Project 4 is an integral component of the Dartmouth Superfund Research Program. Over the past 18 years, we designed and tested methods of measuring environmentally relevant levels of exposure to metals and applied novel biomarkers of exposure, susceptibility, and early response to large- scaled, population-based epidemiologic studies in the US. To date, we have tested over 8,000 households for arsenic (As), of which over 3,500 had private water systems. A GIS analysis of the data (performed in collaboration with the Trace Element Analysis Core) revealed distinct "clusters" of high household water As levels. Since 2009, we successfully established a pregnancy cohort of women who use private wells in one of these cluster regions. This initial funding period was designed to examine the relationship between in utero exposure to arsenic using multiple measures of exposure (drinking water, toenails and urine) on birth outcomes (e.g., fetal growth and gestational age). We also sought to test the hypothesis that methylmercury intake alone, or in combination with other factors, influences fetal growth and gestational age. We plan to conduct a collaborative analysis with the NIEHS-funded New Bedford birth cohort study (adjacent to a Superfund Site). Of the household tap water samples tested thus far, ~15% exceeded the maximum contaminant level for As established by the US EPA of 10 ug/L. While evidence suggests that As is related to adult onset diabetes and hypertension, its effects on these outcomes during pregnancy are uncertain. Thus, we will determine whether As influences glucose and blood pressure control during pregnancy and identify potential genetic susceptibility loci for these effects. Additionally, we will test pregnant women and newborns for markers of systemic inflammation and vascular endothelial dysfunction that have been previously found to relate to As exposure among adults in more highly exposed regions. Our hypothesis is that pregnancy and fetal development represent "windows" of susceptibility to the effects of As on cardiometabolic outcomes. To our knowledge, our study is one of the only molecular epidemiologic investigations of pregnancy and early life exposure to As in vulnerable subgroups of the general population of the U.S. Our goal is to inform risk assessment and management of toxic metal exposure in the U.S., and aid early intervention strategies to prevent adverse health effects from these exposures. ExpandCollapse Abstract