Researchers have identified a sperm-specific protein, and by depleting this protein in mice, they’ve rendered the males infertile – but still quite capable of having sex. The findings, published in Science this week, could one day lead to a male contraceptive.
Birth control pills for women have existed for decades, but what’s the male equivalent? Previous studies have found that a protein called calcineurin – which helps activate immune cells – also plays an important role in male fertility. However, the existence of multiple forms of the protein (called isoforms) in testes has made it difficult to figure out the function of each. But recently, researchers found evidence that calcineurin isoforms that contain a catalytic subunit called PPP3CC and a regulatory sub unit called PPP3R2 are only found in cells that form sperm. PPP3CC joins up with PPP3R2 to form the calcineurin complex during sperm production.
So, Osaka University’s Masahito Ikawa and colleagues examined these sperm-specific calcineurin subunits in more detail. When they knocked out the gene for PPP3CC in male mice, this created a mutation in calcineurin that made the males infertile – though they were still able to copulate.
Their PPP3CC-depleted sperm didn’t swim well and couldn’t penetrate the membrane that surrounds the egg. They weren’t able to fertilize eggs even with in vitro fertilization. Then, the team examined sperm motility using computer-assisted sperm analysis. Turns out, the midpiece that connects the head with the tail of sperm lacking PPP3CC don’t bend the way normal sperm do during a process called hyperactivation, which is required for penetrating the membrane surrounding the egg.
At least two kinds of immunosuppressant drugs, which are commonly used after organ transplants, are known to inhibit calcineurin. Treatment with these drugs for as little as four or five days also rendered the males infertile with inflexible midpieces of sperm. Using the drugs on mature, wild-type spermatozoa in vitro, however, did not affect sperm motility and midpiece flexibility. That means the protein is important for sperm that’s still developing, but not for those that have already matured. Importantly, fertility of the drugged male mice – as well as their sperm motility and midpiece flexibility – recovered a week after the researchers stopped administering the drug.
This sperm-specific calcineurin complex is also found in humans, and perhaps one day, inhibiting sperm calcineurin could be used as a way to develop reversible male contraceptives.