Effects of Arsenic Exposure on 5-methylcytosine and 5-hydroxymethylcytosine, and Effect Modification by Nutritional Status

砷暴露对 5-甲基胞嘧啶和 5-羟甲基胞嘧啶的影响以及营养状况对影响的影响

• 批准号: 9469987
• 负责人: Anne Kristina Bozack
• 金额: $ 3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469987
• 关键词: Address; Adult; Affect; Animal Model; Arsenic; Ascorbic Acid; Attenuated; Bangladesh; Bangladeshi; Binding; Biological; Biological Process; Carbon; Carcinogens; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Coenzymes; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Dietary Intervention; Disease; Environmental Health; Environmental Risk Factor; Enzymes; Epigenetic Process; Exposure to; Folic Acid; Gene Expression; Genes; Goals; Guidelines; Health; Human; Hydroxylation; Impairment; Individual; Inflammation; Malignant Neoplasms; Metabolism; Methods; Methylation; Micronutrients; Modification; Molecular; National Institute of Environmental Health Sciences; Nutritional status; Ontology; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Population; Predisposition; Prevention; Preventive Intervention; Public Health; Reporting; Research; Risk; Strategic Planning; Therapeutic; Umbilical Cord Blood; Vitamin B Complex; World Health Organization; Zinc Fingers; body system; cofactor; contaminated drinking water; demethylation; disorder risk; drinking water; epigenome; functional group; ground water; innovation; insight; methyl group; methylome; novel; public health relevance; skin lesion

PROJECT SUMMARY Background: Arsenic (As) exposure through drinking water persists in many regions of the world. In Bangladesh, 40% of the population is exposed to As concentrations in drinking water exceeding the World Health Organization (WHO) standard of 10 μg/L. Chronic As exposure affects numerous organs and systems, increasing the risk of health conditions including skin lesions, impaired intellectual function, cardiovascular disease, diabetes, inflammation, and cancers. The risk for adverse health effects associated with As exposure persists even decades after the exposure has ended. Changes in the epigenome, including DNA methylation (DNAm), may be a common mechanism underlying As-induced health outcomes. Micronutrients involved in methyl transfer (e.g., folate) and active DNA demethylation (e.g., vitamin C) may modify the association between As exposure and epigenetic dysregulation. Aims: The proposed research will utilize existing loci- specific DNAm data (5-methylcytosine, 5-mC; and 5-hydroxymethylcytocsine, 5-OHmC) from two existing studies of As-exposed Bangladeshi adults. The following aims will be addressed: (1) investigate the effects of As exposure on loci-specific %5-mC and %5-OHmC; (2) investigate effect modification of the association between As exposure and DNAm by folate and vitamin C status; and (3) identify biological and molecular functions associated with genes containing As-induced epigenetic dysregulation through gene ontology (GO) enrichment analyses. Aim 3 will include an exploratory component to develop a novel statistical approach to GO analyses to reduce bias due to uneven probe coverage among genes on DNAm microarrays. Significance and innovation: This research may provide insights to the epigenetic mechanisms underlying the association between chronic As exposure and disease, as well as differences in susceptibility due to nutritional status, which can inform strategies for minimizing health risks through therapeutic drugs or nutritional interventions. The proposed research is particularly innovative in addressing the relationship between As exposure, nutritional status, and DNAm (%5-mC and %5-OHmC); these associations have not previously been investigated on the loci-specific level. Investigating loci-specific DNAm through GO analyses will also allow for the identification of molecular and biological functions impacted by As-induced epigenetic dysregulation. This research addresses the NIEHS Strategic Plan goals including “identify[ing] and understand[ing] fundamental shared mechanisms or common biological pathways, e.g.,…epigenetic changes…in order to enable the development of applicable prevention and intervention strategies” (NIEHS Goal 1) and “understand[ing] individual susceptibility…resulting from environmental factors…to facilitate prevention and decrease public health burden” (NIEHS Goal 2).

项目概要 背景：世界许多地区仍然存在通过饮用水接触砷 (As) 的情况。在 孟加拉国40%的人口接触饮用水中砷的浓度超过世界 卫生组织（WHO）标准为10 μg/L。慢性砷暴露会影响许多器官和系统， 增加健康状况的风险，包括皮肤损伤、智力功能受损、心血管疾病 疾病、糖尿病、炎症和癌症。与砷暴露相关的不良健康影响的风险 甚至在暴露结束几十年后仍然存在。表观基因组的变化，包括 DNA 甲基化 (DNAm)，可能是 As 引起的健康结果的常见机制。微量营养素参与 甲基转移（例如叶酸）和主动 DNA 去甲基化（例如维生素 C）可能会改变这种关联 砷暴露与表观遗传失调之间的关系。目的：拟议的研究将利用现有的位点 来自两个现有的特定 DNAm 数据（5-甲基胞嘧啶，5-mC；和 5-羟甲基胞嘧啶，5-OHmC） 对暴露于砷的孟加拉国成年人的研究。将解决以下目标：（1）研究影响 作为位点特异性 %5-mC 和 %5-OHmC 的暴露； (2)考察协会的修改效果 叶酸和维生素 C 状态决定砷暴露与 DNAm 之间的关系； (3) 鉴定生物和分子 通过基因本体论 (GO) 与含有 As 诱导的表观遗传失调的基因相关的功能 富集分析。目标 3 将包括一个探索性部分，以开发一种新颖的统计方法 GO 分析可减少由于 DNAm 微阵列上基因之间探针覆盖不均匀而导致的偏差。意义 和创新：这项研究可能为该关联背后的表观遗传机制提供见解 慢性砷暴露与疾病之间的关系，以及由于营养状况导致的易感性差异， 这可以为通过治疗药物或营养干预措施最小化健康风险的策略提供信息。 拟议的研究在解决砷暴露之间的关系方面特别具有创新性， 营养状况和 DNAm（%5-mC 和 %5-OHmC）；这些协会以前没有被 在位点特异性水平上进行研究。通过 GO 分析研究位点特异性 DNAm 也将允许 鉴定受 As 诱导的表观遗传失调影响的分子和生物功能。这 研究涉及 NIEHS 战略计划目标，包括“识别和理解基本原理” 共享机制或共同的生物途径，例如……表观遗传变化……以便使 制定适用的预防和干预策略”（NIEHS 目标 1）和“理解[ing] 个人易感性……由环境因素引起……以促进预防并减少公众感染 健康负担”（NIEHS 目标 2）。