In sexual reproduction, sperm contribute half the genomic material required to create offspring, yet core molecular mechanisms essential for their formation are undefined. When formed normally, sperm can navigate the female reproductive tract via motility from a specialized flagellum, undergo capacitation as a final step in attaining the capacity to bind an ovulated oocyte, and finally fertilize the oocyte by fusion of the head with the oocyte plasma membrane that initiates delivery of the haploid paternal genome.
However, core molecular mechanisms essential for their formation are undefined.
A new study identified a gene in multiple mammalian species that could lead to a highly effective, reversible, and non-hormonal male contraceptive for humans and animals.
The study by Washington State University identified gene expression of a gene called Arrdc5 in the testicular tissue of mice, pigs, cattle, and humans. Knocking out this gene in mice leads to infertility by impacting their sperm count, movement, and shape.
Jon Oatley, senior author and professor in WSU’s School of Molecular Biosciences said, “The study identifies this gene for the first time as being expressed only in testicular tissue, nowhere else in the body, and multiple mammalian species express it. When this gene is inactivated or inhibited in males, they make sperm that cannot fertilize an egg, and that’s a prime target for male contraceptive development.”
Scientists also discovered other potential molecular targets for male contraceptive development. However, the Arrdc5 gene is specific to the male testes and found in multiple species.
Notably, a disorder known as oligoasthenoteratospermia, or OAT, is caused by the gene’s absence and results in severe infertility. The most specific diagnosis for male infertility in humans, this disorder results in less sperm production, slower movement, and a deformed shape, making it impossible for the sperm to fuse with an egg.
In the WSU study, the male mice lacking this gene generated sperm that was 28% less active, traveled 2.8 times slower than normal mice, and had defective heads and mid-pieces in 98%.
According to the study, this gene’s protein product is necessary for healthy sperm production. The next task for Oatley’s team will be to develop a medication that will prevent the creation or operation of that protein.
Any hormonal interference wouldn’t disrupt this protein. This is a serious obstacle in male contraception as testosterone plays other roles beyond sperm production in men, including building bone mass and muscle strength, as well as red blood cell production.
Scientists noted, “Designing a drug to target this protein would also make it easily reversible as a contraceptive.”
Oatley said, “Because the gene is found across mammalian species, this knowledge also holds promise for use in animals.”
Scientists studied available biological data on DNA and protein sequences in mammals and found the gene in almost every known mammal species.
Oatley said, “Developing a way to curb population growth and stop unwanted pregnancies is important for the future of the human race. Right now, we don’t have anything on the male side for contraception other than surgery, and only a small percentage of men choose vasectomies. If we can develop this discovery into a solution for contraception, it could have far-ranging impacts.”
Journal Reference:
- Giassetti, M.I., Miao, D., Law, N.C. et al. ARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis. Nat Commun 14, 2111 (2023). DOI: 10.1038/s41467-023-37735-y