Identifying the Safe and Adequate Folic Acid Intake Range Using Biomarkers in 2 Mouse Models.

Area of Science:

• Nutritional biochemistry
• Toxicology
• Animal models in research

Background:

• High folic acid (FA) intake is inconsistently linked to adverse effects in animal and human studies.
• Determining the relevance of FA doses used in animal models to human intake levels is crucial for accurate interpretation.

Purpose of the Study:

• To establish biomarkers for inadequate (plasma homocysteine) and excessive (plasma unmetabolized FA) folic acid intake in mice.
• To correlate FA intake levels in mouse diets with these biomarkers.

Main Methods:

• Mice were fed diets with varying FA concentrations (0-40 mg/kg) for 12 weeks.
• Plasma and red blood cell folate levels, plasma homocysteine, and unmetabolized FA (UMFA) were measured.
• Kidney pathology and blood counts were assessed at study termination.

Main Results:

• Plasma homocysteine normalized at low FA doses (≥0.2 mg/kg).
• Plasma and red blood cell folate levels showed dose-dependent increases, reaching homeostasis over time.
• Elevated plasma UMFA was observed only at the highest FA doses (20 and 40 mg/kg), indicating supraphysiological levels.

Conclusions:

• The standard control diet (AIN-93) contains a higher-than-adequate FA level (2 mg/kg).
• Commonly used FA doses in mouse studies are often supraphysiological, potentially explaining inconsistent findings.
• Caution is advised when extrapolating results from high-dose FA mouse studies to human FA exposure and health outcomes.