CHILDHOOD DIOXIN EXPOSURE AND ENERGY HOMEOSTASIS DYSREGULATION

描述（由研究者提供）：最近的流行病学研究报告了多氯二苯并-对二恶英（pcdd）、多氯二苯并呋喃（pcdf）和多氯联苯（PCBs）的血清浓度与血清葡萄糖和胰岛素升高以及2型糖尿病（T2DM）的高风险相关。这些研究大多是横断面的，无法确定血清pcdd和pcdf（此处称为二恶英）与多氯联苯与这些结果之间的时间关联或确定关键暴露期。这些研究都不是在儿童中进行的。在过去二十年中，儿童肥胖和2型糖尿病的发病率大幅增加。致病因素包括饮食、身体活动和遗传易感性。流行病学研究表明，二恶英和多氯联苯等环境暴露也可能起作用。肥胖和2型糖尿病与糖代谢受损、血脂异常和血清脂肪因子改变有关。最近的研究表明，儿童能量平衡的这些生物标志物的改变可能先于并促进肥胖和2型糖尿病的发展。我们建议将代谢异常的测量纳入一项正在进行的纵向队列研究中，评估俄罗斯查帕耶夫斯克499名男孩的血清二恶英和多氯联苯与生长和青春期发育的关系。我们的研究已经进行到第四年了，这些8到9岁的男孩每年都会接受评估，并将从青春期一直跟踪到成年。在登记时，男孩们提供了血液样本进行二恶英和多氯联苯分析，使我们能够测量青春期周围的暴露程度。我们每年进行身体检查，包括拟人化测量，并收集详细的家庭医疗、饮食和居住信息。我们建议扩展本研究的最初目的，以评估较高的青春期周围血清二恶英和多氯联苯水平是否与能量稳态失调有关，并特别关注葡萄糖、脂质和脂肪细胞代谢以及肥胖。我们将利用出生体重和体重指数的医疗记录信息、年度体检和两年一次的生化生物标志物血清分析，对从青春期到青春期的这些关联进行前瞻性评估。我们全面的数据收集将使我们能够评估这些暴露和诸如热量摄入和身体活动等因素对结果的相互作用。该应用程序的前瞻性设计将允许我们评估在青春期周围暴露于高浓度二恶英和多氯联苯是否与随后的葡萄糖失调、脂肪和脂肪因子代谢改变以及肥胖增加有关。公共卫生相关性：虽然饮食和体育活动是众所周知的肥胖和糖尿病的危险因素，但越来越多的证据表明，环境暴露于化学品也可能起作用。在人类研究中，二恶英和多氯联苯（PCBs）与糖尿病风险增加有关，在动物研究中，二恶英和多氯联苯与体脂增加有关。此申请将评估

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.