PROJECT SUMMARY
Internalizing problems, most prominently anxiety and depressive disorders affect > 400 million people globally.
Rooted in early development starting in utero, there is a steep rise in these disorders in the transition to
adolescence. Identifying those at risk as early in life as possible is critical in order to ensure optimal
development and prevention. There has been growing interest in studying the role of nutritional factors in
modifying effects of chemical environmental exposures, as nutrition is amenable to intervention. Our group was
recently funded to examine the role of prenatal exposure to metals and their mixtures on early life
neurobehavioral domains linked to a greater risk of developing anxiety and depressive disorders later in
childhood (R01 ES033436, RJ Wright PI). In addition, we demonstrated that several nutrients, particularly
those with antioxidant potential (e.g., vitamin A) can mitigate the impacts of metals on fetal growth, providing
proof of concept for this proposal. The joint associations between maternal prenatal nutrition and in utero metal
exposures in influencing offspring’s internalizing disorders remain poorly understood, particularly beginning in
the prenatal period. To overcome existing knowledge gaps, we will examine the joint associations of prenatal
exposure to maternal nutrition and heavy metals on young children’s internalizing problems and related
prefrontal cortex (PFC) functions in the PRogramming of Intergenerational Stress Mechanisms (PRISM)
cohort. PRISM is a racially and ethnically diverse urban sample with extant data on prenatal urinary metal
exposure and children’s neurobehavioral outcomes measured at ages 6 months and 3-5 years. We will
leverage available data on maternal prenatal nutrition assessed two ways - (i) using a food frequency
questionnaire (FFQ) and (ii) measurement of additional micronutrient biomarkers in maternal blood and urine
obtained in pregnancy. This will enable us to determine how maternal nutrition affects internalizing behaviors in
early childhood as well as to examine the modifying effects of optimal or inadequate intake of key
micronutrients on associations between metals and neurobehavioral outcomes. We hypothesize that increased
intake or higher measured levels of antioxidant micronutrients (e.g., retinol, carotenoids, tocohperhols) will
mitigate associations between prenatal metal exposures and internalizing problems whereas lower intake or
levels of iodine will interact with metals to enhance risk of neurobehavioral problems. Novel advanced
statistical modeling will consider interactions between metal and micronutrient mixtures allowing examination of
non-linear relationships between mixtures and internalizing problems. Applying mixture analysis and agonistic
selection of nutrients has the potential to characterize modifiers that have not been identified in studies focused
on a single nutrient or a specific diet pattern. Sex-specific effects will also be explored. Understanding the
independent and modifying effects of key micronutrients in the relationship between prenatal metal exposures
and early indicators of psychiatric risk is arguably critical to informing future interventions.
