Excess folic acid intake increases DNA de novo point mutations
Xuanye Cao, Jianfeng Xu, Ying Lin, Robert M. Cabrera, Qiuying Chen, Chaofan Zhang, John Steele, Xiao Han, Steven S. Gross, Bogdan J. Wlodarczyk, James R. Lupski, Wei Li, Hongyan Wang, Richard H. Finnell, Yunping Lei
Abstract
It is well established that folic acid (FA) supplementation can significantly reduce the risk of birth defects, including neural tube defects (NTDs) 1 and congenital heart defects (CHDs) 2 . More than 80 nations have adopted mandatory FA food fortification programs 3 . With additional FA intake from different dietary supplements, a portion of the population is exposed to FA concentrations over the 0.4 mg recommended daily allowance (RDA) 4 . These people include women who had a prior NTD complicated pregnancy and are planning to start a new pregnancy 5 , and men with fertility issues who are treated with high-dose FA (12.5 times of RDA) supplementation to improve sperm counts 6 . However, there is a lack of research on whether excessive FA intake has the potential to harm human beings. Recently, a case with “pseudo-MTHFR” syndrome was reported, a wild-type MTHFR Caucasian woman with a history of infertility received a high FA exposure (5 mg/day, 12.5 times of RDA), which resulted in her homocysteine levels being elevated to 17.2 μmol/L, more than double the reference homocysteine level (7.8 μmol/L). After treatment with 5-methyltetrahydrofolate (5-MTHF, 500 μg daily), her Hcy level decreased to 8.2 μmol/L, an appropriate baseline level for wild-type MTHFR individuals 7 . Other reported adverse effects of high folate intake include acute nephrotoxicity, vitamin B12 deficiency and other unwanted effects 8 . Since FA is crucial for DNA synthesis and methylation, we were concerned that excess FA administration might adversely affect the prevalence of DNA point mutations as was observed in studies of folate deficiency 9 . To this end, we sought to quantify the potential impact of FA supplementation on de novo spontaneous mutation rates and its effect on whole-genome methylation modification.