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Adequate folic acid in the diet may be important for both men and women of reproductive age, new UC Berkeley/U.S.D.A. study suggests
26 February 2001

By Robert Sanders, Media Relations

Berkeley - Getting enough folic acid in the diet may be as important for prospective fathers as it is for mothers-to-be, according to a new study by scientists at the University of California, Berkeley, and the Western Human Nutrition Research Center (WHNRC) in Davis.

Doctors already urge pregnant women and women who may become pregnant to take folic acid or folate supplements to lessen the risk of having children with neural tube defects such as spina bifida. Good dietary sources include fortified breakfast cereals, leafy greens, legumes and orange juice.

The new study, published in the February issue of Fertility and Sterility, found that low levels of folic acid in men are associated with decreased sperm count and decreased sperm density.

In addition, the researchers suspect that low folate levels may correlate with poor synthesis and repair of sperm DNA and thus greater risk of chromosome breaks and subsequent cancer in their offspring.

"We think it's time to look not just at mothers and how nutrition affects their progeny, but also at men, the other half of fertility," said nutritionist Lynn M. Wallock, PhD, an assistant research scientist at the Children's Hospital of Oakland Research Institute. Wallock, who works in the laboratory of Professor Bruce N. Ames of UC Berkeley's Department of Molecular and Cell Biology, was a research chemist with the WHNRC at the time of the study.

"Few nutritionists pay attention to diet and its role in male reproductive health," she said. "Based on our work and that of others, we think diet has a very large effect."

A 1991 study by the same group found that men with low levels of vitamin C had more genetic damage in their sperm, and that smokers were at even greater risk.

"Our findings are just an indication that many modifiable behaviors - poor diet, smoking, alcohol consumption - affect reproductive health," said Ames, who is a professor of the graduate school in the College of Letters & Science. "It seems prudent for both men and women who are expecting to produce children to eat a balanced diet containing five to nine daily servings of fruits and vegetables, to consider taking a modest multivitamin supplement as insurance and to stop smoking."

The study was led by Wallock, Ames, Dr. Robert A. Jacob at the WHNRC, part of the Agricultural Research Service of the U.S. Department of Agriculture, and Dr. Tsunenobu Tamura of the University of Alabama at Birmingham.

Wallock examined the link between sperm and blood levels of folic acid and semen quality in 24 smokers and 24 nonsmokers. Folic acid levels in semen reflect dietary folic acid intake, she discovered. She distinguished between two types of folic acid: a methyl form, required for producing the amino acid methionine; and a non-methyl form, which is required for producing one of the components of DNA.

She found that a low level of the non-methyl form - the form involved in synthesis of DNA - was associated with both low sperm count and density. This was true of both smokers and nonsmokers, though smokers, in addition, showed an imbalance of the two types of folic acid; they had less of the non-methyl form. This may reflect other problems, Wallock said.

Ames and Wallock suspect that the non-methyl folate fraction of seminal fluid is likely to be important for sperm integrity, possibly to prevent defective repair of DNA and consequent chromosome breaks. Ames and his UC Berkeley colleagues proposed in 1997 a mechanism by which folate deficiency could cause chromosome breaks and cancer, based on the fact that when sufficient folate is not available to synthesize DNA, chromosomes can break.

Normally, DNA is made up of four different nucleic acids: adenine, cytosine, thymine and guanine. The non-methyl folate is responsible for converting a related nucleic acid base, uracil, into thymine for incorporation into DNA.

If folic acid is in short supply, Ames found, thymine levels drop and a large amount of uracil instead of thymine is incorporated into human DNA. This leads to chromosome breaks when DNA is being repaired and subsequent mutations. The findings in the Fertility and Sterility report support this model, the authors claim.

Wallock noted that childhood cancer is thought to be due to inheriting one mutant gene from one of the parents, and that most mutations in the fertilized egg come from the sperm. Some scientists theorize that men pass on mutations to their offspring twice as often as women.

Others also have found associations between male health and the health of their children. Andrew Wyrobek of Lawrence Livermore National Laboratory, for example, has shown that male smokers have more sperm with an abnormal number of chromosomes. These data make more plausible the increasing epidemiological evidence that smoking fathers have more children with childhood cancer, Wallock said. Further support comes from a 1997 paper by Chinese researchers that showed that the offspring of children of smoking, compared to non-smoking, fathers have a 3-4 fold increased rate of developing three of the most common types of childhood cancer.

The Ames group is currently investigating the effect of inadequate intake of other vitamins on genetic damage to sperm. Wallock, in particular, plans to look for specific genetic damage in the sperm of men with low folate levels.

The research was supported by the U.S.D.A. Agricultural Research Service, California's Tobacco Related Diseases Research Program, the National Foundation for Cancer Research, the Department of Energy and the National Institute of Environmental Health Sciences of the National Institutes of Health.

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