CHILDHOOD DIOXIN EXPOSURE AND ENERGY HOMEOSTASIS DYSREGULATION

描述(由研究人员提供)：最近的流行病学研究报告了多氯二苯并-对二恶英(PCDDs)、多氯二苯并呋喃(PCDFs)和多氯联苯(PCbs)的血清浓度与血糖和胰岛素升高以及更高的2型糖尿病(T2 DM)风险之间的关系。这些研究大多是横断面的，无法确定血清中多氯二苯并二恶英和多氯二苯并呋喃(这里称为二恶英)和多氯联苯与这些结果之间的时间关联或关键暴露时间。这些研究都不是在儿童中进行的。在过去的二十年里，儿童肥胖症和2型糖尿病的发病率大幅上升。促成因素包括饮食、体力活动和遗传易感性。流行病学研究表明，环境暴露，如二恶英和多氯联苯，也可能起到一定作用。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，儿童体内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T2 DM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，评估血清二恶英和多氯联苯与俄罗斯查帕夫斯克499名男孩生长和青春期发育的关系。我们正处于这项研究的第四年，在这项研究中，8至9岁的男孩每年接受评估，并将从青春期一直跟踪到成年。在注册时，男孩们提供了二恶英和多氯联苯分析的血液样本，允许我们测量青春期周围的暴露。我们每年进行体检，包括人格化测量，并收集详细的家庭医疗、饮食和居住信息。我们建议扩展这项研究的最初目标，以评估青春期血清二恶英和多氯联苯水平升高是否与能量平衡失调有关，尤其是糖、脂、脂肪细胞代谢和肥胖症。我们将使用出生体重和体重指数的医疗记录信息、每年的体检和两年一次的生化生物标志物血清分析，前瞻性地评估从青春期到青春期的这些相关性。我们的全面数据收集将使我们能够评估这些暴露与卡路里摄入量和体力活动等因素对结果的相互作用。该应用的前瞻性设计将使我们能够评估在青春期周围暴露于升高的二恶英和多氯联苯是否与随后的血糖失调、脂肪和脂肪因子代谢改变以及肥胖症增加有关。公共卫生相关性：虽然饮食和体力活动是肥胖和糖尿病的众所周知的风险因素，但越来越多的证据表明，环境暴露于化学品也可能起到作用。在人类研究中，二恶英和多氯联苯(PCB)与糖尿病风险增加有关，在动物研究中，与更多的体脂有关。此应用程序将评估 俄罗斯男孩血液中二恶英和多氯联苯水平较高是否与血糖、胰岛素和低密度胆固醇以及身体脂肪增加的风险增加有关，这将为环境化学物质在糖尿病和肥胖症发展中的作用提供重要的科学见解。

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.