Knockout of the gene causes the number of sperm cells to decrease and the shape and motility of the remaining sperm cells to change so that they are no longer able to fertilize an egg.
In short: by switching off this gene, researchers can make a man infertile. That can be read in the magazine Nature Communications.
The study deals with the Arrdc5 gene. The gene is expressed in the testes of mice, pigs, cows and humans. And experiments in mice now indicate that silencing this gene has some major implications for male fertility. For example, switching off the gene in male mice resulted in their producing 28 percent fewer sperm cells. And the sperm produced by these mice also moved 2.8 times more slowly than in mice with a normally functioning Arrdc5 gene. Also, the lion’s share of the sperm cells of the mice without a working Arrdc5 gene looked very different; as many as 98 percent of the sperm cells had an abnormal shape. And all those changes meant that the mice without the Arrdc5 gene were no longer able to fertilize a female. “When this gene is deactivated or inhibited in men, they can no longer make sperm suitable for fertilizing an egg,” said researcher Jon Oatley.
According to the researchers, the fact that switching off the gene has such a far-reaching effect can be traced back to the protein encoded by the Arrdc5 gene. This protein is necessary for normal sperm production. And so gene silencing can lead to reduced and abnormal sperm.
A pill for men
The identification of this gene – which is only expressed in the testicles – and the role it plays in sperm production and therefore male fertility, is just the prelude to more. Because at the moment Oatley and colleagues are investigating whether they can find or develop a drug that can prevent the production or functioning of the protein encoded by Arrdc5.
If that quest succeeds, they’ve in fact found a birth control pill for men. It would be a huge breakthrough. Because in 2023, contraception is still often the responsibility of women. This is mainly because she has more options when it comes to contraception. For example, a woman can choose from the pill, an IUD, a vaginal ring, the contraceptive injection, a pessary or a contraceptive patch. For men there is much less to choose from. He could use a condom. Or – but that is a fairly rigorous solution – opt for sterilization. In recent years, researchers have made frantic attempts to expand the options for men, with a particular focus on developing a contraceptive pill for men. But that hasn’t turned out to be so easy. Previous attempts to undermine male fertility with a pill often failed because the pill had several unwanted side effects, such as a lowered libido or health problems due to tampering with the sex hormones. The effect of some drugs also turned out to be hardly or not reversible, so that in the best-case scenario men would only be fertile again long after they had stopped taking the pill.
What makes the discovery of Arrdc5 so promising now is that knocking out this gene – or the protein it codes for – doesn’t seem to have those adverse side effects. For example, there is no need to fiddle with the man’s endocrine system to thwart the production or functioning of the protein encoded by Arrdc5. This is important, because previous candidate pills for men often messed with testosterone, causing infertility, but also producing nasty side effects. This is because testosterone is not only important for sperm production, but also plays an important role in the production of red blood cells and the maintenance of bone mass and muscle strength. In addition, a birth control pill that targets the protein encoded by Arrdc5 would not have an irreversible effect. In short: men who would take such a pill would not be permanently infertile. “You don’t want to take away the ability to make sperm forever,” says Oatley. “You just want to prevent sperm from being produced correctly. Because then you can theoretically stop taking the pill, after which sperm will be produced in a normal way again.”
Although the researchers are now focusing on the search for a male pill, they point out once again that the Arrdc5 gene is not only found in human testes. It occurs in the testicles of almost all mammalian species. And that makes it an interesting target in the search for contraceptives for other animal species. Such means could perhaps make the still widely used, but quite drastic, castration of animals superfluous. And if ways can be found to administer such agents to wild animals, we may be able to better manage their populations and prevent infestations.
However, it is still a distant future for now; the researchers are currently focusing on the development of a male pill, suitable for use among people. “Developing a way to slow down population growth and prevent unwanted pregnancies is really, really important for the future of the human race,” says Oatley. “At the moment there are not many options for men – apart from sterilization – and only a small percentage of men opt for such an operation. If we can develop this discovery into a contraceptive solution, it could have far-reaching consequences.”