Molecular and clinical endocrine impacts of arsenic exposure in children

儿童砷暴露对分子和临床内分泌的影响

基本信息

批准号：
8762725
负责人：
Maria Argos
金额：
$ 35.75万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762725
关键词：
7 year old Adolescence Adult Air Animal Model Arsenic Bangladesh Biological Assay Birth Blood Pressure Blood specimen Cardiovascular Diseases Cell model Characteristics Child Childhood Clinical Clinical assessments Corticotropin Data Diabetes Mellitus Dust Elderly Endocrine Endocrine Disruptors Environment Environmental Health Epidemiologic Studies Epidemiology Equilibrium Evaluation Exposure to Fasting Female Female of child bearing age Food Functional disorder Future Gene Expression Gene Expression Alteration Gene Expression Regulation Genes Genetic Genetic Polymorphism Genotype Glucose Growth Health Health Policy Health Priorities Height Heterogeneity Hormonal Hormone Receptor Hour Hydrocortisone Insulin Insulin Resistance Intervention Investigation Kidney Diseases Knowledge Lead Life Literature Liver diseases Lung diseases Malignant Neoplasms Measures Mediating Metabolism Methyltransferase Modeling Molecular Molecular Profiling Mothers Oncogene Deregulation Outcome Participant Pathology Pathway interactions Peripheral Blood Mononuclear Cell Phenotype Physicians Plasma Population Population Study Predisposition Pregnancy Pregnancy Outcome Pregnant Women Prevention Public Health RNA Reporting Reproduction Research Risk Risk Reduction Sampling Soil Steroids Thyroid Hormones Thyrotropin Thyroxine Toxic effect Triiodothyronine Visit base cognitive function cohort disorder risk drinking water early childhood follow-up genome-wide improved in utero neurodevelopment novel oxidation population based prenatal public health relevance remediation research clinical testing sex steroid hormone

项目摘要

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.

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，子宫内和儿童早期的砷暴露可能会对儿童期、青春期和以后的疾病风险产生深远的影响，但儿童期与砷相关的临床结果以及潜在的分子途径尚未得到研究。得到充分阐明。据报道，砷是一种有效的内分泌干扰物。敏感时期（例如子宫内和生命早期）荷尔蒙平衡的改变和基因失调可能会导致儿童期和以后生活中出现的临床功能障碍或病理。在本申请中，我们建议对子宫内和生命早期砷暴露的儿童的内分泌功能相关的分子和临床影响进行首次综合评估。利用孟加拉国已建立的基于人群的研究中已列举的 2-7 岁母亲儿童队列，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。拟议的研究将调查以下具体目标：（1）评估子宫内砷暴露和儿童早期砷暴露是否与儿童甲状腺和类固醇激素相关； (2) 评估子宫内砷暴露和儿童早期砷暴露是否与儿童基因表达谱相关； (3) 纵向评估子宫内砷暴露和儿童早期砷暴露是否与儿童内分泌相关表型（即线性生长、血压和胰岛素抵抗）相关。在探索性分析中，我们将评估这些关联是否会因 AS3MT 基因型和儿童性别而改变。我们提出的研究利用独特的研究人群和现有数据来检查可能与子宫内和儿童早期砷暴露有关的儿童内分泌特征和基因表达失调。我们预计，这项拟议研究的结果将从以下几个方面为我们理解砷暴露对健康的影响做出重大科学和公共卫生贡献：（1）提供关于砷暴露与内分泌功能关系的新证据； (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； (3) 将现有的砷暴露人群预防模式从目前侧重于成人人群的暴露补救和风险降低转向针对孕妇、育龄妇女和儿童的公共卫生干预措施。