PROJECT SUMMARY Prior studies have identified associations between prenatal exposure to single classes of endocrine disrupting chemicals (EDCs) and the development of metabolic disease. However, few studies have examined the effect of mixtures of chemicals on perinatal and pediatric outcomes, despite evidence that pregnant women are exposed to multiple EDCs simultaneously that share mechanisms of action. The proposed research will examine environmental mixtures using novel statistical methods to evaluate the effect of prenatal exposure to mixtures of metals, some of which are known EDCs and obesogens, on metabolic trajectory of children during development. It will also evaluate the effect of these metal mixtures on telomere length and mitochondria DNA copy number (mtDNAcn), as biomarkers of oxidative stress and inflammation, during pregnancy and at birth, which may mediate the development of childhood adiposity. This study will harness already collected data from Project Viva, a longitudinal prospective pre-birth cohort designed to examine the extent to which events during early development affect health outcomes during the life course. Over two thousand mothers were enrolled in the study at their initial prenatal visits in eastern Massachusetts between 1999 and 2002, and detailed interviews, questionnaires, and sample collection was performed during pregnancy, at birth, and at distinct developmental time points. The proposed analysis will use data collected during pregnancy, at birth, and at ages seven (mid-childhood) and twelve (early adolescence). Prenatal metals have already been measured and quantified in maternal red blood cells (RBCs) collected during the first trimester of pregnancy. These include six nonessential metals (arsenic, barium, cadmium, cesium, mercury, lead) and four essential metals (magnesium, manganese, selenium, and zinc). A major strength of Project Viva is the unique characterization of weight gain and adiposity, which was measured longitudinally using sensitive measures of adiposity and metabolic function. We will use levels of adipocyte-secreted hormones in cord blood, including leptin and adiponectin, to assess metabolic function at birth and DXA scan measurements to objectively assess adiposity at ages seven and twelve. We will use mtDNAcn and telomere length, measured prenatally during the second trimester of pregnancy and at birth, as biomarkers of oxidative stress and inflammation. These biomarkers will help elucidate the potential molecular pathway mediating the association between EDCs and childhood obesity. The research outlined in this proposal will contribute to the limited knowledge regarding the cumulative effects of in utero exposure to multiple EDCs and may identify potential new targets for intervention in pregnant women.