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

项目总结 背景：在世界许多地区，通过饮用水接触砷(As)的现象依然存在。在……里面 孟加拉国，40%的人口暴露在饮用水中的砷浓度超过世界 卫生组织(世卫组织)标准为10μg/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 即使在暴露结束后的几十年也会持续存在。表观基因组的变化，包括DNA甲基化 (DNaM)，可能是砷引起的健康后果的一个共同机制。所涉及的微量营养素 甲基转移(例如，叶酸)和活性DNA去甲基化(例如，维生素C)可以改变这种联系 在砷暴露和表观遗传失调之间。目的：拟议的研究将利用现有的基因座- 特定的dNaM数据(5-甲基胞嘧啶，5-MC；和5-羟甲基细胞胞苷，5-OHmC)来自现有的 对接触砷的孟加拉国成年人的研究。将解决以下目标：(1)调查 AS暴露于基因座特异性的%5-mc和%5-OHmC；(2)研究关联的效应修饰 通过叶酸和维生素C状态在AS暴露和dNaM之间的关系；以及(3)鉴定生物学和分子 通过基因本体论(GO)研究砷诱导表观遗传失调相关基因的功能 浓缩分析。目标3将包括一个探索性部分，以开发一种新的统计方法 GO分析，以减少由于dNaM微阵列上基因之间的探针覆盖率不均匀而产生的偏差。意义 和创新：这项研究可能为这种联系背后的表观遗传机制提供见解 慢性砷暴露和疾病之间的关系，以及由于营养状况而导致的易感性差异， 可为通过治疗性药物或营养干预将健康风险降至最低的战略提供信息。 这项拟议的研究在解决砷暴露、 营养状况和dNaM(%5-MC和%5-OHmC)；这些关联以前从未 在基因座特异性水平上进行了调查。通过GO分析研究特定基因座的dNaM也将允许 鉴定受砷诱导的表观遗传失调影响的分子和生物功能。这 研究解决了NIEHS战略计划的目标，包括“识别和理解基础” 共享机制或共同的生物途径，例如…表观遗传学变化…为了启用 制定适用的预防和干预战略“(NIEHS目标1)和”了解[ING] 个体敏感度…由环境因素造成的…方便预防，减少公众 健康负担“(NIEHS目标2)。

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).