NEWS RELEASE, 4/8/97 UC Berkeley scientists find link between folic acid deficiency, DNA damage and chromosome breaks

by Robert Sanders

Berkeley -- Researchers at UC Berkeley have discovered how folic acid deficiency leads to DNA damage, emphasizing the dietary importance of this B vitamin in reducing the risk of heart disease, cancer and even brain damage. The study also showed that for people deficient in folic acid, supplementing the diet with folic acid can reduce DNA damage. Folic acid or folate is found in abundance in leafy green vegetables and fruit -- orange juice is a good source -- and has long been recognized as an essential micronutrient in the diet. Despite this, 10 percent of the population and an estimated 50 percent of some low-income minority populations have a folic acid deficiency. Folic acid deficiency has been linked in various studies to an increased risk of heart disease, cancer and various types of brain dysfunction. In addition, pregnant women are urged to take folic acid supplements to reduce the risk of neural tube defects such as spina bifida. Until now, however, how folic acid deficiency causes such problems has been poorly understood. The first clue was the discovery of a link between folic acid deficiency and breaks in chromosomes made by James T. MacGregor of SRI's Toxicology Laboratory in Menlo Park, Calif. How low levels of folic acid cause chromosome breaks was not known, however, though the UC Berkeley group suspected it had something to do with the way DNA is made and repaired. "We've now worked out the mechanism by which this happens," said Bruce N. Ames, professor of biochemistry and molecular biology at the University of California at Berkeley. Researchers have shown that in folate deficiency synthesis of the DNA base thymine from its precursor, uracil, is inhibited, causing uracil to accumulate in the cell. Ames and his team suspected that such conditions make cells misincorporate uracil into their DNA in place of thymine, and that in removing uracil from DNA the cells' built-in repair system sometimes creates breaks in both the DNA and chromosomes. Such breaks could lead to cancer and various other diseases. To test this hypothesis, Ames and his colleagues Ben Blount, then a graduate student and now at the Centers for Disease Control and Prevention in Atlanta; and Matthew M. Mack, a postdoctoral researcher at UC Berkeley, developed a way to detect uracil misincorporation into DNA. Their study, reported in the April 1 issue of the Proceedings of the National Academy of Sciences, confirmed the hypothesis. In a group of human volunteers with folic acid deficiency they found massive incorporation of uracil into DNA and subsequent chromosome breaks. Supplementation of these subjects with folic acid significantly decreased the high levels of uracil in their DNA and reduced the levels of chromosome breaks, "suggesting that in folate-deficient people increased folate intake may decrease the risk of many types of cancer." "The levels of uracil in the DNA of folate-deficient people are extremely high, on the order of 4 million uracils per cell," Mack said. "This is greater than most estimates of lesions thought to result from oxidative damage to DNA, suggesting that the consumption of both folic acid and antioxidants in the diet are important to prevent DNA damage." "We have shown conclusively that uracil in DNA and chromosome breaks are linked, and furthermore, that both can be reversed by giving folic acid in the diet," Ames added. While the recommended daily allowance (RDA) of folic acid is around 200 micrograms per person, Ames thinks this level is too low, based on this and other studies. "We suspect that we should be consuming higher amounts, because at blood levels of folic acid expected by consuming the RDA we can see chromosome breaks," he said. He noted that the federal government reduced the RDA for folic acid from 400 to 200 micrograms per day because they felt that too much would mask symptoms of vitamin B12 deficiency, which if left untreated can lead to irreversible peripheral nerve damage. Ames pointed out, however, that B12 is abundant in meat, so that B12 deficiency is uncommon outside the elderly and vegetarians. Certainly consumption of both B12 and folate should be considered important, he said. DNA damage is detrimental to cells that grow and divide. In the brain, cells called glial cells may also be susceptible to the DNA damaging effects of folic acid deficiency. "We think brain damage could be caused by chromosome breaks," Ames said. "B12 deficiency, which also appears to cause uracil misincorporation into DNA, seems to knock out glial cells surrounding nerves in the periphery, for example." Folic acid is also known to lower blood levels of homocysteine, an amino acid which at high levels has been linked to heart disease, hypertension and stroke. It is estimated that high levels of homocysteine are responsible for 10 percent of all cases of heart disease, Ames said, and that supplementation with folic acid could decrease the incidence of heart disease. Ames continues to be involved in studies of the health effects of folic acid deficiency. In a recent study, preliminary results by his group and Lynn Wallock and Robert Jacob of the USDA Western Regional Nutrition Center suggest that men consuming low levels of folic acid have decreased sperm count and density. Coauthors of the PNAS paper include James MacGregor of SRI International and Robert A. Hiatt of the Kaiser Permanente Medical Care Program in Oakland, Calif. The research was supported by the National Cancer Institute and the National Institute of Environmental Health Sciences.