Excess Folic Acid Exposure Increases Uracil Misincorporation into DNA in a Tissue-Specific Manner in a Mouse Model of Reduced Methionine Synthase Expression

• Published in: The Journal of nutrition 2024-11, Vol.154 (11), p.3225-3234
• Main Authors: Heyden, Katarina E, Malysheva, Olga V, MacFarlane, Amanda J, Brody, Lawrence C, Field, Martha S
• Format: Article
• Language: English
• Subjects: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - genetics; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - metabolism; Animals; Diet; DNA; DNA - metabolism; folate; Folic Acid - administration & dosage; Folic Acid - metabolism; Histones - metabolism; Liver - metabolism; Male; methionine synthase; Mice; Mice, Inbred C57BL; Mice, Knockout; unmetabolized folic acid (UMFA); Uracil - metabolism; Vitamin B 12 - metabolism; vitamin B12
• ISSN: 0022-3166; 1541-6100; 1541-6100
• DOI: 10.1016/j.tjnut.2024.09.021

Folate and vitamin B12 (B12) are cofactors in folate-mediated 1-carbon metabolism (FOCM), a metabolic network that supports synthesis of nucleotides (including thymidylate [dTMP]) and methionine. FOCM impairments such as a deficiency or imbalance of cofactors can perturb dTMP synthesis, causing uracil misincorporation into DNA. The purpose of this study was to determine how reduced expression of the B12-dependent enzyme methionine synthase (MTR) and excess dietary folic acid interact to affect folate distribution and markers of genome stability in mouse tissues. Heterozygous Mtr knockout mice (Mtr+/–) model the FOCM-specific effects of B12 deficiency. Folate accumulation and vitamer distribution, genomic uracil concentrations, and phosphorylated histone H2AX (γH2AX) immunostaining were measured in male Mtr+/+ and Mtr+/− mice weaned to either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a high folic acid (HFA) diet (20 mg/kg folic acid) for 7 wk. Exposure to the HFA diet led to tissue-specific patterns of folate accumulation, with plasma, colon, kidney, and skeletal muscle exhibiting increased folate concentrations compared with control. Liver total folate did not differ. Although unmetabolized folic acid (UMFA) increased 10-fold in mouse plasma with HFA diet, UMFA accounted for