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大幅增加。这些疾病会一直持续到成年，并容易发展为2型糖尿病（T2D）和心血管疾病（CVD）。最近的证据表明，在关键的发育时期暴露于内分泌干扰化学物质（EDCs）可能是独立于饮食和身体活动的代谢紊乱的危险因素。无机砷（iAs）是一种有害化学物质，与低出生体重和儿童生长不良（如身高和体重较低）有关。儿童被认为特别容易受到iAs的影响，因为他们的身体生长迅速，内分泌和代谢系统正在成熟。然而，大多数评估砷化污染对儿童健康影响的流行病学研究都是横断面的，在砷化污染地下水水平高的地区进行，不能代表大多数人口的接触情况，而且缺乏饮食和/或个人接触措施。我们建议前瞻性地研究青春期前尿iAs与青少年生长、血压以及生长和代谢的血清生物标志物之间的关系。我们还将评估尿中砷种类和代谢物浓度的环境和饮食预测因素。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耶夫斯克499名男孩的尿砷种类和代谢物，来检查有机氯化合物（OCs）和铅与生长和性成熟的关系。查帕耶夫斯克是一个工业城市，砷和有机碳污染是由当地工业向环境释放的氯化和其他化学物质造成的，包括有机砷化学武器刘易斯。我们的初步数据表明，男孩的尿液iAs水平高于美国人口，但远低于高iAs地区，如孟加拉国。8-9岁的男孩被跟踪到18 -19岁。入学时，男孩提供血液和尿液样本用于青春期前暴露评估，并收集病史、社会经济地位、与主要工业污染者的居住距离和饮食等详细数据。男孩每年接受体检、生物电阻抗测量和尿液收集；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易受影响的青春期前暴露对青少年生长和血压的影响，这一时期生长变化的表现可能特别明显。此外，由于不寻常的当地工业污染和该队列普遍消费当地种植的食物，将评估饮食在iAs暴露中的作用和iAs暴露的影响。最后，我们的研究将首次评估尿液iAs与青少年生长和能量代谢的血清生物标志物的关联，为iAs与成人T2D和CVD相关的潜在生物学机制提供见解。

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.