Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese

了解砷和锰代谢影响的跨学科方法

• 批准号: 10263257
• 负责人: Mary Gamble
• 金额: $ 62.58万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263257
• 关键词: Affect; Area; Arsenic; Arsenicals; Bangladesh; Bayesian Modeling; Biological; Biological Markers; Blood; Chronic; Chronic Disease; Clinical Trials; Collaborations; Country; Data; Disease; Dose; Double-Blind Method; Environmental Medicine; Etiology; Excision; Excretory function; Exposure to; Folic Acid; Folic Acid Deficiency; Funding; Gambling; Genes; Goals; Health; Human; Individual; Ingestion; Intervention; Joints; Knowledge; Malignant Neoplasms; Manganese; Measures; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Modification; Nested Case-Control Study; Neurotoxins; Onset of illness; Outcome; Participant; Pathway interactions; Pattern; Pattern Recognition; Persons; Phenotype; Placebos; Plasma; Policies; Process; Public Health; Randomized; Randomized Controlled Trials; Research; Research Design; Resolution; Risk; S-Adenosylmethionine; Sampling; Systems Biology; Toxic effect; Urine; Walkers; Water; Work; biobank; body system; contaminated drinking water; design; drinking water; folic acid supplementation; fortification; innovation; interdisciplinary approach; longitudinal analysis; metabolome; metabolomics; methyl group; novel; placebo group; prevent; programs; skin lesion; ultra high resolution; urinary

Project Summary Arsenic (As) exposure afflicts >140 million people in 70+ countries worldwide, including the U.S., and contributes to cancer and many other chronic diseases. Chronic exposure to manganese (Mn), a known neurotoxin, through contaminated drinking water afflicts 50+ countries, including the U.S., and may interact with As exposure for some outcomes. Furthermore, enforceable drinking water standards and biomarkers of Mn exposure are lacking. Strategies to identify individuals at risk are urgently needed. Despite years of research, the mechanisms by which As exposure leads to adverse health outcomes remains poorly understood. Innovative approaches are needed to characterize metabolic effects of As and Mn exposures – prior to disease onset – to begin to better understand the underlying mechanisms, ultimately to identify individuals at risk. Once ingested, inorganic As undergoes methylation by S-adenosylmethionine (SAM) to form mono- (MMAs) and di-methyl (DMAs) arsenicals in a process that facilitates urinary As elimination. Methyl groups from folate are required for SAM synthesis. In our recently completed randomized, double-blind, placebo-controlled folic acid clinical trial (FACT) in Bangladesh, we demonstrated that FA supplementation significantly increased As methylation to DMAs and thereby lowered blood As and blood MMAs, a toxic intermediate. We propose to leverage data and biological samples from FACT to employ novel ultra high- resolution metabolomics (HRM) analyses to identify metabolites and metabolic pathways associated with As exposure, As exposure reduction, As methylation and the independent and joint effects of Mn exposure. The unique FACT study design includes provision of As-removal filters with/without FA supplementation (400 or 800 µg/d × 12 or 24 weeks). This design permits us to identify and validate novel metabolites and pathways altered by As exposure and As methylation profiles (Aim 1a); Mn exposure (Aim 1b); and reduction in As exposure (Aim 2a). Aims 2b-c allow us to identify persistence/reversibility by FA treatment, including effects of dose-dependent increases in As methylation facilitated by FA supplementation; and the impact of co-exposure to Mn (Aim 2d). In a new collaboration with Dr. Walker, Director of the Metabolomics Center at Mt. Sinai, we will combine FACT’s rigorous RCT approach–the best possible design to determine causality in humans–with our HRM platform that interrogates thousands of metabolites and most metabolic pathways. We will use dose- and duration-dependent approaches to enhance the rigor of our findings. In Aim 3a, in a new collaboration with Dr. Kioumourtzoglou at Columbia, we will use novel and robust pattern recognition approaches to identify specific metabolic patterns that are impacted by As and Mn exposures. Aim 3b will use hierarchical modeling to comprehensively quantify the As and Mn impacts on the pathways identified in Aims 1 and 2. The findings of this study may inform policy decisions regarding FA fortification programs in As-endemic areas and may identify biomarkers of As and Mn exposure that may inform decisions on drinking water standards.

项目摘要 全球70多个国家（包括美国）和 有助于癌症和许多其他慢性疾病。长期暴露于锰（MN），已知的 神经毒素通过受污染的饮用水折磨50多个国家，包括美国，并可能互动 与某些结果的接触。此外，可强制执行的饮用水标准和生物标志物 缺乏MN暴露。迫切需要识别有风险的人的策略。尽管多年 研究，作为暴露导致不良健康结果的机制仍然很差 理解。需要创新的方法来表征AS和MN暴露的代谢作用 - 在疾病发作之前 - 开始更好地了解潜在机制，最终确定 有危险的个人。摄入后，无机通过s-腺苷甲氨酸（SAM）进行甲基化以形成 单（MMA）和二甲基（DMA）砷在促进尿液中的过程中。甲基 叶酸的组是SAM合成所必需的。在我们最近完成的随机双盲中， 安慰剂控制的叶酸临床试验（事实）在孟加拉国，我们证明了FA补充 随着对DMA的甲基化的显着增加，从而降低了血液和血液MMA，一种有毒 中间的。我们建议利用从事实到员工的数据和生物样本的新型超高 - 分辨率代谢组学（HRM）分析以识别与AS相关的代谢物和代谢途径 暴露是减少暴露，作为甲基化以及MN暴露的独立和关节作用。 独特的事实研究设计包括提供无FA补充的驱动器过滤器（400 或800 µg/d×12或24周）。这种设计使我们能够识别和验证新型的代谢物和途径 随着暴露和甲基化曲线的改变而改变（AIM 1A）； MN暴露（AIM 1B）;并减少AS 曝光（AIM 2A）。 AIMS 2B-C使我们能够通过FA治疗确定持久性/可逆性，包括 通过补充FA制备的甲基化剂量依赖性增加；以及共同暴露的影响 到MN（AIM 2D）。在与西奈山代谢组中心主任沃克博士的新合作中，我们 将结合事实严格的RCT方法 - 确定人类因果关系的最佳设计 - 我们的HRM平台询问了数千种代谢产物和大多数代谢途径。我们将使用剂量 - 以及持续时间依赖的方法来增强我们发现的严格性。在AIM 3A中，与 哥伦比亚的Kioumourtzoglou博士，我们将使用新颖而健壮的模式识别方法来识别 受AS和MN暴露影响的特定代谢模式。 AIM 3B将使用分层建模 全面量化AS和MN对目标1和2中确定的途径的影响。 这项研究可以为有关ASEDIMIC地区FA防御计划的政策决定提供信息，并可能 确定AS和MN暴露的生物标志物，可以为饮用水标准的决定提供信息。