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Bibliography Tag: neurodevelopmental toxicity

Sagiv et al., 2019

Sagiv, S. K., Bruno, J. L., Baker, J. M., Palzes, V., Kogut, K., Rauch, S., Gunier, R., Mora, A. M., Reiss, A. L., & Eskenazi, B.; “Prenatal exposure to organophosphate pesticides and functional neuroimaging in adolescents living in proximity to pesticide application;” Proceedings of the National Academy of Sciences of the United States of America, 2019; DOI: 10.1073/pnas.1903940116.


We have reported consistent associations of prenatal organophosphate pesticide (OP) exposure with poorer cognitive function and behavior problems in our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort of Mexican American youth in California’s agricultural Salinas Valley. However, there is little evidence on how OPs affect neural dynamics underlying associations. We used functional near-infrared spectroscopy (fNIRS) to measure cortical activation during tasks of executive function, attention, social cognition, and language comprehension in 95 adolescent CHAMACOS participants. We estimated associations of residential proximity to OP use during pregnancy with cortical activation in frontal, temporal, and parietal regions using multiple regression models, adjusting for sociodemographic characteristics. OP exposure was associated with altered brain activation during tasks of executive function. For example, with a 10-fold increase in total OP pesticide use within 1 km of maternal residence during pregnancy, there was a bilateral decrease in brain activation in the prefrontal cortex during a cognitive flexibility task (β = -4.74; 95% CI: -8.18, -1.31 and β = -4.40; 95% CI: -7.96, -0.84 for the left and right hemispheres, respectively). We also found that prenatal OP exposure was associated with sex differences in brain activation during a language comprehension task. This first functional neuroimaging study of prenatal OP exposure suggests that pesticides may impact cortical brain activation, which could underlie previously reported OP-related associations with cognitive and behavioral function. Use of fNIRS in environmental epidemiology offers a practical alternative to neuroimaging technologies and enhances our efforts to assess the impact of chemical exposures on neurodevelopment. FULL TEXT

Jusko et al., 2012

Jusko, T. A., Klebanoff, M. A., Brock, J. W., & Longnecker, M. P.; “In-utero exposure to dichlorodiphenyltrichloroethane and cognitive development among infants and school-aged children;” Epidemiology, 2012, 23(5), 689-698; DOI: 10.1097/EDE.0b013e31825fb61d.


BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and dichlorodiphenyldichloroethylene (DDE) has been associated with developmental and cognitive impairment among children. We examined this association in an historical cohort in which the level of exposure was greater than in previous studies.

METHODS: The association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the United States from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years, using the Wechsler Intelligence Scale for Children.

RESULTS: Although levels of DDT and DDE were relatively high in this population (median DDT concentration, 8.9 mug/L; DDE, 24.5 mug/L), neither were related to Mental or Psychomotor Development scores on the Bayley Scales nor to Full-Scale Intelligence Quotient at 7 years of age. Categorical analyses showed no evidence of dose- response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0.

CONCLUSIONS: Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years in this cohort. FULL TEXT

Gallegos et al., 2016

Gallegos, Cristina E., Bartos, Mariana, Bras, Cristina, Gumilar, Fernanda, Antonelli, Marta C., & Minetti, Alejandra; “Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring;” NeuroToxicology, 2016, 53, 20-28; DOI: 10.1016/j.neuro.2015.11.015.


The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety.

Bakian et al., 2019

Bakian, Amanda V., & VanDerslice, James A.; “Pesticides and autism;” BMJ, 2019, 364, l1149; DOI: 10.1136/bmj.l1149.


Editorial in response to von Ehrenstein et al., 2019.


Attina et al., 2016

Attina, T. M., Hauser, R., Sathyanarayana, S., Hunt, P. A., Bourguignon, J. P., Myers, J. P., DiGangi, J., Zoeller, R. T., & Trasande, L.; “Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis;” Lancet Diabetes and Endocrinol, 2016, 4(12), 996-1003; DOI: 10.1016/S2213-8587(16)30275-3.


BACKGROUND: Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison.

METHODS: We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (euro1=$1.33).

FINDINGS: The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2.33% of GDP] vs $217 billion [1.28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12.6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion).

INTERPRETATION: EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention.

FUNDING: Endocrine Society, Ralph S French Charitable Foundation, and Broad Reach Foundation. FULL TEXT

Crall et al., 2018

Crall, James D, Switzer, Callin M, Oppenheimer, Robert L, Ford Versypt, Ashlee N, Dey, Biswadip, Brown, Andrea, Eyster, Mackay, Guerin, Claire, Pierce, Naomi E, Combes, Stacey A, & de Bivort, Benjamin L, “Neonicotinoid exposure disrupts bumblebee nest behavior, social networks, and thermoregulation,” Science, 2018, 362(6415), 683-686. DOI: 10.1126/science.aat1598.


Neonicotinoid pesticides can negatively affect bee colonies, but the behavioral mechanisms by which these compounds impair colony growth remain unclear. Here, we investigate imidacloprid’s effects on bumblebee worker behavior within the nest, using an automated, robotic platform for continuous, multicolony monitoring of uniquely identified workers. We find that exposure to field-realistic levels of imidacloprid impairs nursing and alters social and spatial dynamics within nests, but that these effects vary substantially with time of day. In the field, imidacloprid impairs colony thermoregulation, including the construction of an insulating wax canopy. Our results show that neonicotinoids induce widespread disruption of within-nest worker behavior that may contribute to impaired growth, highlighting the potential of automated techniques for characterizing the multifaceted, dynamic impacts of stressors on behavior in bee colonies. FULL TEXT

Roberts et al., 2019

Roberts, J. R., Dawley, E. H., & Reigart, J. R., “Children’s low-level pesticide exposure and associations with autism and ADHD: a review,” Pediatric Research, 2019, 85(2), 234-241. DOI: 10.1038/s41390-018-0200-z.


Pesticides are chemicals that are designed specifically for the purpose of killing or suppressing another living organism. Human toxicity is possible with any pesticide, and a growing body of literature has investigated possible associations with neurodevelopmental disorders. Attention deficit disorder with or without hyperactivity (ADHD) and autism spectrum disorder (ASD) are two of these specific disorders that have garnered particular interest. Exposure to toxic chemicals during critical windows of brain development is a biologically plausible mechanism. This review describes the basic laboratory science including controlled pesticide dosing experiments in animals that supports a mechanistic relationship in the development of ADHD and/or ASD. Epidemiological relationships are also described for low-level pesticide exposure and ADHD and/or ASD. The available evidence supports the hypothesis that pesticide exposure at levels that do not cause acute toxicity may be among the multifactorial causes of ADHD and ASD, though further study is needed, especially for some of the newer pesticides. FULL TEXT

Hernández-Plata et al., 2015

Hernández-Plata, Isela, Giordano, Magda, Díaz-Muñoz, Mauricio, & Rodríguez, Verónica M., “The herbicide glyphosate causes behavioral changes and alterations in dopaminergic markers in male Sprague-Dawley rat,” NeuroToxicology, 2015, 46, 79-91. DOI: 10.1016/j.neuro.2014.12.001.


Glyphosate (Glyph) is the active ingredient of several herbicide formulations. Reports of Glyph exposure in humans and animal models suggest that it may be neurotoxic. To evaluate the effects of Glyph on the nervous system, male Sprague-Dawley rats were given six intraperitoneal injections of 50, 100, or 150mg Glyph/kg BW over 2 weeks (three injections/week). We assessed dopaminergic markers and their association with locomotor activity. Repeated exposure to Glyph caused hypoactivity immediately after each injection, and it was also apparent 2 days after the last injection in rats exposed to the highest dose. Glyph did not decrease monoamines, tyrosine hydroxylase (TH), or mesencephalic TH+ cells when measured 2 or 16 days after the last Glyph injection. In contrast, Glyph decreased specific binding to D1 dopamine (DA) receptors in the nucleus accumbens (NAcc) when measured 2 days after the last Glyph injection. Microdialysis experiments showed that a systemic injection of 150mg Glyph/kg BW decreased basal extracellular DA levels and high-potassium-induced DA release in striatum. Glyph did not affect the extracellular concentrations of 3,4-dihydroxyphenylacetic acid or homovanillic acid. These results indicate that repeated Glyph exposure results in hypoactivity accompanied by decreases in specific binding to D1-DA receptors in the NAcc, and that acute exposure to Glyph has evident effects on striatal DA levels. Additional experiments are necessary in order to unveil the specific targets of Glyph on dopaminergic system, and whether Glyph could be affecting other neurotransmitter systems involved in motor control.

Cattani et al., 2017

Cattani, D., Cesconetto, P. A., Tavares, M. K., Parisotto, E. B., De Oliveira, P. A., Rieg, C. E. H., Leite, M. C., Prediger, R. D. S., Wendt, N. C., Razzera, G., Filho, D. W., & Zamoner, A., “Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress,” Toxicology, 2017, 387, 67-80. DOI: 10.1016/j.tox.2017.06.001.


We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[(14)C]-glutamate uptake and increased (45)Ca(2+) influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-kappaB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. FULL TEXT

von Ehrenstein et al., 2019

von Ehrenstein, O. S., Ling, C., Cui, X., Cockburn, M., Park, A. S., Yu, F., Wu, J., & Ritz, B., “Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study,” BMJ, 2019, 364, l962. DOI: 10.1136/bmj.l962.


OBJECTIVE: To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder.

DESIGN: Population based case-control study.

SETTING: California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics.

POPULATION: 2961 individuals with a diagnosis of autism spectrum disorder based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, revised (up to 31 December 2013), including 445 with intellectual disability comorbidity, were identified through records maintained at the California Department of Developmental Services and linked to their birth records. Controls derived from birth records were matched to cases 10:1 by sex and birth year.

EXPOSURE: Data from California state mandated Pesticide Use Reporting were integrated into a geographic information system tool to estimate prenatal and infant exposures to pesticides (measured as pounds of pesticides applied per acre/month within 2000 m from the maternal residence). 11 high use pesticides were selected for examination a priori according to previous evidence of neurodevelopmental toxicity in vivo or in vitro (exposure defined as ever v never for each pesticide during specific developmental periods).

MAIN OUTCOME MEASURE: Odds ratios and 95% confidence intervals using multivariable logistic regression were used to assess associations between pesticide exposure and autism spectrum disorder (with or without intellectual disabilities) in offspring, adjusting for confounders.

RESULTS: Risk of autism spectrum disorder was associated with prenatal exposure to glyphosate (odds ratio 1.16, 95% confidence interval 1.06 to 1.27), chlorpyrifos (1.13, 1.05 to 1.23), diazinon (1.11, 1.01 to 1.21), malathion (1.11, 1.01 to 1.22), avermectin (1.12, 1.04 to 1.22), and permethrin (1.10, 1.01 to 1.20). For autism spectrum disorder with intellectual disability, estimated odds ratios were higher (by about 30%) for prenatal exposure to glyphosate (1.33, 1.05 to 1.69), chlorpyrifos (1.27, 1.04 to 1.56), diazinon (1.41, 1.15 to 1.73), permethrin (1.46, 1.20 to 1.78), methyl bromide (1.33, 1.07 to 1.64), and myclobutanil (1.32, 1.09 to 1.60); exposure in the first year of life increased the odds for the disorder with comorbid intellectual disability by up to 50% for some pesticide substances.

CONCLUSION: Findings suggest that an offspring’s risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother’s residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure. Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability. FULL TEXT

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