BioWorld International Correspondent

LONDON - A new generation of contraceptives, which act by blocking receptors on sperm that detect chemicals released by the egg, could be available one day, new research suggests. Scientists based in Germany and the U.S. found a molecule that blocks activation of a receptor found on human sperm and prevents sperm from swimming toward the source of a molecule that attracts them.

Marc Spehr, a postdoctoral research fellow at Ruhr University Bochum in Bochum, Germany, told BioWorld International, "Much more research is needed, but we can speculate that if this molecule completely blocks the activity of the receptor we studied, and if the receptor turns out to be one of the most important factors in the chemotactic behavior of sperm, then it should be possible to block the path-finding ability of sperm in the human female genital tract, so providing an alternative to current hormone-based methods of contraception."

Spehr, who carried out the study with collaborators at the University of California at Los Angeles, is now embarking on a project to examine molecules found in the follicular fluid of human eggs in order to find those that have a similar structure to the ones used in the recently completed study.

"We don't think that the molecules we found, which attract the sperm and activate the receptor, are the natural attractants. But we think there might be structurally related compounds that are secreted somewhere in the female genital tract, perhaps from the egg or by the follicular cells, that induce the chemotactic behavior of sperm," Spehr said.

He also wants to investigate other similar receptors that are known to be present on human sperm, and find out what their role is in fertilization and chemotaxis.

An account of the study appears in the March 28, 2003, issue of Science under the title, "Identification of a Testicular Odorant Receptor Mediating Human Sperm Chemotaxis."

Scientists have known for about a decade that receptors belonging to the same family as those present in the nose, that help us recognize odors, also are present on vertebrate sperm. Spehr said, "It makes sense that such receptors are found in the nose, but we wanted to find out what they were doing in sperm."

Spehr and his colleagues initially decided to examine whether members of a gene cluster located on chromosome 17 and coding for certain olfactory receptors were expressed on sperm. They found that two were. One had already been described by a different group. They investigated the other one, called hOR17-4, further.

They first engineered the gene encoding hOR17-4 into human embryonic kidney cells, so that those expressed hOR17-4 on their surfaces. Using a calcium-sensitive dye, which would turn the cells from green to red if the receptor was activated, they screened a mixture of 100 compounds to try to find a ligand that would have the desired effect.

They were in luck. One of the 100 compounds activated the receptor. By studying the structure of this compound and identifying other compounds with a similar structure, they were able to find a molecule that was even more potent in activating hOR17-4.

That molecule, called bourgeonal, had been one of the original 100 molecules the researchers had used to screen for ligands. Yet, surprisingly, at the point where the team had split the 100 molecules into 10 groups of 10 in their search for the activating compound, the mixture containing bourgeonal had not activated the receptor.

They had, serendipitously, stumbled across an inhibitor of hOR17-4, called undecanal. That compound was able to abolish the activation of hOR17-4 in their experimental system of engineered human embryonic kidney cells.

Further experiments showed that bourgeonal could trigger the calcium response in sperm, indicating that it could activate the receptor on the sperm. "After this," Spehr said, "we knew that this receptor was functionally expressed on sperm, and not just an incidental finding. So we went on to ask whether bourgeonal could also elicit chemotactic behavior by the sperm."

They found that the ligands they had identified as the most potent activators of hOR17-4 were also the most effective inducers of chemotactic behavior by sperm, which swam directly to the source of the bourgeonal, for example. Undecanal, they also found, could block this chemotactic behavior.

Spehr said, "These results suggest that we have discovered, at least in part, one important component that might be important for the path-finding abilities of sperm and the chemotactic process that takes place within the female body."

Part of his future work will involve generating transgenic mice that lack the gene encoding hOR17-4. "We think it would be interesting to find out whether such mice that lack this receptor would be infertile," Spehr said.