Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arenic

描述（由申请人提供）： 慢性砷暴露目前影响着全世界约1.4亿人。摄入的无机砷（InAs）甲基化为甲基胂酸（MMA）和二甲基胂酸（DMA）依赖于叶酸依赖的一碳代谢，并促进尿砷（As）的消除。我们最近完成了一项在孟加拉国Araihazar的200名叶酸缺乏的As暴露居民中补充叶酸（FA）的随机安慰剂对照试验。结果表明，叶酸缺乏症和高同型半胱氨酸血症（HHcys）与甲基化As的能力降低，是As诱导的皮肤病变的危险因素。此外，FA补充剂有助于消除，并显着降低血液中的叶酸缺乏的个人的浓度。我们还确定，血砷是一个很好的生物标志物的作为暴露，并直接与作为诱导的皮肤病变的风险。虽然这些发现是非常引人注目的，几个基本问题必须解决之前，旨在评估FA补充剂对As诱导的疾病相关结果的可能影响的大规模干预。拟议的研究将解决以下问题：目的1：a）FA补充剂是否会降低一般人群的血砷浓度？B）较高剂量的FA是否会导致bAs的逐渐降低？目标2：a）血砷下降的时间过程是什么，在什么时候达到血砷的最低点？B）在停止补充FA后，由于组织储存中的As释放，血液中的As是否反弹？目标3：a）FA降低血As和同型半胱氨酸的能力是否可以通过增加一种新的替代方法来增强：减少甲基化需求。我们先前发现尿肌酸酐（肌酸的分解代谢物）是迄今为止As甲基化的最强预测因子，并且尿肌酸酐较低的参与者发生As诱导的皮肤病变的风险增加。尿肌酐受肌酸（来自肉类）的饮食摄入量影响，其下调内源性肌酸生物合成。由于肌酸的生物合成是甲基的主要消费者，我们将测试的假设，肌酸补充剂将备用甲基，降低同型半胱氨酸，促进甲基化的，从而降低血砷。为了回答所有这些问题，我们建议进行一项随机、双盲、安慰剂对照试验，比较FA（两种剂量和持续时间）、肌酸和肌酸加FA。这些干预措施的积极结果将有巨大的治疗潜力，改善长期的健康后果，作为暴露的许多人群的风险。公共卫生相关性：慢性砷（As）暴露目前影响着全世界超过1.4亿人。摄入砷的甲基化依赖于叶酸依赖的一碳代谢，并促进尿砷消除。我们最近在孟加拉国Araihazar的叶酸缺乏的砷暴露居民中完成了一项补充叶酸的试验。结果表明，叶酸缺乏症和高同型半胱氨酸血症与甲基化能力降低，是砷引起的皮肤病变的危险因素。此外，补充叶酸有助于消除砷，并显着降低血液中的砷浓度的14%，在个人谁是叶酸缺乏。使用我们以前发表的工作数据，我们估计通过补充FA减少血As，皮肤病变（皮肤癌的前体）的人群归因风险降低百分比为13%。拟议的研究将解决有关治疗剂量和持续时间的基本问题，并将测试一种新的治疗方法，以进一步降低血砷。考虑到全球暴露人群的规模以及众多相关健康后果的严重性，我们认为这项工作非常重要，因为它意味着简单，低成本，低风险的干预可能会降低数十万人的疾病风险。

DESCRIPTION (provided by applicant): Chronic arsenic (As) exposure currently affects roughly 140 million people worldwide. Methylation of ingested inorganic arsenic (InAs) to methylarsonic- (MMA) and dimethylarsinic acids (DMA) relies on folate- dependent one carbon metabolism and facilitates urinary arsenic (As) elimination. We recently completed a randomized placebo-controlled trial of folic acid (FA) supplementation in 200 folate-deficient As-exposed residents of Araihazar, Bangladesh. The results indicate that folate deficiency and hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate As and are risk factors for As-induced skin lesions. Furthermore, FA supplementation facilitates As elimination and significantly lowers blood As concentrations in individuals who are folate deficient. We have also determined that blood As is a good biomarker of As exposure and is directly associated with the risk for As-induced skin lesions. While these findings are extremely compelling, several fundamental questions must be addressed prior to a large scale intervention aimed at assessing the possible impact of FA supplementation on As-induced disease-related outcomes. The proposed studies will address the following questions: Aim 1: a) Does FA supplementation lower blood arsenic concentrations in the general population? b) Does a higher dose of FA lead to an incremental lowering of bAs?, Aim 2: a) What is the time-course of the decline in blood As, and at what point is a nadir in blood As achieved? b) Is there a rebound in blood As after the cessation of FA supplementation due to release of As from tissue stores? Aim 3: a) Can the ability of FA to lower blood As and homocysteine be enhanced by the addition of a novel new alternative approach: reduce methylation demand. We have previously found that urinary creatinine (a catabolite of creatine) is by far the strongest predictor of As methylation, and that participants with lower urinary creatinine are at increased risk for As- induced skin lesions. Urinary creatinine is influenced by dietary intake of creatine (derived from meat), which downregulates endogenous creatine biosynthesis. Since creatine biosynthesis is the major consumer of methyl groups, we will test the hypothesis that creatine supplementation will spare methyl groups, lower homocysteine and facilitate the methylation of As, and thereby lower blood As. To answer all of these questions, we propose to conduct a randomized, double-blind, placebo controlled trial of FA (a comparison of two doses and durations), creatine, and creatine plus FA. Positive results of these interventions would have enormous therapeutic potential for ameliorating the long-term health consequences of As exposure for the many populations at risk. PUBLIC HEALTH RELEVANCE: Chronic arsenic (As) exposure currently affects more than 140 million people worldwide. Methylation of ingested arsenic relies on folate-dependent one carbon metabolism and facilitates urinary arsenic elimination. We recently completed a trial of folic acid supplementation in folate-deficient As-exposed residents of Araihazar, Bangladesh. The results indicate that folate deficiency and hyperhomocysteinemia are associated with a reduced capacity to methylate As and are risk factors for As-induced skin lesions. Furthermore, folic acid supplementation facilitates As elimination and significantly lowers blood As concentrations by 14% in individuals who are folate deficient. Using data from our previously published work, we estimate that by reducing blood As with FA supplementation, the percent reduction in population attributable risk for skin lesions (the precursors for skin cancer) to be 13%. The proposed studies will address fundamental questions regarding the dose and duration of therapy and will test a novel new therapeutic approach to further lower blood As. Considering the magnitude of the exposed population worldwide, and the severity of the numerous associated health outcomes, we feel this work is highly significant as it implies that a simple, low-cost, low-risk intervention could potentially reduce disease risk for hundreds of thousands of people.