Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arenic

描述(由申请人提供)： 慢性砷(As)暴露目前影响全球约1.4亿人。摄入的无机砷(InAs)甲基化为甲基砷酸(MMA)和二甲基砷酸(DMA)依赖于叶酸依赖的碳代谢，促进尿砷(As)的排出。我们最近完成了一项补充叶酸(FA)的随机安慰剂对照试验，试验对象为200名暴露于孟加拉国阿拉伊哈扎尔的叶酸缺乏的居民。结果表明，叶酸缺乏和高同型半胱氨酸血症(HHcys)与AS甲基化能力降低有关，是As引起皮肤损害的危险因素。此外，补充FA有助于AS的消除，并显著降低叶酸缺乏患者的血液As浓度。我们还确定，血砷是砷暴露的良好生物标志物，并与砷引起的皮肤损害的风险直接相关。虽然这些发现非常令人信服，但在大规模干预之前必须解决几个基本问题，旨在评估补充FA对AS诱导的疾病相关结果的可能影响。拟议的研究将解决以下问题：目标1：a)补充FA是否降低了普通人群的血液砷浓度？B)更高剂量的FA是否导致BAS的递增降低？目标2：a)血液AS下降的时间过程是什么，在什么时候血液达到最低点？B)停止补充FA后，血液中是否有因组织中的AS释放而出现的反弹？目的3：a)添加一种新的替代方法：减少甲基化需求，可以增强FA降低血AS和同型半胱氨酸的能力吗？我们之前发现，尿肌酸(肌酸的一种分解代谢物)是迄今为止预测AS甲基化的最强指标，尿肌酐较低的参与者患AS诱发皮肤损害的风险增加。尿肌酐受饮食中肌酸(来自肉类)的摄入量的影响，而肌酸的摄入量会下调内源性肌酸的生物合成。由于肌酸生物合成是甲基的主要消耗，我们将检验补充肌酸可以减少甲基，降低同型半胱氨酸，促进AS的甲基化，从而降低血液中AS的假设。为了回答所有这些问题，我们建议对FA(两种剂量和持续时间的比较)、肌酸和肌酸加FA进行随机、双盲、安慰剂对照试验。这些干预措施的积极结果将具有巨大的治疗潜力，可以改善暴露于砷对许多处于危险中的人群的长期健康后果。公共卫生相关性：慢性砷暴露目前影响全球超过1.4亿人。摄入的砷的甲基化依赖于叶酸依赖的碳代谢，促进尿砷的排出。我们最近完成了一项在孟加拉阿拉伊哈扎尔暴露于叶酸缺乏的居民中补充叶酸的试验。结果表明，叶酸缺乏和高同型半胱氨酸血症与AS甲基化能力降低有关，是AS引起皮肤损害的危险因素。此外，补充叶酸有助于砷的消除，并显著降低叶酸缺乏者的血液砷浓度14%。使用我们之前发表的研究数据，我们估计，通过像补充FA一样减少血液，皮肤病(皮肤癌的先兆)的人群归因风险降低了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，以进一步降低血液AS。考虑到全球受影响人群的规模以及与之相关的众多健康后果的严重性，我们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会潜在地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.