Impact of High-dose Folic Acid Supplementation on Pathways Linked to DNA Formation

Study Overview
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Brief Summary
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Periconceptional supplementation with folic acid - the synthetic form of the B-vitamin folate - reduces the occurrence of adverse pregnancy outcomes such as spina bifida. The underlying biochemical mechanisms for how folic acid affects health outcomes however are unknown. The naturally occurring form 5-methyltetrahydrofolate (5-MTHF) is now available and discussed as an adequate substitute to folic acid. This study aims to determine the effect of folic acid compared to 5-MTHF on cellular mechanisms. Stable isotope tracer protocols will be used that allow determining the effect of folic acid on the dynamics of metabolic pathways in the human body. Hypothesis: Supplementation with high-dose folic acid alters the turnover rate of folate dependent pathways in healthy humans; but 5-MTHF does not. Genetic variations in a key enzyme of the folate metabolism will aggravate the effect of folic acid on the metabolic pathways.

Official Title
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Metabolic Consequences of High-Dose Folic Acid Supplementation on Kinetics of 1-Carbon Metabolism

Conditions
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One-carbon Metabolism in Healthy Individuals

Intervention / Treatment
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* Dietary Supplement: Folic acid
* Dietary Supplement: 5-methyltetrahydrofolate, calcium salt


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy Body mass index of between 19-24 kg/m2 Normal folate, vitamin B12, and B6 status Exclusion Criteria: Unable to swallow tablets Unable to receive intravenous catheters Use of vitamin supplements, amino acid or protein supplements for more than six months before study participation Chronic consumption of a high-protein diet (e.g. Atkins Diet) Medical conditions such as diabetes, asthma, cancer, cardiovascular disease, a history of neural tube defect (such as spina bifida) affected pregnancy, have had gastrointestinal surgery, abnormal kidney, thyroid function, or psychiatric illness, or any other chronic disease Pregnancy or lactation Smoking, use of recreational drugs, and/or consumption of more than one alcohol drink per day or more than seven per week. Use of long-term prescription medication such as hormonal contraceptives, antidepressants, anticonvulsants, anticoagulants, or other chronic medication Blood donation in the last three months prior to study start Unable to provide informed consent, or unable to read and write English Low compliance to intervention as determined by early steady-state or reduction in blood folate concentrations

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folic acid supplementation<br>Folic acid will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism. | Dietary Supplement: Folic acid<br>* Supplement<br>* Other names: Pteroylmonoglutamic acid;|
| Experimental: 5-MTHF supplementation<br>The calcium salt of 5-methyltetrahydrofolate (5-MTHF; Brand name Metafolin) will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism. | Dietary Supplement: 5-methyltetrahydrofolate, calcium salt<br>* Supplement<br>* Other names: Levomefolic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plateau enrichment of infused amino acid tracers and related metabolites to quantify turnover rates of folate dependent pathways |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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folic acid, folate, 5-methyltetrahydrofolate, supplements, women, one-carbon metabolism, methionine, DNA methylation, in vivo kinetics