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 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: The hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes, i.e., deficits in social communication and repetitive, restricted behavior, is now currently being explored by us and others. To add knowledge in this research area, we exposed male and female rat pups 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. Ex vivo magnetic resonance imaging revealed many neuroanatomical phenotypes in male and female juvenile rats; however, only the females exposed to the 0.3 mg/kg dose passed our strict correction for multiple comparisons. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Conclusions: This work characterizes a rat model of developmental CPF exposure that exhibits adverse behavioral and widespread anatomical 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. Keywords: Animal models, behavior, autism, neurodevelopment, toxicology, pesticides, chlorpyrifos, imaging, social, rat

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

“…Juvenile social play. At PND 38±1, social play behavior was assessed following a protocol described previously (Berg et al, 2018;Berg et al, 2020a;Berg et al, 2020b). Each subject rat was placed with a freely moving, unfamiliar, strain-, sex-, and age-matched wildtype 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.…”

Recent Studies of Rodent Ultrasonic Vocalizations and Their Use in Experimental Models

“…The consistent association of 22 kHz and 50 kHz vocalizations with aversive or appetitive states, respectively, and the dual emotional arousal system makes these vocalizations particularly useful for numerous preclinical studies and models, particularly in physiological, psychological, neurological, psychiatric, and neurodevelopmental investiga-tions. Therefore, rat ultrasonic vocalizations have been used in studies of human social psychopathologies [384], the screening of drugs for numerous conditions, particularly anxiolytic and antidepressant drugs [385][386][387], studies of schizophrenia [388], Parkinson's disease [389], bipolar disorder [390], post-traumatic stress disorder [391], alcohol use disorders [392,393], neurodevelopmental damages [394], immunity [395], affective component of pain [229], addiction [216,335], effects of malnutrition [396] and many other disorders and diseases. The present review should help in the interpretation of the results of these and future studies.…”