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Genetic Discovery Could Enable Non-Hormonal Male Contraceptive

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Washington State University (WSU) researchers have identified a gene – Arrdc5 – which is expressed in the testicular tissue of mammals, which they suggest could be a promising target for male contraceptive development. The study is published in Nature Communications.

Male contraceptives are limited

Current male contraceptive options are suboptimal, limited to the use of condoms – which do not guarantee effectiveness – and the surgical procedure of a vasectomy. Much of the responsibilities associated with birth control use are consequently placed on women.

For decades, scientists have sought novel methods for male contraceptives, including hormonal and non-hormonal approaches. Several compounds are in pre-clinical and clinical development. Jon Oatley, professor at the WSU’s School of Molecular Biosciences, and colleagues have published a new study to identify genetic targets for male contraceptives.

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Creating a transcriptome profile of the testes

Using single-cell RNA sequencing (scRNA-seq) the researchers created transcriptome profiles of testicular tissue from cattle, mice and pigs. Their aim was to identify specific genes that are expressed in germ cells that are associated with the production of sperm, a process called spermatogenesis. Tissues were analyzed from different animals to identify genes that are conserved across different species, increasing the likelihood of the preclinical studies being translatable to humans.

What is the transcriptome?

During the process of transcription, DNA is transcribed to RNA. RNA sequences expressed in a cell therefore mirror the DNA sequence from which they were transcribed. By analyzing the transcriptome, scientists can understand which genes are “turned on” or “turned off” in a cell. This is helpful to determine which genes are associated with specific biological functions.

From the initial candidate gene list, an α-arrestin protein-encoding gene Arrdc5 was subject to further investigation, due to the mRNA for this gene being detected only in the testes in mice, pigs and cattle.

Arrdc5 knock-out results in infertility

To explore the biological function of this gene in vivo, Oatley and colleagues used CRISPR-Cas9 genome editing to generate knock-out mice lacking Arrdc5. The knock-out mice produced 28% less sperm – of which 98% had abnormal structural features – which moved 2.8 times slower than control mice.

“The study identifies this gene for the first time as being expressed only in testicular tissue, nowhere else in the body, and it’s expressed by multiple mammalian species,” says Oatley. “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.”

In humans, Arrdc5 expression is enriched in the male testes. Based on the results of this work, Oatley’s team plan to design a drug that can inhibit the function of the encoded protein. Interestingly, such methods would not require the use of hormones, which is a known bottleneck in the development of male contraceptives. “Ideally, a drug-based reversible male contraceptive would target the end phase of spermatogenesis to render sperm incapable of natural fertilization. In this way, the testicular size would not be reduced, the endocrine system would be unperturbed and precursor spermatogenic cell types (e.g., spermatogonia) would not be impacted,” Oatley and team write in the publication.

There could also be options for reversible male contraceptives too; a bonus, considering that this is a key limitation of surgical vasectomies. “You don't want to wipe out the ability to ever make sperm – just stop the sperm that are being made from being made correctly,” Oatley explains. “Then, in theory, you could remove the drug and the sperm would start being built normally again.”

Curbing population growth in humans and in the animal kingdom

A provisional patent has been filed by the research team, who state that it’s important to give humans an increased level of control over their reproduction: “Developing a way to curb population growth and stop unwanted pregnancies is really important for the future of the human race,” notes Oatley. “Right now, we don't really 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.”

Targeting Arrdc5 could open doors for additional contraceptive methods in the animal kingdom too, the researchers emphasize. They explored available DNA data and protein sequences from mammal species, discovering that the gene is expressed in every known mammal. In livestock particularly, this approach could prevent or reduce castration practices currently used to control reproduction.

Reference: Giassetti MI, Miao D, Law NC, et al. ARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis. Nat Comms. 2023;14(1):2111. doi: 10.1038/s41467-023-37735-y

This article is a rework of a press release issued by Washington State University. Material has been edited for length and content.