Increasingly, prospective epidemiological studies link maternal stress during pregnancy with adverse neurodevelopment in children. Recent evidence also suggests that perinatal ambient air pollution exposure may have neurotoxic effects. While historically research has focused on how social and physical environmental factors independently affect children's health, evolving research underscores the importance of studying interactive effects. Moreover, marginalized populations of lower-socioeconomic position (SEP) are exposed disproportionately to traffic- related pollutants while living in adverse social circumstances or communities that are socially toxic. Consequently, these populations experience both increased stress and increased chemical pollution. Social x chemical interactions may account for more variance in explaining risk than the main effects of either factor alone. Relevant studies in urban populations are rare and none assess stress and air pollution together. Studies of mechanistic pathways linking perinatal air pollution and/or stress to neurodevelopment are equally sparse. We take advantage of an established pregnancy cohort - the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project (R01 HL080674, RJ Wright PI), with prospectively characterized exposure to ambient pollutants starting in pregnancy coupled with extensive assessment of pre- and postnatal stress, as well as relevant confounders and mediators. We can draw from our biomarker archive including assessments of prenatal maternal hypothalamic-pituitary-adrenal (HPA) axis (e.g., cortisol), infant autonomic nervous system (ANS) and HPA axis function at age 6 months, and DNA banked for future genetic assays to explore mechanisms. In this application, we are proposing the addition of neurocognitive and behavioral testing in n=815 ACCESS children at age 6 years. We will then test the main effects of perinatal exposure to chronic ambient air pollution and/or psychological stress on these neuropsychiatric outcomes. We will next examine whether air pollution effects are modified by psychosocial stress. Mechanisms to be explored include perinatal stress (& air pollution)-elicited disruption in the maternal prenatal HPA axis and the child's HPA axis and ANS response. Finally, to further explore biological mechanisms by which air pollutants and stress impact neurodevelopment, genetic susceptibility factors will be examined. PUBLIC HEALTH RELEVANCE: This study will examine the effects of perinatal exposure to traffic-related air pollution on childhood neurobehavioral and cognitive development in urban children. In addition to independent effects of air pollution, the study will also examine the potential modifying effects of the social environment (i.e., psychological stress) and genetic susceptibility on these relationships. Such knowledge may inform efforts to design programs that improve neurodevelopmental trajectories in high-risk urban populations disproportionately exposed to adverse physical and social environments.