Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos

Abstract

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 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. 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, 0.3, or 1.0 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-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. Conclusions This 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.

Social Behavior and Ultrasonic Vocalizations in a Genetic Rat Model Haploinsufficient for the Cross-Disorder Risk Gene Cacna1c

“…In humans, UBE3A deletions cause Angelman syndrome characterized by severe developmental delay and intellectual disability, most notably lack of language acquisition [101]. Finally, we found that environmental risk factors associated with neurodevelopmental disorders, most notably early life exposure to the organophosphorus pesticide chlorpyrifos, reduced social approach behavior in response to 50-kHz USV playback [103]. Specifically, chlorpyrifos exposure led to a dose-dependent inhibition of social approach behavior, with the two highest doses completely blocking the social approach response in females but not males.…”

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in theUbe3aDeletion Rat Model of Angelman Syndrome

“…At PND 38 ± 1, social play behavior was assessed following a protocol described previously ( Berg et al, 2018 , 2020a , b ). Each subject rat was placed with a freely moving, unfamiliar, strain-, sex-, and age-matched WT stimulus rat for 10 min in a clean, empty test arena (illuminated to ∼30 lux) containing a thin layer of clean bedding.…”

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

“…On PND 10, neonatal rats were assessed by collecting 40-kHz vocalizations made when isolated from the dam and littermates following a previously described protocol [ 16 , 50 , 60 , 61 ]. Rat pups were selected from the nest at random and placed in a small plastic container with clean bedding.…”