Project 4: One-Carbon Metabolism, Oxidative Stress and As Toxicity

项目4：一碳代谢、氧化应激及毒性

基本信息

批准号：
8065867
负责人：
Mary Gamble
金额：
$ 23.95万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-21 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8065867
关键词：
Accounting Address Adult Age Antioxidants Area Arsenic Basic Science Belief Biochemical Pathway Biological Biomedical Research Blood Blood Circulation Carbon Child Clinical Cohort Studies Cross-Sectional Studies Cysteine Data Defense Mechanisms Deoxyguanosine Disease Dose Electron Spin Resonance Spectroscopy Enrollment Erythrocytes Exposure to Folate Glutathione Glutathione Disulfide High Prevalence Homocysteine Homocystine Human Hyperhomocysteinemia Individual Intervention Intervention Studies Link Lipids Malondialdehyde Measures Metabolism Methylation Nested Case-Control Study Nutritional Nutritional status Outcome Oxidative Stress Participant Plasma Plasma Proteins Population Predisposition Process Recruitment Activity Regulation Risk Factors Sampling Superfund Testing Time Toxic effect Tube Urine Visit Whole Blood Work cohort drinking water electron donor follow-up indexing member modifiable risk oxidation oxidative DNA damage oxidative damage prevent primary outcome programs repository response skin lesion urinary

项目摘要

Two overarching themes of the biomedical research of this Superfund Program addressed in this project relate to a) the metabolism of arsenic (As) and b) As-induced oxidative stress. There is significant variability in progression from As exposure to clinical manifestations of disease. Several studies have led to the hypothesis that nutritional status may account for a substantial portion of this variability. Inorganic As is methylated via one-carbon metabolism, a biochemical pathway that is dependent on folate for recruitment of one-carbon groups. We wish to expand our studies, which have begun to characterize the impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation. Glutathione (GSH), a key component of the primary antioxidant defense mechanism, and the electron donor for As reduction, is synthesized from homocysteine, and this synthesis is regulated by intermediates of onecarbon metabolism. A great deal of basic research, including salient work from members of our group, points to the growing belief that As depletes glutathione (GSH) and induces oxidative stress. However, the relationship between As exposure and oxidative stress has not been rigorously examined in human populations. The first specific aim of this proposal will utilize the repository of biological samples established by the Cohort Study (Project #2) to conduct a nested case-control study to identify modifiable risk factors (e.g. oxidative stress and/or hyperhomocysteinemia) related to increased susceptibility to As-induced skin lesions. The remaining specific aims will take advantage of the expansion of our study area (and installation of Asfree tube wells) in Projects #3 and #7 to recruit 375 new adults who are currently exposed to As. In Specific Aim 2, we will address a fundamental question: To what extent do urinary As metabolites reflect As metabolites in the circulation? In Specific Aim 3, we will conduct a cross-sectional study to test the hypotheses that higher concentrations of s-adenosylhomocysteine (SAH) and lower concentrations of GSH are associated with reduced As methylation. In Specific Aim 4, we propose to examine dose-response relationships between As exposure and oxidative stress. Finally, we will test the hypothesis that reduction of As exposure alleviates oxidative stress. The proposed studies have the potential to a) substantiate that As induces oxidative stress and depletes GSH in a human population, b) link As-induced oxidative stress and/or nutritional status to an arsenic-related clinical outcome, and c) expand our understanding of the mechanisms underlying these processes. Such findings would have significant implications for the identification of potential targeted interventions for preventing As-toxicity.

本项目涉及超级基金计划生物医学研究的两个总体主题涉及 a) 砷 (As) 的代谢和 b) As 诱导的氧化应激。存在显着的变异性从砷暴露到疾病的临床表现的进展过程。多项研究导致假设营养状况可能是造成这种变异的很大一部分原因。无机原样通过单碳代谢进行甲基化，这是一种依赖叶酸募集的生化途径一碳基团。我们希望扩大我们的研究，这些研究已经开始表征一碳代谢的营养调节对 As 甲基化个体间变异的影响。谷胱甘肽 (GSH)，主要抗氧化防御机制的关键成分，也是电子供体用于 As 还原，由同型半胱氨酸合成，该合成受 onecarbon 中间体调节代谢。大量的基础研究，包括我们小组成员的杰出工作，越来越多的人相信砷会消耗谷胱甘肽 (GSH) 并引发氧化应激。然而，砷暴露与氧化应激之间的关系尚未在人体中得到严格检验人口。该提案的第一个具体目标是利用生物样本库建立的队列研究（项目#2）进行巢式病例对照研究，以确定可改变的风险因素（例如氧化应激和/或高同型半胱氨酸血症）与砷引起的皮肤损伤的易感性增加有关。其余的具体目标将利用我们研究区域的扩展（以及 Asfree 的安装）管井）在项目＃3和＃7中招募375名目前接触砷的新成年人。具体来说目标 2，我们将解决一个基本问题：尿液 As 代谢物在多大程度上反映 As 循环中的代谢物？在具体目标 3 中，我们将进行横断面研究来测试假设较高浓度的 s-腺苷同型半胱氨酸 (SAH) 和较低浓度的 GSH 与 As 甲基化减少有关。在具体目标 4 中，我们建议检查剂量反应砷暴露与氧化应激之间的关系。最后，我们将检验减少的假设由于暴露可以减轻氧化应激。拟议的研究有可能 a) 证实诱导氧化应激并消耗人群中的 GSH，b) 将 As 诱导的氧化应激和/或营养状况对砷相关临床结果的影响，以及 c) 扩大我们对其机制的理解这些过程的基础。这些发现将对识别预防 As 毒性的潜在针对性干预措施。