High-dose folic acid supplementation results in significant accumulation of unmetabolized homocysteine, leading to severe oxidative stress in Caenorhabditis elegans
Kyohei Koseki,
Yukina Maekawa,
Tomohiro Bito,
Yukinori Yabuta,
Fumio Watanabe
Affiliations
Kyohei Koseki
The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan
Yukina Maekawa
Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan
Tomohiro Bito
The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan; Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan
Yukinori Yabuta
The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan; Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan
Fumio Watanabe
The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan; Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori, 680-8553, Japan; Corresponding author. The United Graduate School of Agricultural Sciences, Tottori University, 4Koyama-Minami, Tottori city, Tottori, 680-8553, Japan.
Using Caenorhabditis elegans as a model animal, we evaluated the effects of chronical supplementation with high-dose folic acid on physiological events such as life cycle and egg-laying capacity and folate metabolism. Supplementation of high-dose folic acid significantly reduced egg-laying capacity. The treated worms contained a substantial amount of unmetabolized folic acid and exhibited a significant downregulation of the mRNAs of cobalamin-dependent methionine synthase reductase and 5,10-methylenetetrahydrofolate reductase. In vitro experiments showed that folic acid significantly inhibited the activity of cobalamin-dependent methionine synthase involved in the metabolism of both folate and methionine. In turn, these metabolic disorders induced the accumulation of unmetabolized homocysteine, leading to severe oxidative stress in worms. These results were similar to the phenomena observed in mammals during folate deficiency.
