Molecular and clinical endocrine impacts of arsenic exposure in children

描述（由申请人提供）：砷与许多健康结果相关，包括癌症、心血管、呼吸、肝脏和肾脏疾病、神经发育、生殖和糖尿病。支持这些关联的许多流行病学文献都评估了成年期的砷暴露。虽然越来越多的流行病学文献表明，子宫内和幼儿期的砷暴露可能会深刻影响儿童、青春期和以后生活中的疾病风险，但儿童期砷相关的临床结果以及潜在的分子途径尚未得到充分阐明。据报道，砷是一种强效的内分泌干扰物。在敏感时期，如在子宫和生命早期，激素平衡和基因失调的改变可能导致临床功能障碍或在儿童和以后的生活中表现出来的病理。在本申请中，我们建议对子宫内和生命早期砷暴露的儿童进行首次与内分泌功能相关的分子和临床影响的综合评估。在孟加拉国已有的基于人群的研究中，我们使用了一组已经枚举的2-7岁儿童，我们建议对500对母子进行随访，以评估儿童的内分泌相关特征。

DESCRIPTION (provided by applicant): Arsenic is associated with a number of health outcomes including cancers, cardiovascular, respiratory, liver, and kidney diseases, neurodevelopment, reproduction, and diabetes. Much of the epidemiologic literature supporting these associations has evaluated arsenic exposure in adulthood. While there is a growing epidemiologic literature to suggest that arsenic exposure during in utero and early childhood periods may profoundly influence disease risk in childhood, adolescence, and later life, arsenic-related clinical outcomes in childhood as well as underlying molecular pathways have not yet been fully elucidated. Arsenic has been reported to be a potent endocrine disruptor. Alterations in hormonal balance and gene deregulation in sensitive periods such as in in utero and early life may lead to clinical dysfunction or pathologies manifest in childhood and later life. In this application, we propose to conduct the first comprehensive evaluation of molecular and clinical impacts, as related to endocrine function, in children with well-characterized in utero and early life arsenic exposure. Using an already enumerated cohort of 2-7 year old children from mothers in established population-based studies in Bangladesh, we propose to conduct follow-up visits of 500 mother-child pairs to evaluate endocrine- related characteristics in the children. The proposed research will investigate the following Specific Aims: (1) to evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with thyroid and steroid hormones in children; (2) to evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with gene expression profiles in children; and, (3) to longitudinally evaluate whether in utero arsenic exposure and early childhood arsenic exposure are associated with endocrine-related phenotypes (i.e., linear growth, blood pressure, and insulin resistance) in children. In exploratory analyses, we will evaluate whether these associations are modified by AS3MT genotype and child sex. Our proposed study takes advantage of a unique study population and existing data to examine endocrine characteristics and gene expression deregulation in children that may be related to in utero and early childhood arsenic exposure. We expect that the results from this proposed research would make major scientific and public health contributions toward our understanding of the health effects of arsenic exposure in several ways: (1) provide novel evidence with respect to arsenic exposure in relation to endocrine function; (2) support whether endocrine dysfunction and/or gene deregulation mediate associations between arsenic exposure and endocrine-related phenotypes; and, (3) shift the existing prevention paradigm for arsenic exposed populations, which currently focuses on exposure remediation and risk reduction in adult populations towards public health interventions targeted for pregnant-women, women of child-bearing age, and children.