DESCRIPTION (provided by applicant): The prevalence of insulin resistance, dyslipidemia, and high blood pressure has increased substantially among children in recent decades. These conditions track into adulthood, and predispose to subsequent development of type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). Recent evidence shows that exposure to endocrine disrupting chemicals (EDCs) during key developmental periods may be a risk factor for metabolic disorders independent of diet and physical activity. Inorganic arsenic (iAs), an EDC, has been linked to low birth weight, and poor childhood growth (e.g. lower height and weight). Children are considered especially vulnerable to iAs, because of their rapid physical growth and maturing endocrine and metabolic systems. However, most epidemiologic studies assessing iAs effects on children's health have been cross-sectional, conducted in areas with high iAs groundwater levels not representative of most population exposures, and lacking in diet and/or individual exposure measures. We propose to prospectively examine the associations of prepubertal urinary iAs with adolescent growth, blood pressure, and serum biomarkers of growth and metabolism. We will also evaluate environmental and dietary predictors of urinary concentrations of arsenic species and metabolites. We will leverage our ongoing longitudinal cohort study examining the association of organochlorine compounds (OCs) and lead with growth and sexual maturity among 499 boys in Chapaevsk, Russia by measuring urinary arsenic species and metabolites in this population. Chapaevsk is an industrial city with arsenic and OC contamination secondary to environmental releases of chlorinated and other chemicals, including the organo-arsenic chemical weapon lewisite, by local industry. Our preliminary data demonstrate that the boys' urine iAs levels are higher than the U.S. population but much lower than high water iAs regions such as Bangladesh. Boys enrolled at ages 8-9 years were followed until 18 -19 years old. At entry, boys provided blood and urine samples for prepubertal exposure assessment, and detailed data was collected on medical history, socioeconomic status, residential proximity to the primary industrial polluter, and diet. Boys underwent annual physical exams, bio-electric impedance measures, and collection of urine; blood was collected biennially. These extensive prospectively collected outcome and covariate measures will provide us with a unique opportunity to assess the effect of iAs exposure during the vulnerable prepubertal period with adolescent growth and blood pressure, a time when manifestations of altered growth may be particularly evident. Furthermore, by virtue of unusual local industrial contamination with iAs and the cohort's prevalent consumption of locally grown foods, diet's role in iAs exposure and iAs exposure effects will be assessed. Finally, our study will be the first to assess urinary iAs associations with serum biomarkers of adolescent growth and energy metabolism, providing insight into the underlying biological mechanisms of iAs associations with adult T2D and CVD.

PUBLIC HEALTH RELEVANCE: Inorganic arsenic (iAs) has been associated with reduced childhood growth, and in adults with type 2 diabetes mellitus, hypertension, and cardiovascular disease. Epidemiologic studies suggest that endocrine disrupting environmental chemicals, such as iAs, may contribute to the rising prevalence of childhood metabolic health disorders such as insulin resistance, dyslipidemia, and high blood pressure. Our proposal will prospectively evaluate whether childhood iAs exposure is associated with subsequent impaired growth, higher blood pressure, and metabolic dysregulation in an established longitudinal cohort of Russian boys. This research will provide insights into the health consequences of childhood arsenic exposure.