Abstract
Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. ASD affects one in 54 children in the United States, one in 89 children in Europe, and one in 277 children in Asia, with an estimated worldwide prevalence of 1–2%. While there is increasing consensus that ASD results from complex gene x environment interactions, the identity of specific environmental risk factors and the mechanisms by which environmental and genetic factors interact to determine individual risk remain critical gaps in our understanding of ASD etiology. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been linked to altered neurodevelopment in humans. Preclinical studies demonstrate that PCBs modulate signaling pathways implicated in ASD and phenocopy the effects of ASD risk genes on critical morphometric determinants of neuronal connectivity, such as dendritic arborization. Here, we review human and experimental evidence identifying PCBs as potential risk factors for ASD and discuss the potential for PCBs to influence not only core symptoms of ASD, but also comorbidities commonly associated with ASD, via effects on the central and peripheral nervous systems, and/or peripheral target tissues, using bladder dysfunction as an example. We also discuss critical data gaps in the literature implicating PCBs as ASD risk factors. Unlike genetic factors, which are currently irreversible, environmental factors are modifiable risks. Therefore, data confirming PCBs as risk factors for ASD may suggest rational approaches for the primary prevention of ASD in genetically susceptible individuals.
Highlights
Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors
In primary rat hippocampal neurons, the Polychlorinated biphenyls (PCBs) 95 sensitization of ryanodine receptor (RyR) triggers the release of intracellular Ca2+ from the endoplasmic reticulum (ER), which activates the mechanistic target of rapamycin signaling to initiate translational mechanisms that stimulate dendritic growth [118]
Whether the PCB effects on intestinal physiology are linked to changes in the enteric nervous system remains to be determined, but, collectively, these observations suggest that the question of whether PCBs contribute to deficits in autonomic and sensory function in individuals with ASD is deserving of further exploration
Summary
Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. The complexity of heritable risk factors contributing to ASD likely creates a range of sensitivities to environmental risk factors [32], which masks clear associations between exposure and diagnosis To overcome these challenges and to inform more targeted epidemiologic studies, experimental models are being leveraged to identify environmental chemicals that modulate the same signaling pathways and neurodevelopmental events as ASD susceptibility genes [32,33]. Recent reports demonstrating the prevalence of the lower-chlorinated congener PCB 11 in commercial milk products in northern California [39], and evidence that PCB 95, a higher-chlorinated congener, is the second most abundant PCB detected in the air in schools in the United States [40], suggest that humans may be exposed to both higher- and lower-chlorinated PCBs via diet and inhalation [41]. We propose mechanisms by which PCBs may interact with ASD risk genes to increase the risk and/or severity of ASD and discuss the potential for PCBs to contribute to the core symptoms, and common comorbidities of ASD using bladder dysfunction as an example
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