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5 June 2000
Evidence Of Faulty DNA Repair In Infertile Men
by George Atkinson

Some infertile men have mutations or errors in their DNA code, suggesting that faulty DNA repair may be a reason for their infertility, according to UC San Francisco researchers.

Moreover, this kind of DNA repair problem is similar to that found in certain kinds of cancer patients, and is linked to the abnormal growth of tumor cells. This finding has prompted the UCSF researchers to wonder if some infertile men could pass the problem of faulty DNA repair to offspring conceived through high technology- assisted reproduction methods. If so, this could potentially increase the risk of these children also being infertile, and might also predispose them to developing cancer, according to the researchers.

The research will be published in the June edition of the British journal Human Reproduction. The research, which was a small study of ten men, was performed in the laboratory of Renee Reijo Pera, MD, UCSF assistant professor in the departments of Obstetrics, Gynecology and Reproductive Sciences, Urology, Human Genetics and Physiology.

"The conclusion is that some male infertility may be related to a larger problem of defective DNA repair. This is encouraging news because it helps us explain why some men are infertile. What is worrisome, though, is that defective DNA repair has a long association with cancer," said Paul Turek, MD, another study author and UCSF associate professor of urology. "The implications are that maybe infertility is not a minor problem. Maybe there is a very good reason for men to be infertile."

Of all couples in America who are trying to conceive, 20 percent cannot, Turek said. Among those, half are due to male factor infertility. And many of the cases of male infertility are unexplained, Turek said. Common causes of male infertility include dilated veins in the scrotum (varicoceles), infections and toxin exposure.

"A significant portion of the infertility we can't explain now is probably going to end up being genetic," Turek said. "That's a lot of people."

In addition, other researchers in the past have discovered that certain cancers, including a form of colon cancer, are associated with defective DNA repair. In 1995, the journal Cell published two papers in which the genes responsible for DNA repair in mice were altered to see what happened. The mice developed tumors, as was expected. But the mice also became infertile, which was not expected.

"We wondered if infertile men with failing testicles that had a "look" similar to the testes from the altered mice would also show defective DNA repair," Reijo Pera said. "We asked if the testis tissue of these infertile men showed certain "fingerprints" characteristic of a problem repairing DNA."

The current UCSF study included five men with normally functioning testes and five whose testes made little or no sperm, also called testes failure. Investigators sequenced testes tissue DNA from both groups and found an increased frequency of certain DNA mutations or errors in the group with testes failure. These men had 100-fold higher error rate in their DNA than the men with normally functioning testes, Reijo Pera said.

This small study may help explain some cases of male infertility, but also raises several questions, Turek said. The findings need to be expanded to include many more infertile men to get a feel for the real impact of the research, he said.

Also, given what scientists know about defective DNA repair and cancer, researchers need to pay attention to what the consequences of this might be for infertile couples, Turek said. One concern is the health of pregnancies and children conceived with assisted reproductive techniques, such as intracytoplasmic sperm injection (ICSI) in cases of male infertility due to testes failure. This precise technique helps couples with severe male factor infertility have babies by injecting a single live sperm directly into the center of a human egg. The technique is very powerful because it can be used with sperm from the testes where they are made, as well as from the ejaculate.

"With ICSI, natural selection barriers that normally exist during conception may be broken down. If a couple has a genetic problem, it may be transmitted to children in a way that might not occur normally." Turek said. "At this time, it is not at all clear whether a problem like this, that exists in the sex cells of an infertile man, will be seen at all in his offspring if ICSI is used."

Perhaps problems with DNA repair will not be passed along to children conceived through ICSI because such problems may simply result in miscarriages. Defective DNA repair is also commonly found in spontaneously aborted embryos, Reijo Pera said, suggesting babies who make it to term would not have this problem.

Alternatively, children with DNA repair defects may survive to term. Theoretically, they could then have an increased risk of infertility, or possibly even tumor formation later in life, according to the study. "We don't know which scenario will be true." Turek said.

Turek said researchers should follow-up on the health and development of ICSI children in couples with severe male factor infertility from testes failure to help sort out these issues.

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