Abstract
BackgroundNeurodevelopmental 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 may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with 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 that 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 intellectual delay or disability, ADHD, or ASD.MethodsWe 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, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4.ResultsThese 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-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group.ConclusionsThis work generated and characterized 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 the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.
Highlights
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
Isolation-induced ultrasonic vocalizations (USV) were collected for 3 min as social communication signals in rat pups, as previously described [33]
CPF-exposed pups emitted significantly fewer USV across early development (Fig. 1a F(2, 90) = 286.5, p < 0.001; Fig. 1b F(2, 90) = 267.7, p < 0.001). They learn to temperature regulate, open their eyes, and are less reliant on maternal care, which is why USV decrease in number over developmental days
Summary
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. Epidemiological studies suggest that 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 intellectual delay or disability, ADHD, or ASD. Among the most widely used insecticides are the organophosphorus pesticides (OPs), which include chlorpyrifos, parathion, and diazinon [9, 10]. Experimental studies have demonstrated an association between prenatal exposure to OPs and abnormal developmental reflexes [19]. The UC Davis Childhood Autism Risks from Genetics and Environment (CHARGE) study [8, 18] reported significant associations between prenatal OP exposures and mental and motor delays and an increased risk of autism spectrum disorder (ASD). A recent metaanalysis of the epidemiological data concluded that there is a positive association between CPF and neurodevelopmental disorders, which warranted further investigation of CPF developmental neurotoxicity [21]
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