CHILDHOOD DIOXIN EXPOSURE AND ENERGY HOMEOSTASIS DYSREGULATION

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DESCRIPTION (provided by investigator): Recent epidemiologic studies have reported associations of serum concentrations of polychlorinated dibenzo- p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) with elevated serum glucose and insulin, and greater risk of type 2 diabetes mellitus (T2DM). Most of these studies have been cross-sectional and were unable to establish a temporal association or identify critical exposure periods between serum PCDDs and PCDFs (herein referred to as dioxins) and PCBs with these outcomes. None of these studies were conducted among children. In the last two decades, the incidence of childhood obesity and T2DM has increased substantially. Contributory factors include diet, physical activity, and genetic predisposition. Epidemiological studies suggest environmental exposures such as dioxins and PCBs may also play a role. Obesity and T2DM are associated with impaired glucose metabolism, dyslipidemia, and altered serum adipokines. Recent research suggests that alterations in these biomarkers of energy homeostasis in children may precede and promote the development of obesity and T2DM. We propose to incorporate measurements of metabolic abnormalities into an ongoing longitudinal cohort study evaluating the associations of serum dioxins and PCBs with growth and pubertal development in 499 boys in Chapaevsk, Russia. We are in the fourth year of this study in which the boys, enrolled at 8 to 9 years old, are evaluated yearly, and will be followed through puberty to adulthood. At enrollment, the boys provided blood samples for dioxin and PCB analyses, permitting us to measure peri-pubertal exposure. We perform annual physical examinations that include anthropomorphic measurements, and collect detailed family medical, dietary, and residential information. We propose to extend the original aims of this study to evaluate whether higher peri- pubertal serum dioxins and PCB levels are associated with dysregulation of energy homeostasis, with a specific focus on glucose, lipid, and adipocyte metabolism, and adiposity. We will prospectively evaluate these associations from peri-puberty through adolescence, using medical record information for birth weight and ponderal index, annual physical exams and biennial serum analysis for biochemical biomarkers. Our comprehensive data collection will enable us to assess the interactions of these exposures and factors such as caloric intake and physical activity on the outcomes. The application's prospective design will permit us to evaluate whether exposure to elevated dioxins and PCBs during the peri-pubertal period is associated with subsequent glucose dysregulation, altered fat and adipokine metabolism, and increased adiposity. PUBLIC HEALTH RELEVANCE: Although diet and physical activity are well-known risk factors for obesity and diabetes, there is increasing evidence that environmental exposure to chemicals may also play a role. Dioxins and polychlorinated biphenyls (PCBs) have been linked with increased risk of diabetes in human studies, and to greater body fat in animal studies. This application will assess whether higher blood levels of dioxins and PCBs in Russian boys are associated with increased risk of higher blood glucose, insulin, and low density cholesterol as well as greater body fat, which will provide important scientific insights into the role of environmental chemicals in the development of diabetes and obesity.