Folic acid does not elevate formaldehyde in mice and humans

Folic acid - an essential vitamin added to flour and cereals and prescribed at high doses for cancer patients and people with blood disorders - does not elevate toxic formaldehyde in the body, according to a new study on mice and human cancer patients who consumed high doses.

Folic acid, a synthetic form of folate, which is found naturally in many foods, is converted into bioactive forms of folate, namely tetrahydrofolate. Previous studies have shown that in a test tube and incell culture, tetrahydrofolate naturally decomposes to release formaldehyde, a carcinogen and genotoxin known to damage DNA. These results raised the question of whether the same thing happens in the body, which has direct health implications for the millions of people who take folic acid.

This was addressed by a new Cornell study, published Aug. 12 in the journal EMBO Molecular Medicine and conducted in partnership with the Cayuga Cancer Center, showing that while tetrahydrofolate does indeed increase formaldehyde and DNA damage in cell culture, no evidence of this toxin or DNA damage was found in mice or human cancer patients who received high doses of folic acid.

"Our study provides reassurance, particularly for patients who need higher levels of folic acid supplementation, that formaldehyde is not increased as a toxic side effect," said Dr. Meng Wang, assistant professor in the Division of Nutritional Sciences, shared jointly by the College of Human Ecology and the College of Agriculture and Life Sciences (CALS), and the paper's senior author. "This is especially important for cancer patients with Fanconi anemia, a rare cancer syndrome caused by deficiency in a DNA repair pathway against toxins like formaldehyde."

Mammals cannot make folate (vitamin B9), an essential nutrient needed to support normal cell growth such as building DNA. While the nutrient is naturally rich in foods including beans, spinach and asparagus, folic acid - a stable and synthetic form of folate - is often recommended as a supplement in higher doses. Folic acid is widely added to breads and cereals, prescribed during pregnancy to prevent birth defects, to people with blood disorders such as sickle cell anemia and to cancer patients during chemotherapy treatment.

To stringently test if folic acid intake elevates formaldehyde, the researchers used genetically modified mice that lacked a formaldehyde detoxification enzyme or the ability to repair formaldehyde-induced DNA damage. Both models make the mice far more sensitive to formaldehyde and its associated DNA damage, thus even small elevations in formaldehyde-induced DNA damage become detectable.

The mice were then fed either a diet with normal levels of folate for eight weeks, or a diet supplemented with folic acid equal to 10 times the daily requirements for the same time period. The researchers then used sensitive mass spectrometry to look for formaldehyde that was bound to DNA known as DNA adducts, which correlated with exposure to free formaldehyde and served as a stable biomarker. Despite finding increased tetrahydrofolate in the livers of mice fed a high folic acid diet, the researchers found no increased formaldehyde or damaging effects to tissue or DNA.

To test their animal findings in humans, Wang's team collaborated with study co-author Dr. Anthony Mato, an oncologist at the Cayuga Cancer Center at Cayuga Health, to examine blood samples from local cancer patients prescribed high dose folic acid supplementation. "It was critical to obtain human data to confirm whether our results also translated into the human population," Wang said. "The results mirror the finding in our mouse studies." In the blood from nine patients taking high dose folic acid compared to 15 patients not taking folic acid, the levels of folate increased but formaldehyde-DNA adducts did not.

Chris Mellor, a postdoctoral researcher in Wang's lab, is the paper's first author. Co-authors include Martha Field, an associate professor in the College of Human Ecology; John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research at Weill Cornell Medicine; and Guillermo Burgos-Barragan, an instructor in Blenis' lab.

The study was supported by the National Institutes of Health, the St. Baldrick's Foundation, the American Association for Cancer Research and Fanconi Cancer Foundation, Cornell University CALS Moonshot Award, and the Center for Vertebrate Genomics.