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Mistakes of the father
Repair genes and infertility
Edward R. Winstead

The genome, like an Impressionist painting, is a hard thing to reproduce. Some letters in the genetic code are deleted or inverted as cells divide, but most errors are fixed by "repair" genes, a cell's version of spell-checking software. When repairs are made normally, cell division goes off without a hitch; when they aren't, the result can be abnormal cell growth and cancer. This month, researchers report that another consequence of faulty DNA repair may be male infertility. Since technology is making fathers out of men who otherwise wouldn't be, the researchers say, children conceived this way may be at risk for health problems related to the DNA mistakes of their fathers.

Testis tissue from a fertile man.

The new study is the first to investigate repair genes and reproduction in humans. Researchers at the University of California, San Francisco, found that six infertile men had 100 times the expected rate of DNA errors in testis tissue. Whether the infertility is due to these errors is not known, nor is it known why DNA repair failed in these men. But the evidence of a link between infertility and DNA repair has certainly raised questions about the potential risks to children conceived with the help of fertility treatments.

Testis tissue with arrest of spermatogenesis in an infertile man.

"Classically, DNA repair has been linked to cancers, and some infertile men may have problems repairing their DNA," says Paul J. Turek, director of UCSF's Male Reproductive Laboratory. The findings suggest that the offspring of men who benefit from fertility treatments may not have the normal complement of repair genes and may be at risk for cancer, in addition to infertility. "The size of the risk is not known," says Turek.

Excluding testicular cancer, no previous studies have linked cancer and infertility in men, according to Renee Reijo Pera, of the Department of Obstetrics, Gynecology, and Reproductive Sciences at UCSF. Male infertility in general is poorly understood. Most insurance companies and many physicians don't view male infertility as a medical problem, and the leading fertility treatments are so new that data on the offspring of infertile men don't exist.

an efficient way to ban a species

"We've been taking infertility lightly as a disease," says Turek. "But it turns out that infertility might not be a minor problem." From an evolutionary perspective, infertility is the ultimate health problem. Turek points out that infertility is a perfect way to eliminate a species, making him wonder if the condition isn't simply part of nature's plan. Putting the brake on reproduction certainly stops the spread of faulty genes.

Of course, natural selection never counted on intracytoplasmic sperm injection, or ICSI. This treatment (pronounced ixsy) injects a single live sperm directly into the center of a human egg. ICSI was developed in the early nineties and can help men with a very low sperm count. No one knows whether it has any long-term negative effects for the child.

what we don't know about high-tech pregnancies

"We need a lot more information about these procedures, and it's time we learned about the risks," says Reijo Pera. The pilot study was not meant to answer questions about the risks of high-tech pregnancies. "Our hope is that now researchers at many different clinics will begin collecting data," she says.

The team at UCSF studied 6 infertile men and 5 controls. David Nudell, then of the Department of Obstetrics, Gynecology, and Reproductive Sciences, counted the DNA mistakes in the testes and blood of the subjects, something that apparently had not been done before. The repair problems in the affected men were confined to the testes. How a child's health might be affected by defects that exist only in the father's reproductive cells is not clear, the researchers concluded. The study appears in the June issue of the British journal Human Reproduction.

inspiration comes from mice with colon cancer

Like his colleagues, Turek wants more data. He will not use these findings to recommend for or against ICSI, but he will tell infertile couples about the study as they decide if ICSI is right for them. Importantly, he adds, "I would consider this new information to be in the 'risk' and not the 'benefit' column of ICSI."

An unexpected finding in laboratory mice was the inspiration for the study. Faulty DNA repair has been linked to colon cancer in humans, and in 1995 researchers found that mice with colon cancer also were infertile. While reading the scientific papers from the cancer studies, one of the UCSF researchers realized that the testis tissue in the infertile mice resembled that of testis tissue in infertile men.

"It wasn't a huge leap to go from the mouse data to the hypothesis that faulty DNA repair might be associated with infertility in both species," says Reijo Pera. The fortuitous connection does emphasize, she adds, what scientists stand to learn by studying all aspects of complex genetic disorders in model organisms like the mouse. No one could have predicted that giving mice colon cancer would have revealed the link between DNA repair and infertility.

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Nudell, D., Castillo, M., Turek, P.J. & Reijo Pera, R. Increased frequency of mutations in DNA from infertile men with meiotic arrest. Hum Reprod 15, 1289-1294 (June 2000).

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