Older mice without GPX5 are more likely to have offspring with developmental defects
The absence of a protein that protects sperm could have disastrous consequences for a male’s mate and his offspring.
A new study by researchers in France shows that a protein called glutathione peroxidase 5, or GPX5, stands guard over sperm and helps prevent oxidative damage to their DNA. Without this protective protein, older mice (and perhaps men) run a higher risk of siring offspring with developmental defects, including some severe enough to lead to miscarriage, the team reports in the July Journal of Clinical Investigation.
Scientists have debated whether to bother measuring DNA damage in male reproductive cells, says R. John Aitken, a reproductive biologist at the University of Newcastle in Callaghan, Australia. Typically the egg repairs any damage in its fertilization partner, so scientists have been more concerned with what happens in the egg than the sperm.
The new report, which Aitken calls “a landmark study,” confirms that oxidants, hyper-reactive chemicals that break DNA, in sperm can be a source of developmental defects in offspring. The findings also suggest drugs that fight such damage could help prevent birth defects.
“If oxidants are part of the cause, then maybe antioxidants are part of the cure,” Aitken says.
Researchers led by Joël Drevet, a reproductive biologist at Blaise Pascal University in Clermont-Ferrand, genetically engineered mice to lack GPX5. The protein is normally produced in the epididymis, a structure where sperm are stored before release from the body.
These sperm are immature and vulnerable because they lack machinery to repair DNA damage. Some oxidation is necessary to help sperm fully mature, but too much can break DNA, Drevet says. The sperm are bathed in antioxidants, one of which is GPX5, that help ward off excess damage.
GPX5 fights damage from hydrogen peroxide, a very damaging chemical to sperm, Aitken says.
Young male mice lacking GPX5 had no obvious defects in their sperm and no fertility problems, the team reports. When those mice reached about a year old (middle aged for a mouse), they were still able to fertilize eggs and their sperm looked fine externally. But the older males’ mates had more miscarriages and their offspring had more developmental defects compared with male mice that have GPX5. The team also found as much DNA damage in the sperm of mice lacking GPX5 as in sperm that were intentionally damaged with hydrogen peroxide.
Other antioxidants may compensate when the mice are young, and the egg may be able to repair some DNA damage. But oxidant-fighting capabilities decline with a mouse’s age, and the egg’s DNA-repair mechanisms can be overwhelmed if the sperm brings in too much broken DNA.
No one knows if GPX5 is involved in human cases of infertility, miscarriages or developmental defects, but studies have shown that defects in a gene for a related protein called GPX4 are associated with infertility in people, Drevet says. Drevet and his colleagues plan to test which types of antioxidants might help protect sperm from DNA damage.
Chabory, E. et al. 2009. Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice. Journal of Clinical Investigation 119(July), online June 22 doi:10.1172/JCI38940
Aitken, R. J. 2009. Gpx5 protects the family jewels. Journal of Clinical Investigation 119(July) doi:10.1172/JCI39688