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: 10064382
• 负责人: Mary Gamble
• 金额: $ 63.61万
• 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/10064382
• 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.

项目概要 包括美国在内的全球 70 多个国家/地区超过 1.4 亿人受到砷 (As) 暴露的影响 长期接触锰（Mn），一种已知的 神经毒素通过受污染的饮用水影响着包括美国在内的 50 多个国家，并且可能会相互作用 此外，可强制执行的饮用水标准和生物标志物。 尽管已经存在多年，但仍然缺乏识别高危人群的策略。 研究表明，砷暴露导致不良健康结果的机制仍然很薄弱 需要创新的方法来表征砷和锰暴露的代谢影响—— 在疾病发作之前——开始更好地了解潜在机制，最终确定 一旦摄入，无机砷就会被 S-腺苷甲硫氨酸 (SAM) 甲基化形成。 单甲基砷 (MMA) 和二甲基砷 (DMA) 促进尿中砷的消除。 在我们最近完成的随机、双盲、 在孟加拉国进行的安慰剂对照叶酸临床试验 (FACT)，我们证明补充 FA 显着增加 DMA 的 As 甲基化，从而降低血液 As 和血液 MMA（有毒物质） 我们建议利用 FACT 的数据和生物样本来采用新型超高 分辨率代谢组学 (HRM) 分析可识别与 As 相关的代谢物和代谢途径 暴露、砷暴露减少、砷甲基化以及锰暴露的独立和联合效应。 独特的 FACT 研究设计包括提供带/不带 FA 补充的除砷过滤器（400 或 800 µg/d × 12 或 24 周）。该设计使我们能够识别和验证新的代谢物和途径。 因砷暴露和砷甲基化谱（目标 1a）而改变；锰暴露（目标 1b）和砷减少； 暴露（目标 2a）使我们能够确定 FA 治疗的持久性/可逆性，包括 FA 治疗的影响。 FA 补充促进 As 甲基化的剂量依赖性增加以及共同暴露的影响； 在与西奈山代谢组学中心主任 Walker 博士的新合作中，我们 将结合 FACT 严格的 RCT 方法（确定人类因果关系的最佳设计）与 我们的 HRM 平台可询问数千种代谢物和大多数代谢途径，我们将使用剂量-。 在与目标 3a 的新合作中，我们采用了依赖于持续时间的方法来提高研究结果的严谨性。 哥伦比亚大学的 Kioumourtzoglou 博士，我们将使用新颖且强大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将使用分层模型。 全面量化砷和锰对目标 1 和 2 中确定的途径的影响。 这项研究可能会为有关 As 流行地区 FA 强化计划的政策决策提供信息，并可能 确定砷和锰暴露的生物标志物，可以为饮用水标准的决策提供信息。