PROJECT SUMMARY Maternal toxicant exposure and nutritional status during pregnancy contribute to the emergence of attention deficit hyperactivity disorder (ADHD) and serious externalizing behavioral problems. A prevailing belief is that toxicants and fetal micronutrient deficiencies disrupt fetal brain development, with subsequent long-term implications for offspring health and development. However, evidence that prenatal toxicant exposure and micronutrient imbalances influence fetal neural systems in humans is lacking, as is evidence that changes in the fetal brain precede nutrient- and toxicant-related developmental concerns of childhood. Filling these gaps in knowledge is critical, given the high prevalence of prenatal toxicant exposure worldwide and evidence that events during gestation influence long-range health and well-being. The central objective of this proposal is to examine development of human neural networks in utero, and to link variation in prenatal brain development to prenatal toxicant and nutrient levels (measured in the fetus) and to child outcomes. This will be done in a way that is sensitive both to chemical mixture effects and to time-variant exposure across the course of gestation, which are both likely to have specific neurodevelopmental consequences. We will pair advances in fetal resting-state functional connectivity (RSFC) MRI with innovations in tooth-biomarker assays to rigorously investigate associations between prenatal chemical/micronutrient exposures and human fetal neural connectome development, and will determine how exposome and connectome development in utero relate to child neurobehavioral development. Data collection in a Detroit-based pregnancy cohort was initiated more than 7 years ago, beginning with fetal brain RSFC MRI. Children have been followed over time, with assessments at birth, 7 months, age 3 and age 5, and have begun to naturally shed their deciduous teeth. The primary aims of this project are to (i) identify fetal brain connectome abnormalities associated with prenatal toxicant exposure and micronutrient imbalance, and identify key windows of gestational vulnerability; (ii) evaluate prenatal exposures and fetal neural connectivity as longitudinal predictors of executive function, externalizing problems and school readiness at age 5; and (iii) isolate protective factors in the postnatal environment that promote resilient outcomes in children with prenatal micronutrient deficiency and toxicant exposure. We will thus be able to meaningfully evaluate whether and how prenatal nutrient availability and toxic exposure events affect functional neurocircuitry of the developing fetal brain, and the longer-term neurobehavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of both the longitudinal effects of micronutrient and toxicant exposures in the prenatal period and the origins of child neurobehavioral disorders.

PUBLIC HEALTH RELEVANCE Through analysis of tooth biomarkers, in utero neural development, psychosocial environment during early childhood, and multiple indicators of child neurobehavioral development, we will achieve better mechanistic understanding of neurodevelopmental sequelae associated with micronutrient and toxicant exposures during pregnancy. Further, by assessing potentially modifiable psychosocial environmental factors, this work has potential to inform development of novel prevention and intervention strategies.