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、呼吸系统、肝脏和肾脏疾病、神经发育、生殖和糖尿病。许多支持这些关联的流行病学文献已经评估了成年期的砷暴露。虽然有越来越多的流行病学文献表明，在子宫内和幼儿期的砷暴露可能会深刻地影响儿童，青少年和以后的生活中的疾病风险，砷相关的临床结果在儿童以及潜在的分子途径尚未完全阐明。据报道，砷是一种强有力的内分泌干扰物。在敏感时期，如在子宫内和生命早期，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期和以后的生活中表现出的病理。在这项申请中，我们建议进行第一次全面评估的分子和临床的影响，有关内分泌功能，在儿童的特点是在子宫内和生命早期的砷暴露。 使用孟加拉国已建立的基于人口的研究中母亲的2-7岁儿童的已枚举队列，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。 本研究的主要目的是：（1）探讨宫内砷暴露和儿童早期砷暴露是否与儿童甲状腺激素和类固醇激素有关;（2）探讨宫内砷暴露和儿童早期砷暴露是否与儿童基因表达谱有关;以及（3）纵向评估子宫内砷暴露和儿童早期砷暴露是否与内分泌相关表型（即，线性生长、血压和胰岛素抵抗）。在探索性分析中，我们将评估这些关联是否被AS 3 MT基因型和儿童性别所改变。 我们提出的研究利用了独特的研究人群和现有的数据来研究儿童的内分泌特征和基因表达失调，这可能与子宫内和儿童早期砷暴露有关。我们期望这项研究的结果将在以下几个方面为我们理解砷暴露对健康的影响做出重大的科学和公共卫生贡献：（1）提供关于砷暴露与内分泌功能相关的新证据;（2）支持内分泌功能障碍和/或基因失调是否介导砷暴露与内分泌相关表型之间的关联;以及（3）改变目前针对砷暴露人群的预防模式，目前的重点是针对孕妇、育龄妇女和儿童的公共卫生干预措施，而目前的重点是成人人群的暴露补救和风险降低。

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.