(P11-032-23) Exposure to Excess Dietary Folic Acid Does Not Affect Tissue Folic Acid Accumulation in a Mouse Model of Vitamin B12 Deficiency

Objectives: Folate and vitamin B12 serve as cofactors in folate-mediated one-carbon metabolism, a series of one-carbon transfer reactions to generate nucleotides and methyl groups for essential cell processes. While folate deficiency is rare in the U.S. due to fortification and supplementation, B12 deficiency persists in some subpopulations such as older adults and vegans/vegetarians. The folate-B12 relationship has received increased attention, as observational data in humans has associated the combination of elevated folate status with low or deficient B12 status (known as “high folate/low B12”) with a wide array of negative health outcomes: worsened clinical markers of B12 deficiency, poor response to B12 treatment, and increased risk for cognitive impairment among older adults. However, there is little data from B12-deficient model systems investigating the molecular mechanisms underlying these associations.

Methods: The methionine synthase (Mtr) knockout mouse was used as a model of a functional vitamin B12 deficiency. Mtr^+/+ and Mtr^+/- mice were weaned to either an AIN93-G based control (C) diet containing 2 mg folic acid/kg or high folic acid (HFA) diet containing 20 mg folic acid/kg to explore the combined effects of excess folic acid and B12 deficiency on tissue and plasma folate accumulation and distribution.

Results: Mtr^+/- genotype increased 5-methylTHF levels in plasma by 45% (genotype effect, p < 0.001). The HFA diet increased total folate levels in plasma and red blood cells by >4-fold (p < 0.0001); Mtr genotype did not affect plasma total folate levels.  We observed a 2-fold increase in total folate levels in colon and kidney tissue with exposure to HFA diet (p < 0.0001). Total folate levels in liver, brain, and skeletal muscle were largely unchanged by HFA exposure. Regardless of folic acid content in the diet, folic acid accounted for less than 1% of total folate present in colon or liver tissue.

Conclusions: Exposure to a 10-fold excess of dietary folic acid did not lead to tissue folic acid accumulation in tissues, though total folate levels were increased in plasma and red blood cells. A functional B12 deficiency, as modeled by reduced Mtr expression, led to increased plasma 5-methylTHF levels and altered tissue folate distribution but did not affect tissue folic acid accumulation.

Funding Sources: National Defense Science and Engineering Graduate Fellowship