Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arenic

慢性砷暴露目前影响着全世界约1.4亿人。甲基化 摄入的无机砷（InAs）转化为甲基胂酸（MMA）和二甲基胂酸（DMA）依赖于叶酸- 依赖一碳代谢，促进尿砷（As）清除。我们最近完成了一个 200例叶酸缺乏砷暴露者补充叶酸的随机安慰剂对照试验 Araihazar，孟加拉国结果表明，叶酸缺乏和高同型半胱氨酸血症 （HHcys）与甲基化As的能力降低有关，是As诱导皮肤损伤的危险因素。 病变此外，补充FA有助于消除As并显着降低血液As 叶酸缺乏的个体中的浓度。我们还确定，血液A是一个很好的 砷暴露的生物标志物，并直接与砷诱导的皮肤病变的风险。 虽然这些发现非常令人信服，但必须先解决几个基本问题 大规模干预旨在评估FA补充对As诱导的 疾病相关的结果。拟议的研究将解决以下问题：目标1： 补充砷会降低一般人群的血砷浓度吗？B）较高剂量的FA 导致bAs？逐渐降低，目标2：a）血液As下降的时间过程是什么， 什么时候是血的最低点？B）FA停药后血As是否有反弹 补充由于释放作为从组织商店？目的3：a）FA降低血砷的能力 通过增加一种新的替代方法：减少甲基化， 需求我们以前发现，尿肌酸酐（肌酸的分解代谢产物）是迄今为止最强的 作为甲基化的预测因子，尿肌酐较低的参与者患As- 诱发皮肤损伤。尿肌酐受肌酸（来自肉类）的饮食摄入量影响， 下调内源性肌酸生物合成。由于肌酸的生物合成是肌酸的主要消耗者， 甲基，我们将测试肌酸补充剂将节省甲基，降低 同型半胱氨酸和促进As的甲基化，从而降低血As。 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 FA（两种剂量和持续时间的比较）、肌酸和肌酸加FA的对照试验。积极 这些干预措施的结果将具有改善长期健康的巨大治疗潜力 砷暴露对许多处于危险中的人群的后果。

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.