncholinergic mechanisms likely related to the neurobehavioral and cognitive deficits observed in individuals chronically exposed to this pesticide.
[dos Santos, A.A., Naime, A.A., de Oliveira, J. et al. Long-term and low-dose malathion exposure causes cognitive impairment in adult mice: evidence of hippocampal mitochondrial dysfunction, astrogliosis and apoptotic events. Arch Toxicol 90, 647–660 (2016). https://doi.org/10.1007/s00204-015-1466-0] - Measurements of Chlorpyrifos Levels in Forager Bees and Comparison with Levels that Disrupt Honey Bee Odor-Mediated Learning Under Laboratory Conditions
Chlorpyrifos is an organophosphate pesticide used around the world to protect food crops against insects and mites. Despite guidelines for chlorpyrifos usage, including precautions to protect beneficial insects, such as honeybees from spray drift, this pesticide has been detected in bees in various countries, indicating that exposure still occurs. Here, we examined chlorpyrifos levels in bees collected from 17 locations in Otago, New Zealand, and compared doses of this pesticide that cause sub-lethal effects on learning performance under laboratory conditions with amounts of chlorpyrifos detected in the bees in the field. The pesticide was detected at 17 % of the sites sampled and in 12 % of the colonies examined. Amounts detected ranged from 35 to 286 pg.bee−1, far below the LD50 of ~100 ng.bee−1. We detected no adverse effect of chlorpyrifos on aversive learning, but the formation and retrieval of appetitive olfactory memories was severely affected. Chlorpyrifos fed to bees in amounts several orders of magnitude lower than the LD50, and also lower than levels detected in bees, was found to slow appetitive learning and reduce the specificity of memory recall. As learning and memory play a central role in the behavioral ecology and communication of foraging bees, chlorpyrifos, even in sublethal doses, may threaten the success and survival of this important insect pollinator.
[Urlacher, E., Monchanin, C., Rivière, C. et al. Measurements of Chlorpyrifos Levels in Forager Bees and Comparison with Levels that Disrupt Honey Bee Odor-Mediated Learning Under Laboratory Conditions. J Chem Ecol 42, 127–138 (2016). https://doi.org/10.1007/s10886-016-0672-4] - 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. ] - 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.
[Berna van Wendel de Joode, Ana M. Mora, Christian H. Lindh, David Hernández-Bonilla, Leonel Córdoba, Catharina Wesseling, Jane A. Hoppin, Donna Mergler, Pesticide exposure and neurodevelopment in children aged 6–9 years from Talamanca, Costa Rica, Cortex, Volume 85, 2016, Pages 137-150, ISSN 0010-9452, https://doi.org/10.1016/j.cortex.2016.09.003.] - 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] - Effect of subacute poisoning with bifenthrin on locomotor activity, memory retention, haematological, biochemical and histopathological parameters in mice
Bifenthrin (BIF) is a pyrethroid (PYR) insecticide. The target point for PYR's toxic action are voltage sensitive sodium channels in the central nervous system (CNS). Intoxication with PYRs results in motor activity impairment and death in insects. Although PYRs are considered to be safe for mammals, there were numerous cases of pyrethroid poisoning in humans, animals and pets described. The general population is chronically exposed to PYRs via grain products, dust and indoor air. Therefore new questions arise: whether PYRs act in a dose-additive fashion in the course of subacute poisoning, are there other target organs (but brain) for BIF and if there is one common mechanism of its' toxic action in different organs. The objective of this work was to characterize the effect of BIF at the doses of 4 or 8 mg/kg injected intraperitoneally (i.p.) daily for 28 consecutive days on memory and motor activity, hematological, biochemical and histopathological parameters in mice. BIF at the doses of 8 mg/kg or 4 mg/kg of body mass was administered i.p. daily to the mice for 28 consecutive days. Motor function was measured on day 1, 7, 14 and 28 and memory retention was tested in a passive avoidance task on day 2, 7, 14 and 28. BIF significantly impaired memory retention on day 2. BIF decreased locomotor activity at every stage of the experiment in a single dose depending manner. No behavioral cumulative effect was observed. Subacute poisoning with the higher dose of BIF caused anaemia, elevated white blood cell count (WBC), elevated alanine transaminase (ALT), superoxide dismuthase (SOD), and decreased glutathione peroxidase (GPx) activity. Lymphocyte infiltrates were visualized in the livers.
[Nieradko-Iwanicka B, Borzecki A, Jodlowska-Jedrych B. Effect of subacute poisoning with bifenthrin on locomotor activity, memory retention, haematological, biochemical and histopathological parameters in mice. J Physiol Pharmacol. 2015 Feb;66(1):129-37. PMID: 25716972.] - Hippocampal ER Stress and Learning Deficits Following Repeated Pyrethroid Exposure
Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.
[Muhammad M. Hossain, Emanuel DiCicco-Bloom, Jason R. Richardson, Hippocampal ER Stress and Learning Deficits Following Repeated Pyrethroid Exposure, Toxicological Sciences, Volume 143, Issue 1, January 2015, Pages 220–228, https://doi.org/10.1093/toxsci/kfu226] - 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.] - Subacute poisoning of mice with deltamethrin produces memory impairment, reduced locomotor activity, liver damage and changes in blood morphology in the mechanism of oxidative stress
Background
Deltamethrin (DEL) is a synthetic pyrethroid (PYR) insecticide, potent neurotoxicant. The current investigation was envisaged to explore behavioral, biochemical and morphologic effects of subacute poisoning with DEL in mice and to find one common mechanism of these changes.
Methods
Mice were daily injected ip with different doses of DEL: 8.3, 20.75 or 41.5 mg/kg bw for 28 days. Their memory retention in passive avoidance task (PA), fresh spatial memory in a Y-maze and locomotor activity were measured once weekly. On day 29, blood morphology, alanine transaminase (ALT) activity and creatinine concentration in the blood sera, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the livers and kidneys. Livers were examined with light microscopy.
Results
Significant impairment of memory retention was recorded on day 2, 7 and 28 after exposure to DEL. Fresh spatial memory was significantly impaired by the highest dose of DEL on day 1, 14 and 28. Locomotor activity was reduced at every stage of experiment in all the groups exposed to DEL. In the animals exposed to the highest dose of DEL activities of alanine transaminase (ALT) and SOD were elevated, GPx was reduced, lymphocyte infiltrates were detected in the livers and there were changes in blood morphology.
Conclusion
The results obtained indicate that liver and bone marrow, apart from the central nervous system (CNS) are damaged in the course of subacute poisoning with DEL. The possible common mechanism of the damage is oxidative stress.
[Barbara Nieradko-Iwanicka, Andrzej Borzęcki, Subacute poisoning of mice with deltamethrin produces memory impairment, reduced locomotor activity, liver damage and changes in blood morphology in the mechanism of oxidative stress, Pharmacological Reports, Volume 67, Issue 3, 2015, Pages 535-541, ISSN 1734-1140, https://doi.org/10.1016/j.pharep.2014.12.012.] - 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.] - Ameliorating the Developmental Neurotoxicity of Chlorpyrifos: A Mechanisms-Based Approach in PC12 Cells
Background
Organophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation.
Objectives
We evaluated mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons.
Results
In undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication.
Conclusions
Our results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects.
[Slotkin, T.A. et al. (2007) Ameliorating the Developmental Neurotoxicity of Chlorpyrifos: A Mechanisms-Based Approach in PC12 Cells, Environmental Health Perspectives. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC1964921/. ]
- 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] - Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation
Chlorpyrifos is a widely used organophosphate insecticide that is a suspected developmental neurotoxin. Although chlorpyrifos exerts some effects through cholinesterase inhibition, recent studies suggest additional, direct actions on developing cells. We assessed the effects of chlorpyrifos on nuclear transcription factors involved in cell replication and differentiation using in vitro and in vivo models. HeLa nuclear protein extracts were incubated with the labeled consensus oligonucleotides for AP-1 and Sp1 transcription factors in the presence and absence of chlorpyrifos. In concentrations previously shown to affect cell development, chlorpyrifos reduced AP-1, but not Sp1 DNA-binding activity. Next, chlorpyrifos was incubated with PC12 cells either during cell replication or after initiation of differentiation with NGF. Chlorpyrifos evoked stage-specific interference with the expression of the transcription factors: Sp1 was reduced in replicating and differentiating cells, whereas AP-1 was affected only during differentiation. Finally, neonatal rats were given apparently subtoxic doses of chlorpyrifos either on postnatal days 1–4 or 11–14 and the effects were evaluated in the forebrain (an early-developing, cholinergic target region) and cerebellum (late-developing region, poor in cholinergic innervation). Again, chlorpyrifos evoked stage-specific changes in transcription factor expression and binding activity, with greater effects on Sp1 during active neurogenesis, and effects on AP-1 during differentiation. The changes were present in both forebrain and cerebellum and were gender-specific. These results indicate that chlorpyrifos interferes with brain development, in part by multiple alterations in the activity of transcription factors involved in the basic machinery of cell replication and differentiation. Noncholinergic actions of chlorpyrifos that are unique to brain development reinforce the need to examine endpoints other than cholinesterase inhibition.
[Crumpton, T., Seidler, F. and Slotkin, T. (2000) Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation, Brain Research. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0006899399023574.] - 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.]
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