Excess folate elevates formaldehyde genotoxicity in cell lines but not in mice or humans

Folate metabolites are chemically unstable: spontaneous decomposition releases formaldehyde, a genotoxin in blood stem cells and a human carcinogen. Despite this, folic acid consumption frequently exceeds the Recommended Dietary Allowance and is prescribed at high doses for patients with blood disorders. However, the impact of excess folate on endogenous formaldehyde genotoxicity in vivo has not been studied. We find that excess tetrahydrofolate (THF) treatment of cell lines elevates formaldehyde-DNA adducts and genotoxicity. To test this in vivo, we fed a high-folic acid diet (10-fold above standard) to mice with heightened sensitivity to formaldehyde: detoxification-impaired Adh5^-/- mice, and Fanconi anemia DNA repair mutants Fanca^-/- and Fancj^-/-. In contrast to cell lines, elevated tissue THF was not associated with increased formaldehyde-DNA adducts nor blood stem cell attrition. Finally, in cancer patients, high-dose folic acid therapy elevated plasma folic acid but did not increase formaldehyde-DNA adducts in peripheral blood mononuclear cells. In conclusion, increased folate in vivo does not elevate endogenous formaldehyde genotoxicity in sensitized mouse models or humans.