Assessing the risk of excess folic acid intake

It is well established that folic acid supplementation can significantly reduce the risk of birth defects, including neural tube defects like spina bifida, the most common birth defect of the central nervous system and the second most common of all structural birth defects. More than 80 nations, including the U.S. 25 years ago, have established mandated folic acid food fortification programs, which have been successful.

“However, there is a lack of research on whether excessive folic acid intake has the potential to harm human beings,” said co-corresponding author, Dr. Richard H. Finnell, William T. Butler, M.D., Distinguished Chair Professor in the Center for Precision Environmental Health and the departments of molecular and cellular biology, molecular and human genetics and medicine at Baylor College of Medicine.

There are reports of adverse effects associated with high folate intake in humans. In this study published in the journal Cell Discovery, Finnell and his colleagues investigated in an animal model the potential effect of folic acid supplementation on DNA mutation rates and other genetic modifications such as whole genome methylation, which can change how much of any given gene product gets expressed in cells.

The animals received one of three folic-acid-supplemented diets: folic acid low, folic acid control and folic acid high. “Compared to the mutation frequency of the folic acid-control diet group, that of the folic acid-low diet group increased two-fold and the folic acid-high diet group increased 1.8 fold,” Finnell said.

The researchers found that DNA repair genes were significantly hypermethylated in the folic acid-high diet, suggesting that excess folic acid supplementation may affect the mutation rate by reducing the expression of DNA repair genes and consequently impairing DNA repair activity. Understanding these mechanisms requires further investigation.

“The effects of high- or low-folic acid diets should be confirmed in human population in future studies,” Finnell said. “Our data supports that folic acid supplementation should be restricted to an ideal benefit range. What we have here is a “Goldilocks Effect”: Too little or too much of a good thing (folic acid) may not be such a good thing.”

Other contributors to this work include Xuanye Cao, Jianfeng Xu, Ying L. Lin, Robert M. Cabrera, Qiuying Chen, Chaofan Zhang, John W. Steele, Xiao Han, Steven S. Gross, Bogdan J. Wlodarczyk, James R. Lupski, Wei Li, Hongyan Wang and Yunping Lei. The authors are affiliated with Baylor College of Medicine, Fudan University, Texas Children’s Hospital and Weill Cornell Medical College.

This work was supported by NIH grants (HD081216, HD083809, HD100535, HD067244, HD093758, HD095520, AR076029 and ES032347), William T. Butler M.D., Distinguished Chair endowment and Gulf Coast Consortia training fellowship as part of the Training in Precision Environmental Health Sciences Program funded by NIEHS (T32-ES027801).