Interrelationships among nutrients involved in one-carbon metabolism in Banglades

描述(由申请人提供) 美国国立卫生研究院独立途径奖的总体目的是让霍尔博士获得所需的额外培训，以发展成为一名能够进行研究以调查营养和环境因素之间相互作用的独立研究员。在营养和流行病学背景的基础上，该奖项的指导阶段将提供以下方面的培训：1)研究管理和监督，2)高级营养生物化学和一碳代谢的数学模型，以及3)实验室科学。所获得的技能将应用于当前的研究领域，调查一碳代谢中涉及的营养物质对砷(As)和基因组DNA甲基化的影响。具体地说，两种营养素，胆碱和甜菜碱，即参与甲基化途径的关键营养素，以前没有考虑过与AS和DNA甲基化有关的作用，将被研究。70多个国家的约1.4亿人长期接触受砷污染的饮用水，其浓度远远超过世界卫生组织10 5g/L的标准，这是一种已知会导致皮肤癌、膀胱癌和肺癌以及缺血性心脏病和神经损伤的I类致癌物质。摄入的无机砷(InAs)甲基化为甲基砷酸(MMA)和二甲基砷酸(DMA)依赖于营养依赖的一碳代谢，促进尿砷的排出。DNA一碳代谢甲基化是一种表观遗传修饰，在调节基因表达和维持染色体稳定性方面起着关键作用，并可能在砷诱发癌症的潜在机制中发挥作用。在指导阶段，胆碱和甜菜碱对砷和DNA甲基化的影响将在现有的一项横断面研究中进行，该研究涉及375名接触饮用水中广泛浓度砷的孟加拉国成年人。在独立阶段，将应用在培训期间获得的技能，进一步研究胆碱和甜菜碱在AS和DNA甲基化中的作用，包括它们与其他营养物质，即叶酸和肌酸的相互作用，利用来自600名长期暴露于AS的随机对照试验的数据和生物样本。此外，一碳代谢的数学模型将被用于与临床试验相结合的电子实验中。这些实验将1)允许根据临床试验数据进一步验证模型，2)提供对试验结果的更深层次的机械理解。在这一奖项结束时，霍尔博士将发展成为一名独立的多学科研究员，能够很好地开发与营养/环境相互作用在疾病发展中的作用有关的其他假设。 与公共卫生的相关性：世卫组织估计，在全球范围内，至少70个国家的1.4亿多人暴露在受砷污染的饮用水中，其中大多数在营养不足普遍存在的发展中国家。拟议的胆碱和甜菜碱研究在很大程度上建立在母体研究的目标之上，即确定通过简单、低成本、低风险的单碳代谢营养操作来降低血液砷浓度(即内部砷暴露)的干预措施。我们小组以前的工作表明，在叶酸缺乏的砷暴露人群中补充叶酸有助于砷的消除，并显著降低血砷浓度。然而，也有许多人对叶酸似乎没有反应，这一发现表明FA的疗效有改进的空间，一些人可能会从另一种治疗方法中受益，如胆碱或甜菜碱。考虑到世界各地受影响人群的规模和众多相关健康后果的严重性，调查人员认为这项工作具有非常重要的意义，因为它意味着简单、低成本、低风险的干预措施可能具有改善许多处于危险中的人群的长期健康后果的治疗潜力。

DESCRIPTION (provided by applicant) The overall purpose of this NIH Pathway to Independence Award is for Dr. Hall to gain the additional training needed to develop into an independent investigator capable of conducting studies to investigate interactions between nutritional and environmental factors. Building upon a background in nutrition and epidemiology, the mentored phase of this award will provide training in 1) study management and oversight, 2) advanced nutritional biochemistry and the mathematical modeling of one-carbon metabolism, and 3) laboratory sciences. The acquired skills will be applied to the current area of research, investigating the influence of nutrients involved in one-carbon metabolism on the methylation of both arsenic (As) and genomic DNA. Specifically, the roles of two nutrients, choline and betaine, i.e. key nutrients involved in methylation pathways, which have not previously been considered in relation to As and DNA methylation, will be examined. Roughly 140 million people in over 70 countries are chronically exposed to As-contaminated drinking water at concentrations far exceeding the World Health Organization standard of 10 5g/L. As is a class I carcinogen known to cause cancers of the skin, bladder, and lung, as well as ischemic heart disease and neurologic impairments. Methylation of ingested inorganic arsenic (InAs) to methylarsonic- (MMA) and dimethylarsinic acids (DMA) relies on nutrient-dependent one carbon metabolism and facilitates urinary As elimination. Methylation of DNA via one-carbon metabolism is an epigenetic modification that plays critical roles in the regulation of gene expression and maintenance of chromosomal stability, and may play a role in the underlying mechanism of As-induced carcinogenesis. In the mentored phase, the influence of choline and betaine on methylation of As and DNA will be investigated in an existing cross-sectional study of 375 Bangladeshi adults exposed to a wide range of As concentrations in drinking water. In the independent phase, the skills acquired during the training will be applied to further investigate the roles of choline and betaine, including their interactions with other nutrients, i.e. folate and creatine, in the methylation of both As and DNA utilizing data and biospecimens from a randomized controlled trial of 600 individuals chronically exposed to As. In addition, mathematical models of one-carbon metabolism will be employed to conduct in silico experiments in conjunction with the clinical trial. These experiments will 1) allow the models to be further validated against the clinical trial data and 2) provide a deeper mechanistic understanding of the results from the trial. At the conclusion of this award, Dr. Hall will have developed into an independent multidisciplinary investigator well positioned to develop additional hypotheses related to the role of nutrient/environment interactions in disease development. Public Health Relevance: On a global basis, WHO estimates that more than 140 million people in at least 70 countries are exposed to arsenic (As)-contaminated drinking water, most in the developing world where nutritional deficiencies are common. The proposed studies of choline and betaine build considerably upon the goals of the research of the parent studies, which is to identify interventions to reduce blood As concentrations (i.e. internal As exposure) through simple, low-cost, low-risk nutritional manipulations of one- carbon metabolism. Previous work by our group has shown that folic acid supplementation in folate-deficient As-exposed individuals facilitated As elimination and significantly lowered blood As concentrations. However, the finding that there were also many individuals who did not appear to be responsive to folic acid suggests the possibility that there is room to improve on the efficacy of FA and that some individuals could potentially benefit from another therapeutic modality such as choline or betaine. Considering the magnitude of the exposed population worldwide, and the severity of the numerous associated health outcomes, the investigators feel this work is highly significant as it implies that simple, low-cost, low-risk interventions could have therapeutic potential for ameliorating the long-term health consequences for the many populations at risk.