The discovery of a gene in multiple mammalian species could pave the way for a highly effective, reversible, non-hormonal male contraceptive for humans and animals.
Researchers at Washington State University identified expression of the Arrdc5 gene in the testicular tissue of mice, pigs, cattle, and humans. When they knocked out the gene in mice, they created infertility only in the males, affecting their sperm count, movement, and shape. The researchers detailed their findings in the journal Nature Communications.
“The study identifies for the first time that this gene is expressed only in testicular tissue, nowhere else in the body, and is expressed in multiple mammalian species,” said Jon Oatley, lead author and professor in the School of Molecular Biosciences at WSU. “When this gene is inactivated or inhibited in men, they produce sperm that cannot fertilize an egg, and that is a primary target for the development of male contraceptives.”
While other molecular targets for potential male contraceptive development have been identified, the Arrdc5 gene is specific to the male testis and is found in multiple species. Importantly, missing the gene also causes significant infertility creating a condition called oligoasthenoteratospermia, or OAT. This condition, the most common diagnosis for human male infertility, shows a decrease in the number of sperm produced, slower motility, and a distorted shape that prevents sperm from fusing with an egg.
In the WSU study, male mice lacking this gene produced 28% fewer sperm that moved 2.8 times slower than normal mice, and about 98% of their sperm had abnormal heads and midparts. .
The study indicates that the protein encoded by this gene is necessary for normal sperm production. Oatley’s team will then work on designing a drug that inhibits the production or function of that protein.
Disruption of this protein would not require any hormonal interference, a key hurdle in male contraception, as testosterone performs other roles beyond sperm production in men, including building bone mass and muscle strength, as well as production of red blood cells. Designing a drug that targets this protein would also make it easily reversible as a contraceptive.
“You don’t want to remove the ability to produce sperm, just prevent the sperm that are being produced from being produced properly,” he said. “Then, in theory, you could remove the drug and the sperm would start to build normally again.”
Oatley and the study’s first author, Mariana Giassetti, filed a provisional patent for the development of a male contraceptive based on this gene and the protein it encodes.
Because the gene is found in all mammalian species, this knowledge holds promise for use in animals as well, Oatley said. The team analyzed available biological data on protein and DNA sequences in mammals and found the gene in almost all known mammalian species. This opens up the potential for developing male contraceptives for use in livestock, perhaps replacing castration in some cases as a way to control breeding, and in wildlife when managers seek to limit overpopulation of a species.
The initial approach, however, is to give humans more control over their own reproduction. While many forms of birth control exist for women, they are not always effective or widely available, and more than half of pregnancies worldwide are still unintended, according to the United Nations.
“Developing a way to slow population growth and stop unwanted pregnancies is really important for the future of the human race,” Oatley said. “Right now, we really don’t have anything on the male side for contraception other than surgery and only a small percentage of men choose vasectomy. If we can turn this discovery into a contraception solution, it could have a far-reaching impact.” .”
This study was supported by the National Institutes of Health and the WSU Functional Genomics Initiative, a multi-year university investment to support the development of gene technology research.