Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic

Study Overview
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Brief Summary
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The purpose of this study is to determine whether folic acid, alone or together with creatine supplementation, can lower blood arsenic concentrations and improve the ability to detoxify arsenic.

Detailed Description
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Approximately 140 million people in over 70 countries are chronically exposed to arsenic (As)-contaminated drinking water at concentrations far exceeding the World Health Organization standard of 10 µg/L. As is a 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 folate-dependent one carbon metabolism, utilizing S-adenosylmethionine (SAM) as the methyl donor, and facilitates urinary As elimination. The results from our Nutritional Influences on Arsenic Toxicity (NIAT) study indicate that folate deficiency and hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate arsenic and are risk factors for arsenic-induced skin lesions. Furthermore, folic acid (FA) supplementation does indeed facilitate 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. Collectively, the implication of these findings is that FA has enormous therapeutic potential for ameliorating the long-term health consequences of arsenic exposure for the many populations at risk. However, several fundamental questions remain and will be addressed in this study. This trial is designed to determine 1) whether FA supplementation lowers blood As concentrations in the general Bangladeshi population, 2) at what time point a nadir in blood As is achieved, and 3) whether creatine supplementation, alone or in addition to 400 µg/d FA, will spare methyl groups, resulting in lower blood As, lower homocysteine (Hcys) concentrations, and increased methylation of As. The creatine arms are based on multiple studies that show that urinary creatinine concentrations are a very strong predictor of As methylation. The final step in creatine biosynthesis is the methylation of guanidinoacetate to creatine; this process consumes 50-75% of all SAM-derived methyl groups and is also responsible for 50-75% of all Hcys biosynthesis. Thus, this trial will test the hypothesis that creatine supplementation, which shuts down endogenous creatine biosynthesis, will spare methyl groups, lower Hcys, and increase As methylation.

Official Title
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Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic

Conditions
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High Blood Arsenic Due to Chronic Arsenic Exposure

Intervention / Treatment
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* Other: Placebo
* Dietary Supplement: folic acid
* Dietary Supplement: folic acid
* Dietary Supplement: creatine
* Dietary Supplement: creatine + folic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently exposed to arsenic via contaminated drinking water Well water arsenic concentration > 10 ug/L Between the ages of 20 and 65 Exclusion Criteria: Women who are currently pregnant or plan to become pregnant within the next 6 months Currently taking nutritional supplements Known renal disease Participation in any other clinical trial

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo daily | Other: Placebo<br>* daily, 24 weeks<br>|
| Experimental: Folic Acid 400 ug<br>400 µg folic acid daily | Dietary Supplement: folic acid<br>* 400 ug/d for 12 or 24 weeks<br>|
| Experimental: Folic Acid 800 ug<br>800 µg folic acid daily | Dietary Supplement: folic acid<br>* 800 µg/d for 12 or 24 weeks<br>|
| Experimental: Creatine<br>creatine daily | Dietary Supplement: creatine<br>* 3 mg/d for 12 weeks<br>|
| Experimental: Creatine + Folic Acid<br>creatine + folic acid daily | Dietary Supplement: creatine + folic acid<br>* 3 mg creatine/d + 400 µg folic acid/d for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| blood arsenic concentrations |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arsenic, folate, folic acid, creatine, arsenicosis, nutrition