Neurodevelopmental Toxicity

Bellinger, 2012

David C. Bellinger, “A Strategy for Comparing the Contributions of Environmental Chemicals and Other Risk Factors to Neurodevelopment of Children,” Environmental Health Perspectives, 2012, 120:4, DOI: 10.1289/ehp.1104170

ABSTRACT:

BACKGROUND: The impact of environmental chemicals on children’s neurodevelopment is sometimes dismissed as unimportant because the magnitude of  the impairments are considered to be clinically insignificant. Such a judgment reflects a failure to distinguish between individual and population risk. The population impact of a risk factor depends on both its effect size and its distribution (or incidence/prevalence).

OBJECTIVE:  The objective was to develop a strategy for taking into account the distribution (or incidence/prevalence) of a risk factor, as well as its effect size, in order to estimate its population impact on neurodevelopment of children.

METHODS: The total numbers of Full-Scale IQ points lost among U.S. children 0–5 years of age were estimated for chemicals (methylmercury, organophosphate pesticides, lead) and a variety of medical conditions and events (e.g., preterm birth, traumatic brain injury, brain tumors, congenital
heart disease).

DISCUSSION: Although the data required for the analysis were available for only three environmental chemicals (methylmercury, organophosphate pesticides, lead), the results suggest that their contributions to neurodevelopmental morbidity are substantial, exceeding those of many nonchemical risk factors.

CONCLUSION: A method for comparing the relative contributions of different risk factors provides a rational basis for establishing priorities for reducing neurodevelopmental morbidity in children. FULL TEXT

Feat-Vetel et al., 2018

Feat-Vetel, Justyne, Larrigaldie, Vanessa, Meyer-Dilhet, Geraldine, Herzine, Ameziane, Mougin, Camille, Laugeray, Anthony, Gefflaut, Thierry, Richard, Olivier, Quesniaux, Valerie, Montecot-Dubourg, Celine, & Mortaud, Stephane, “Multiple effects of the herbicide glufosinate-ammonium and its main metabolite on neural stem cells from the subventricular zone of newborn mice,” NeuroToxicology, 2018, 69, 152-163. DOI: 10.1016/j.neuro.2018.10.001.

ABSTRACT:

The globally used herbicide glufosinate-ammonium (GLA) is structurally analogous to the excitatory neurotransmitter glutamate, and is known to interfere with cellular mechanisms involved in the glutamatergic system. In this report, we used an in vitro model of murine primary neural stem cell culture to investigate the neurotoxicity of GLA and its main metabolite, 4-methylphosphinico-2-oxobutanoic acid (PPO). We demonstrated that GLA and PPO disturb ependymal wall integrity in the ventricular-subventricular zone (V-SVZ) and alter the neuro-glial differentiation of neural stem cells. GLA and PPO impaired the formation of cilia, with reduced Celsr2 expression after PPO exposure. GLA promoted the differentiation of neuronal and oligodendroglial cells while PPO increased B1 cell population and impaired neuronal fate of neural stem cells. These results confirm our previous in vivo report that developmental exposure to GLA alters neurogenesis in the SVZ, and neuroblast migration along the rostral migratory stream. They also highlight the importance of investigating the toxicity of pesticide degradation products. Indeed, not only GLA, but also its metabolite PPO disrupts V-SVZ homeostasis and provides a novel cellular mechanism underlying GLA-induced neurodevelopmental toxicity. Furthermore, we were able to demonstrate a neurotoxic activity of a metabolite of GLA different from that of GLA active substance for the very first time. FULL TEXT

Hertz-Picciotto et al., 2018

Hertz-Picciotto, Irva, Sass, Jennifer B., Engel, Stephanie, Bennett, Deborah H., Bradman, Asa, Eskenazi, Brenda, Lanphear, Bruce, & Whyatt, Robin, “Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms,” PLOS Medicine, 2018, 15(10). DOI: 10.1371/journal.pmed.1002671.

SUMMARY POINTS:

• Widespread use of organophosphate (OP) pesticides to control insects has resulted in ubiquitous human exposures.
• High exposures to OP pesticides are responsible for poisonings and deaths, particularly in developing countries.
• Compelling evidence indicates that prenatal exposure at low levels is putting children at risk for cognitive and behavioral deficits and for neurodevelopmental disorders.
To protect children worldwide, we recommend the following:
• Governments phase out chlorpyrifos and other OP pesticides, monitor watersheds and other sources of human exposures, promote use of integrated pest management (IPM) through incentives and training in agroecology, and implement mandatory surveillance of pesticide-related illness.
• Health professions implement curricula on the hazards from OP pesticides in nursing and medical schools and in continuing medical education courses and educate their patients and the public about these hazards.
• Agricultural entities accelerate the development of nontoxic approaches to pest control through IPM and ensure the safety of workers through training and provision of protective equipment when toxic chemicals are to be used. FULL TEXT

Herzine et al., 2016

Ameziane Herzine, Anthony Laugeray, Justyne Feat, Arnaud Menuet, Valérie Quesniaux, Olivier Richard, Jacques Pichon, Céline Montécot-Dubourg, Olivier Perche, and Stéphane Mortaud,”Perinatal Exposure to Glufosinate Ammonium Herbicide Impairs Neurogenesis and Neuroblast Migration through Cytoskeleton Destabilization,” Frontiers in Cellular Neuroscience, 2016, 10:191, DOI: 10.3389/FNCEL.2016.00191.

ABSTRACT:

Neurogenesis, a process of generating functional neurons from neural precursors, occurs throughout life in restricted brain regions such as the subventricular zone (SVZ). During this process, newly generated neurons migrate along the rostral migratory stream to the olfactory bulb to replace granule cells and periglomerular neurons. This neuronal migration is pivotal not only for neuronal plasticity but also for adapted olfactory based behaviors. Perturbation of this highly controlled system by exogenous chemicals has been associated with neurodevelopmental disorders. We reported recently that perinatal exposure to low dose herbicide glufosinate ammonium (GLA), leads to long lasting behavioral defects reminiscent of Autism Spectrum Disorder-like phenotype in the offspring (Laugeray et al., 2014). Herein, we demonstrate that perinatal exposure to low dose GLA induces alterations in neuroblast proliferation within the SVZ and abnormal migration from the SVZ to the olfactory bulbs. These disturbances are not only concomitant to changes in cell morphology, proliferation and apoptosis, but are also associated with transcriptomic changes. Therefore, we demonstrate for the first time that perinatal exposure to low dose GLA alters SVZ neurogenesis. Jointly with our previous work, the present results provide new evidence on the link between molecular and cellular consequences of early life exposure to the herbicide GLA and the onset of ASD-like phenotype later in life.  FULL TEXT

Mesnage et al., 2015

R. Mesnage, N. Defarge, J. Spiroux de Vendomois, G.E. Seralini, “Potential toxic effects of glyphosate and its commercial formulations below regulatory limits,” Food and Chemical Toxicology, 2015, 84, DOI: 10.1016/J.FCT.2015.08.012.

ABSTRACT:

Glyphosate-based herbicides (GlyBH), including Roundup, are the most widely used pesticides worldwide. Their uses have increased exponentially since their introduction on the market. Residue levels in food or water, as well as human exposures, are escalating. We have reviewed the toxic effects of GlyBH measured below regulatory limits by evaluating the published literature and regulatory reports. We reveal a coherent body of evidence indicating that GlyBH could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects. It includes teratogenic, tumorigenic and hepatorenal effects. They could be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time. Some effects were detected in the range of the recommended acceptable daily intake. Toxic effects of commercial formulations can also be explained by GlyBH adjuvants, which have their own toxicity, but also enhance glyphosate toxicity. These challenge the assumption of safety of GlyBH at the levels at which they contaminate food and the environment, albeit these levels may fall below regulatory thresholds. Neurodevelopmental, reproductive, and transgenerational effects of GlyBH must be revisited, since a growing body of knowledge suggests the predominance of endocrine disrupting mechanisms caused by environmentally relevant levels of exposure. FULL TEXT

 

Shaw, 2017

William Shaw, PhD, “Elevated Urinary Glyphosate and Clostridia Metabolites With Altered Dopamine Metabolism in Triplets With Autistic Spectrum Disorder or Suspected Seizure Disorder: A Case Study,” Integrative Medicine, 2017, 16:1.

CONTEXT: Autism is a neurodevelopmental disorder for which a number of genetic, environmental, and nutritional causes have been proposed. Glyphosate is used widely as a crop desiccant and as an herbicide in fields of genetically modified foods that are glyphosate resistant. Several researchers have proposed that it may be a cause of autism, based on epidemiological data that correlates increased usage of glyphosate with an increased autism rate.

OBJECTIVE:  The current study was intended to determine if excessive glyphosate was present in the triplets and their parents and to evaluate biochemical findings for the family to determine the potential effects of its presence.

DESIGN: The author performed a case study with the cooperation of the parents and the attending physician.

SETTING: The study took place at The Great Plains Laboratory, Inc (Lenexa, KS, USA).

PARTICIPANTS: Participants were triplets, 2 male children and 1 female, and their parents. The 2 male children had autism, whereas the female had a possible seizure disorder. All 3 had elevated urinary glyphosate, and all of the triplets and their mother had elevated values of succinic acid or tiglylglycine, which are indicators of mitochondrial dysfunction.

INTERVENTION:
The participants received a diet of organic food only.

OUTCOME MEASURES:
The study performed organic acids, glyphosate, toxic chemicals and tiglylglycine, and creatinine testing of the participants’ urine.

RESULTS:
The 2 male triplets with autism had abnormalities on at least 1 organic acids test, including elevated phenolic compounds such as 4-cresol, 3-[3-hydroxyphenyl]-3-hydroxypropionic acid and 4-hydroxyphenylacetic acid, which have been previously associated with Clostridia bacteria and autism. The female, who was suspected of having a seizure disorder but not autism, did not have elevated phenolic compounds but did have a significantly elevated value of the metabolite tiglylglycine, a marker for mitochondrial dysfunction and/or mutations. One male triplet was retested postintervention and was found to have a markedly lower amount of glyphosate in his urine.

CONCLUSIONS:
The pattern of metabolites in the urine samples of the males with autism are consistent with a recent theory of autism that connects widespread glyphosate use with alteration of animal and human gastrointestinal flora. That theory is that the normally beneficial bacteria species that are sensitive to glyphosate are diminished and harmful bacteria species, such as Clostridia, that are insensitive to glyphosate, are increased following exposure to glyphosate. Excessive dopamine, caused by inhibition of dopamine-beta-hydroxylase by Clostridia metabolites, in turn, produces oxidative species that damage neuronal Krebs cycle enzymes, neuronal mitochondria, and neuronal structural elements such as the neurofibrils.  FULL TEXT

Shelton et al., 2014

Janie F. Shelton, Estella M. Geraghty, Daniel J. Tancredi, Lora D. Delwiche, Rebecca J. Schmidt, Beate Ritz, Robin L. Hansen, and Irva Hertz-Picciotto, “Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study,” Environmental Health Perspectives, 2014, 122:10, DOI: 10.1289/EHP.1307044.

ABSTRACT:

BACKGROUND: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism.

OBJECTIVES: We evaluated whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) study.

METHODS: The CHARGE study is a population-based case–control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997–2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316).

RESULTS: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified.

CONCLUSIONS: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.  FULL TEXT

Szepanowski et al., 2018

Szepanowski, F., Szepanowski, L. P., Mausberg, A. K., Albrecht, P., Kleinschnitz, C., Kieseier, B. C., & Stettner, M., “Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination,” Acta Neuropatholologica, 2018, 136(6), 979-982. DOI: 10.1007/s00401-018-1938-4.

ABSTRACT:

Not available.  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.

ABSTRACT:

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