Arsenic is associated with a number of health outcomes including cancers, cardiovascular, respiratory, liver, and kidney diseases, neurodevelopment, reproduction, and diabetes. Much of the epidemiologic literature supporting these associations has evaluated arsenic exposure in adulthood. While there is a growing epidemiologic literature to suggest that arsenic exposure during in utero and early childhood periods may profoundly influence disease risk in childhood, adolescence, and later life, arsenic-related clinical outcomes in childhood as well as underlying molecular pathways have not yet been fully elucidated. Arsenic has been reported to be a potent endocrine disruptor. Alterations in hormonal balance and gene deregulation in sensitive periods such as in in utero and early life may lead to clinical dysfunction or pathologies manifest in childhood and later life. In this application, we propose to conduct the first comprehensive evaluation of molecular and clinical impacts, as related to endocrine function, in children with well-characterized in utero and early life arsenic exposure. Using an already enumerated cohort of 2-7 year old children from mothers in established population-based studies in Bangladesh, we propose to conduct follow-up visits of 500 mother-child pairs to evaluate endocrine- related characteristics in the children. The proposed research will investigate the following Specific Aims: (1) to evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with thyroid and steroid hormones in children; (2) to evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with gene expression profiles in children; and, (3) to longitudinally evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with endocrine-related phenotypes (i.e., linear growth, blood pressure, and insulin resistance) in children. In exploratory analyses, we will evaluate whether these associations are modified by AS3MT genotype and child sex. Our proposed study takes advantage of a unique study population and existing data to examine endocrine characteristics and gene expression deregulation in children that may be related to in utero and early childhood arsenic exposure. We expect that the results from this proposed research would make major scientific and public health contributions toward our understanding of the health effects of arsenic exposure in several ways: (1) provide novel evidence with respect to arsenic exposure in relation to endocrine function; (2) support whether endocrine dysfunction and/or gene deregulation mediate associations between arsenic exposure and endocrine-related phenotypes; and, (3) shift the existing prevention paradigm for arsenic exposed populations, which currently focuses on exposure remediation and risk reduction in adult populations towards public health interventions targeted for pregnant-women, women of child-bearing age, and children. ExpandCollapse Abstract