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

项目4：一碳代谢、氧化应激及毒性

• 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
• 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

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.

该项目中涉及的这个超级基金计划的生物医学研究的两个总体主题 与a）砷的代谢（AS）和b）AS诱导的氧化应激有关。有很大的可变性 从接触到疾病的临床表现的进展。几项研究导致了 假设营养状况可能占此变异性的很大一部分。无机 通过一碳代谢进行甲基化，这是一种依赖叶酸的生化途径 一碳组。我们希望扩大我们的研究，这些研究已经开始表征 单碳代谢对AS甲基化的个体变异性的营养调节。 谷胱甘肽（GSH），这是主要抗氧化剂防御机制的关键组成部分，电子供体 因为AS还原是由同型半胱氨酸合成的，并且该合成受Onecarbon的中间体调节 代谢。大量基础研究，包括我们小组成员的重要工作， 指出了日益增长的信念，即随着谷胱甘肽（GSH）的耗竭并诱导氧化应激。但是， 在人类中尚未严格检查AS暴露与氧化应激之间的关系 人群。 该提案的第一个具体目的将利用由 队列研究（项目＃2）进行嵌套的病例对照研究，以识别可修改的危险因素（例如， 氧化应激和/或超型半胱氨酸血症）与对AS诱导的皮肤病变的敏感性增加有关。 其余的具体目标将利用我们的研究领域的扩展 管道井）在第3和＃7项目中招募375名新成年人，他们目前接触过AS。具体 目的2，我们将解决一个基本问题：尿液在多大程度上表现为 循环中的代谢产物？在特定的目标3中，我们将进行横断面研究以测试 假设较高浓度的S-腺苷类药物半胱氨酸（SAH）和较低的GSH 与减少作为甲基化有关。在特定目标4中，我们建议检查剂量反应 AS暴露与氧化应激之间的关系。最后，我们将检验以下假设 随着暴露减轻氧化应激。提出的研究有可能a）证实 诱导氧化应激并耗尽了人口中的GSH，b）将AS诱导的氧化应激和/或联系起来 营养状态至与砷相关的临床结果，c）扩大我们对机制的理解 这些过程的基础。这样的发现将对识别的重大影响 潜在的靶向干预措施，以防止毒性。