Scientists discover a gene on which to base a male contraceptive

While birth control pills have been around for over six decades for women, male birth control options are pretty much limited to condoms and vasectomy.

Washington State University researchers say they have discovered a gene in the testicles that may resolve this glaring disparity. Turning off the gene in mice altered sperm shape and movement, causing infertility in male mice, according to the study.

The results could lead to the development of a male birth control pill that would be effective during use and allow sperm to return to normal after stopping treatment.

“The study identifies this gene for the first time as being expressed only in testicular tissue, nowhere else in the body, and it is expressed by multiple species of mammals,” says lead author Jon Oatley, reproductive biologist from Washington State University.

“When this gene is inactivated or inhibited in males, they make sperm that cannot fertilize an egg, and this is a prime target for the development of male contraceptives.”

Sperm cells are quite unique among mammalian cells in that they perform their function outside of the body in which they were produced. They contribute half of the genetic material in sexually reproduced offspring, but the process of sperm production is not fully understood by scientists.

Using RNA sequencing, Oatley and his colleagues looked at genes expressed in sperm-producing cells in mice, cattle and pigs to see if they could find a gene essential for sperm function.

Through extensive cross-referencing of different datasets, they narrowed down their initial list of 10,183 genes to 1 candidate gene. Arrdc5 encodes an α-arrestin molecule called AARDC5, short for arrestin domain-containing protein 5.

Arrestins are a group of proteins that play a role in regulating signaling pathways in the cells of many different organisms, from yeast to humans. ARRDC4, another of the six known mammalian α-arrestins, is highly expressed in mouse sperm ducts, and genetic inactivation of its encoding gene, Arrdc4, impairs sperm movement. But aside from this previous study, little is known about how or if arrestin proteins help make sperm.

AARDC5 is abundant in the testes of humans, mice, cattle and pigs, but scientific research has not yet identified its biological role. The team therefore sought to determine whether this gene could play a key role in the creation and function of sperm.

Sperm from genetically modified mice lacking the ARRDC5 protein were abnormally shaped and could not properly fertilize eggs in the lab, Oatley and colleagues found.

Normally, sperm can move through a woman’s reproductive system using a tail-like structure called a flagellum. They go through a process called capacitation, which allows them to attach to a female egg. The sperm head fuses with the egg and the genetic material from the male is delivered to the egg.

Electron microscopy showed that sperm from ARRDC5-deficient mice had shorter tails and 98% had defects in the head and midpiece, which caused them to move more slowly than sperm from normal mice.

Importantly, female mice lacking the ARRDC5 protein still had normal pregnancies when paired with healthy male mice, suggesting that ARRDC5 only affects male fertility.

Male contraceptives have been in the news for a few years now, but progress has been disappointingly slow. In the meantime, women are mostly responsible for contraception, and this is not without its drawbacks.

A genetic approach that only targets sperm may be reversible and have fewer side effects than interfering with male hormones, as testosterone plays other roles beyond sperm production. And the discovery could one day be used to control breeding livestock, but it’s still a big leap from lab experiments to real-life use.

“You don’t want to destroy the ability to make sperm – just prevent the sperm that is being made from being made properly,” says Oatley.

“So, in theory, you could take the drug out and the sperm would start building normally again.”

Researchers have filed a provisional patent for a male birth control pill based on this genetic discovery, although much more research is needed to see how it works in humans.

“Although our findings clearly show that ARDRDC5 is an essential regulator of sperm morphogenesis, the mechanism of action is undefined,” the authors write in their paper.

“Filling this knowledge gap will be important for understanding how a genetic deficiency might lead to infertility as well as for targeting the molecule for the development of male contraceptives.”

The research has been published in Nature Communication.

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