Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms

Hertz‐Picciotto, Irva; Sass, Jennifer; Engel, Stephanie M.; Bennett, Deborah H.; Bradman, Asa; Eskenazi, Brenda; Lanphear, Bruce P.; Whyatt, Robin M.

doi:10.1371/journal.pmed.1002671

Cited by 185 publications

(86 citation statements)

References 34 publications

(42 reference statements)

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“…The irregular use, environmental contamination, human intoxication and imminent threat with chemical attacks are a current worldwide concern related to the chemistry of OPs. [1][2][3] Indeed, the extensive use of agrochemicals has raised the radar towards the development of reliable monitoring systems and destruction processes for unused stockpiles. Intrinsically related to this is the issue of chemical war.…”

Section: Introductionmentioning

confidence: 99%

Are Imidazoles Versatile or Promiscuous in Reactions With Organophosphates? Insights From the Case of Parathion

Silva

Orth

2019

J. Braz. Chem. Soc.

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Is the broad mechanistic versatility of imidazole towards organophosphates (OPs), that has inspired many catalysts and sensors, beneficial? Herein, a thorough analysis is given seeking to unravel this puzzle. For OPs from the P=O family, imidazole attacks the phosphorus atom exclusively (N-phosphorylates). With the P=S family which are less reactive, an unusual N-alkylation predominates. Surprisingly, imidazole reacts with methyl parathion exclusively at the aliphatic carbon, whilst for the ethylated analogue parathion, imidazole reacts by two pathways: at both the phosphorus and aliphatic carbon, with predominance for the latter. The preference for the electrophilic center can be modulated by the pH. Overall, a mechanistic structure-related trend is observed: imidazole tends to prefer other electrophilic centers than the phosphorus for less reactive OPs. Moreover, this gives important insights concerning the challenging chemistry of imidazole alkylation and the outcomes for monitoring systems that depend on the detection of degradation products. Finally, a thorough comparison with the literature is presented seeking to understand how imidazole reacts towards various OPs. We suggest that the promiscuity of imidazole boosts up its versatility.

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Section: Introductionmentioning

confidence: 99%

Are Imidazoles Versatile or Promiscuous in Reactions With Organophosphates? Insights From the Case of Parathion

Silva

Orth

2019

J. Braz. Chem. Soc.

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“…Pesticide exposures have been linked to several negative human health effects, such as asthma; cancer; and disruption of the nervous, endocrine, and reproductive systems [40][41][42][43][44][45][46]. Young children and pregnant women are particularly sensitive to pesticide exposures [5,7,[47][48][49][50][51], which have been linked to delays in human fetal development and lifelong neurotoxic disabilities [52][53][54][55][56]. Recognizing the risks posed by pesticide exposure highlights the need for further investigation into the underlying molecular mechanisms of action and evidence-based programs of prevention [57].…”

Section: Discussionmentioning

confidence: 99%

“…Research suggests that fetal development is the window of susceptibility for adverse effects of pesticide exposures, although work in this area is conflicting. In particular, the fetal brain is sensitive to toxicants due to rapid growth and development [5][6][7]. Previous studies have shown that OP and carbamate insecticides are neurotoxic due to inhibition of acetylcholinesterase (AChE), resulting in increased levels of the neurotransmitter acetylcholine in the synaptic cleft, impeding cholinergic neurotransmission [8].…”

Section: Introductionmentioning

confidence: 99%

Exposure of Larval Zebrafish to the Insecticide Propoxur Induced Developmental Delays that Correlate with Behavioral Abnormalities and Altered Expression of hspb9 and hspb11

Shields

Hales

Ranspach

et al. 2019

Toxics

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Recent studies suggest that organophosphates and carbamates affect human fetal development, resulting in neurological and growth impairment. However, these studies are conflicting and the extent of adverse effects due to pesticide exposure warrants further investigation. In the present study, we examined the impact of the carbamate insecticide propoxur on zebrafish development. We found that propoxur exposure delays embryonic development, resulting in three distinct developmental stages: no delay, mild delay, or severe delay. Interestingly, the delayed embryos all physically recovered 5 days after exposure, but behavioral analysis revealed persistent cognitive deficits at later stages. Microarray analysis identified 59 genes significantly changed by propoxur treatment, and Ingenuity Pathway Analysis revealed that these genes are involved in cancer, organismal abnormalities, neurological disease, and hematological system development. We further examined hspb9 and hspb11 due to their potential roles in zebrafish development and found that propoxur increases expression of these small heat shock proteins in all of the exposed animals. However, we discovered that less significant increases were associated with the more severely delayed phenotype. This raises the possibility that a decreased ability to upregulate these small heat shock proteins in response to propoxur exposure may cause embryos to be more severely delayed.

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“…The wide use of insecticides has raised a signi cant concern due to possible health effects associated with exposure to these compounds (Carvalho 2006;Dich et al 1997;Hertz-Picciotto et al 2018a;Hertz-Picciotto et al 2018b;Hertz-Picciotto et al 2018c). Insecticides are used globally to control crop pests in agriculture, to reduce household pests, to reduce insect damage to lawns and golf courses, and as mosquito control agents ( (EPA) 2000;Eaton et al 2008;Shelton et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos

Berg

Ching

Bruun

et al. 2020

Preprint

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Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period cannot be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with exposure(s) to environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of developmental delay, ADHD, or ASD. Methods: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes, i.e., deficits in social communication and repetitive, restricted behavior. Male and female rat pups were exposed to CPF at 0.1, 1.0, or 3.0 mg/kg (s.c.) from postnatal days 1-4. Results: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF rats and the corresponding vehicle controls; however there were some interesting trends in females at a dosage of 0.3 mg/kg. Conclusions: This work characterizes a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.

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Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms

Abstract: In a Policy Forum, Irva Hertz-Picciotto and colleagues review the scientific evidence linking organophosphate pesticides to cognitive, behavioral, and neurological deficits in children and recommend actions to reduce exposures.

Cited by 185 publications

References 34 publications

Are Imidazoles Versatile or Promiscuous in Reactions With Organophosphates? Insights From the Case of Parathion

Are Imidazoles Versatile or Promiscuous in Reactions With Organophosphates? Insights From the Case of Parathion

Exposure of Larval Zebrafish to the Insecticide Propoxur Induced Developmental Delays that Correlate with Behavioral Abnormalities and Altered Expression of hspb9 and hspb11

Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos

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