Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arenic

慢性砷(As)暴露目前影响全球约1.4亿人。甲基化 摄入的无机砷(InAs)到甲基砷(MMA)和二甲基砷酸(DMA)依赖于叶酸- 依赖一种碳代谢，促进尿砷(As)的排出。我们最近完成了一项 200名暴露于叶酸缺乏的人群补充叶酸的随机安慰剂对照试验 孟加拉阿拉伊哈扎尔的居民。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诱导皮肤的危险因素 损伤。此外，补充FA有助于AS的消除，并显著降低AS的血液浓度 叶酸缺乏的人体内的浓度。我们还确定，血液是一种好的 砷暴露的生物标志物，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，但必须首先解决几个基本问题 旨在评估补充FA对AS诱导的可能影响的大规模干预 与疾病相关的结果。拟议的研究将解决以下问题：目标1：a)足总 补充剂是否能降低普通人群的血砷浓度？B)使用更高剂量的FA 导致bas？的递增降低，目标2：a)血as下降的时间进程是什么？ 血液的最低点达到了什么程度？B)血液是否有像停止足总后那样的回升 由于面巾纸中的砷释放而导致的补充剂？目的3：A)FA能不能降低AS 和同型半胱氨酸通过添加一种新的替代方法来增强：减少甲基化 需求。我们之前已经发现，尿肌酸(肌酸的一种分解代谢物)是迄今为止最强的 AS甲基化的预测因素，尿肌酐较低的参与者患AS的风险增加- 导致皮肤损伤。尿肌酐受饮食中肌酸(来自肉类)的摄入量的影响， 下调内源性肌酸的生物合成。由于肌酸生物合成是主要的消耗 ，我们将检验补充肌酸会减少甲基的假设， 同型半胱氨酸和促进AS的甲基化，从而降低血液中的AS。 为了回答所有这些问题，我们建议进行随机、双盲、安慰剂试验 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。正性 这些干预措施的结果将对改善长期健康具有巨大的治疗潜力。 暴露于砷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.