Project 4 is an integral component of the Dartmouth Superfund Basic Research Program (SBRP), focusingon the environmental and health impact of toxic metal exposure in the US. We propose to build on 12 yearsof experience designing and testing methods of measuring environmentally relevant levels of exposure andfactors that influence individual susceptibility to metal-related health effects. Accumulating data point to thedeveloping fetus as particularly vulnerable to environmental insults and that early life exposures impactchildhood and adult health. Thus, we propose to test the hypothesis that prenatal exposure to arsenic isassociated with birth outcomes (e.g., birth weight, fetal growth restriction and gestational age) in the NewHampshire population. We also will assess whether individual variation in arsenic metabolism (based onmaternal urinary metabolites, arsenic metabolism genes e.g., GSTO1, GSTO2, AS3T, PNP) and otherfactors (e.g., smoking, folate or polymorphisms in one carbon metabolism genes) modify these effects. Wewill evaluate the reliability of multiple measures of metal exposure (e.g., in drinking water, hair, nails andurine) within mothers and in mother-infant pairs. Secondarily, we will investigate the hypothesis thatmethylmercury intake alone or in combination with other factors influences fetal growth and gestational age.We will conduct a collaborative analysis with the NIEHS-funded New Bedford birth cohort study (adjacent toa Superfund Site) to increase statistical power. Programatically, we will: (1) test innovative strategies for thedetection, characterization and interpretation of gene-environment interactions (with the Integrative BiologyCore (IBC)), (2) explore dietary sources and geographic patterns of metal exposure (with Projects 7, 9), (3)provide a platform for translational molecular, genetic, and proteomic studies (for the IBC, Projects 2, 7, 8, 9)and (4) investigate the functional effects of polymorphisms in metal transporter genes (with the IBC, Projects8, 9). We will expand collaborative and translational activities with other SBRPs, universities and agencies.To our knowledge, the study proposed will represent among the first molecular epidemiologic investigationsof early life exposure to arsenic and mercury in a general population of the US. Our goal is to inform riskassessment and management of toxic metal exposure in the US, and aid early intervention strategies toprevent adverse health effects from these exposures.
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