There is strong evidence that the environment experienced in utero contributes to cardiovascular, metabolic, immunologic, and nervous system health during both childhood and adulthood. Defining children at-risk early in life is critical to improving health outcomes; biomarkers of exposure and outcome are powerful tools to use in risk identification and offer an opportunity to inform the mechanisms involved in the developmental origins of disease. Emerging evidence, from our own laboratories and others, suggests that the placenta, as a master regulator of the intrauterine environment and of fetal development, plays a critical role in the developmental origins of health and disease. Thus, the placenta is an ideal tissue in which to identify functional biomarkers that mediate fetal programming of health. In published and preliminary studies we have demonstrated that exposures, such as arsenic, can alter the patterns of DNA methylation and of gene expression in primary human placental tissue, and we have demonstrated that such alterations are associated with fetal growth and newborn neurobehavioral measures. We aim here to develop novel biomarkers of exposure and outcome by examining the hypothesis that environmental exposures encountered by a pregnant woman impact the epigenetic and gene expression profiles of the infant's placenta and these functional alterations are associated with poor-health outcomes in the children. We will employ the existing resources of the ongoing New Hampshire Birth Cohort Study, and its established biorepository of placental tissues, to allow sensitive and robust assessment of gene expression and genome wide DNA methylation in combination with infant and maternal biomarkers of arsenic exposure. We propose to use state-of-the-art genomic technologies to identify and validate novel profiles of DNA methylation and gene expression susceptible to environmental exposure in human placenta and to examine their association with newborn outcomes including growth, infection and neurodevelopment being assessed in Projects 1 and 2 of the Program. These examinations will provide critical insight into the mechanisms of the developmental origins of lifelong health, highlight novel pathways affected by exposures that drive children's health, and identify novel biomarkers which can be used to find at the earliest points of life, children at-risk so necessary interventions can be employed soon enough to prevent future disease. ExpandCollapse Abstract