Piloting a Novel Approach for Examining Intersecting Environmental Exposures and Social Behavior

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Project Summary/Abstract Rates of neurodevelopmental disorders (NDDs) are rapidly and inexplicably rising with one in six US children aged 3-17 diagnosed with a developmental disability between 2009 and 2017, and nearly 33% of US children aged 13-18 suffering from an anxiety disorder. Mental health disorders such as anxiety and autism spectrum disorder (ASD) manifest in each sex differently and can persist for a lifetime, thus understanding their origins is highly significant. Prenatal exposure to chemical pollutants such as air pollution, plasticizers, and flame retardants (FRs), are hypothesized to be one causal factor elevating NDD risk in both sexes. The available experimental data, however, testing this hypothesis is surprisingly minimal and discordant. Moreover, chemical exposures frequently occur in combination with other stressors known to heighten risk of psychosocial disorders including chronic stress and social isolation. Thus, understanding how multiple adverse environmental “hits” act in combination to exacerbate risk of socioemotional deficits is a critically important but unmet need. This project addresses the pressing need for rigorous, reproducible, human-relevant studies examining potential links between environmental exposures and social deficits common to many NDDs. We will use the prairie vole (Microtus ochrogaster), a well-established, pro-social animal model for exploring the neurobiology of ASD and other social disorders, but generally unfamiliar to toxicologists, to test the hypothesis that father absence during rearing will exacerbate known behavioral deficits induced by developmental exposure to the chemical flame retardant (FR) mixture FireMaster 550, (FM 550) particularly in male offspring. Unlike rats and mice, this species is monogamous and biparental and thus a uniquely suitable model for examining the impact of adverse events on social behavior. Our preliminary data in FM 550 exposed prairie voles reveal heightened anxiety in females and loss of pair bonding in males. The focus on FRs is significant because exposure to this chemical class has long been associated with behavioral and cognitive impairments in humans, including heightened risk of ASD, and human exposure is global and increasing. The proposed self-contained study builds on our prior work by using oral exposure to a human relevant dose, more refined testing strategies to better capture pair bonding behaviors, and the inclusion of father absence as a second adverse childhood exposure; a situation all too common in heavily polluted communities. This innovative, feasibility study is highly responsive to NIH interest in the “exposome” (chemical and experiential) as a driver of children's health. Through this small, defined project we hope to elucidate the impact of combined early life stressors on social traits of relevance to human NDDs in both sexes. Critically, the behavioral results gained from piloting the prairie vole as a powerful tool for toxicology paves the way for future work seeking to identify the mechanisms by which chemical exposures may contribute to the growing prevalence of NDDs in the context of the full exposome.