Effects of Arsenic on Adolescent Growth and Metabolic Health

描述(由申请人提供)：近几十年来，儿童中胰岛素抵抗、血脂异常和高血压的患病率显著增加。这些情况可追溯到成年，并易于随后发展为2型糖尿病(T2D)和心血管疾病(CVD)。最近的证据表明，在关键的发育期暴露于内分泌干扰物(EDCs)可能是与饮食和体力活动无关的代谢紊乱的危险因素。无机砷(IAS)是一种EDC，已被认为与低出生体重和儿童发育不良(如较低的身高和体重)有关。儿童被认为特别容易患上IAS，因为他们身体发育迅速，内分泌和代谢系统日趋成熟。然而，评估国际AS对儿童健康影响的大多数流行病学研究都是横向的，是在国际AS地下水位较高的地区进行的，这些地区不能代表大多数人口的暴露，而且缺乏饮食和/或个人暴露措施。我们建议前瞻性地研究青春期前尿IAS与青春期生长、血压和血清生长代谢生物标记物的关系。我们还将评估环境和饮食对尿砷物种和代谢物浓度的预测。我们将利用我们正在进行的纵向队列研究，通过测量俄罗斯查帕夫斯克499名男孩的尿砷种类和代谢物，检查有机氯化合物(OCS)和铅与生长和性成熟的关系。查巴耶夫斯克是一个工业城市，当地工业对氯化和其他化学品的环境排放造成了砷和有机碳污染，其中包括有机砷化学武器路易斯安石。我们的初步数据显示，这些男孩的尿液IAS水平高于美国人口，但远低于孟加拉国等高水位IAS地区。在8-9岁注册的男孩被跟踪到18-19岁。在入境时，男孩提供血液和尿样用于青春期前暴露评估，并收集了关于病史、社会经济状况、居住地点与主要工业污染者的距离和饮食的详细数据。男孩接受每年一次的体检、生物电阻抗测量和尿液采集；每两年采集一次血液。这些广泛的前瞻性收集的结果和协变量测量将为我们提供一个独特的机会来评估在青春期前脆弱时期暴露于IAS对青少年生长和血压的影响，在这个时期，生长变化的表现可能特别明显。此外，由于不寻常的本地工业对IAS的污染，以及这群人对本地种植食物的普遍消费，将评估饮食在IAS暴露和IAS暴露影响中的作用。最后，我们的研究将首次评估尿IAS与青少年生长发育和能量代谢的血清生物标记物之间的关系，从而深入了解IAS与成人T2D和CVD之间的潜在生物学机制。

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.