Perinatal metal mixture exposure and prenatal maternal stress: Impact on neural and cognitive constructs underlying adolescent risk-taking

PROJECT SUMMARY/ABSTRACT Maladaptive adolescent risk-taking behaviors are a public health concern associated with a variety of adverse health outcomes. Although studies have explored neurobiological mechanisms underlying adolescent risk-taking, few have examined the potential role of early-life environmental exposures. To address this knowledge gap, this proposal utilizes a Developmental Origins of Health and Disease (DOHaD) framework to elucidate early-life environmental influences of adolescent-risk taking, focusing on the unique vulnerability of the perinatal period (prenatal to 1 year postnatal). Throughout the perinatal period, the brain undergoes significant structural and functional maturation, making exposures at any point a risk for abnormal neurodevelopment. Converging epidemiological data suggest that individual metal exposures (e.g., lead, manganese) during this period may contribute to adolescent-risk taking by disrupting the development of subserving brain regions within the reward and/or cognitive control systems (e.g., striatum, prefrontal cortex). However, although metals commonly co-occur in the environment, no epidemiological study to date has assessed the impact of perinatal metal mixture exposure in relation to adolescent risk-taking. Furthermore, evidence suggests prenatal maternal stress (PMS) may enhance metal neurotoxicity, suggesting that combined exposure to PMS and metals may increase risk for maladaptive adolescent risk-taking. Yet, the modifying effect of PMS on metal-associated outcomes has not been studied in the context of adolescent risk-taking. This study proposes to examine associations between perinatal metal mixture exposure on cognitive (Aim 1) and neural (Aim 2) constructs underlying adolescent risk-taking, and to evaluate the modifying role of PMS on these associations (Aim 3). Using state-of-the-art statistical methods, I will analyze existing data (dentine metal biomarkers, maternal stress measures, gambling task fMRI) collected from adolescents enrolled in the Programming Research in Obesity, GRowth, Environment, and Social Stress (PROGRESS) study. My analyses will focus on brain regions associated with reward, risk, and/or cognitive control (e.g., ventral striatum, insula, dorsolateral prefrontal cortex), and the following constructs derived from a computational model of risky decision-making: risk-taking tendency, risk sensitivity, reward sensitivity. I hypothesize that perinatal metal mixture exposure will be significantly associated with alterations in these constructs, and that these associations will be enhanced in offspring exposed to higher PMS. The proposed project is supported by the Icahn School of Medicine at Mount Sinai’s Department of Environmental Medicine and Public Health, which provides a highly cross-disciplinary research environment. By integrating environmental epidemiology, biostatistics, and developmental cognitive neuroscience, the proposed research presents a unique training opportunity in the growing field of environmental developmental neuroscience and will prepare the applicant for an interdisciplinary academic research career. Importantly, the proposed research will also inform public health interventions aimed at improving adolescent health.