While birth control pills have been around for more than six decades for women, male contraception options have been pretty much limited to condoms and vasectomies.
Washington State University researchers say they have discovered a gene in the testes that could solve this glaring disparity. Disabling the gene in mice changed sperm shape and movement, causing infertility in male mice, the study found.
The results could lead to the development of a male contraceptive 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's expressed by multiple mammalian species," says senior author reproductive biologist Jon Oatley from Washington State University.
"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."
Sperm are quite unique among mammalian cells in that they perform their function outside of the body in which they were produced. They contribute half the genetic material to sexually reproduced offspring, yet the process of sperm production is not fully understood by scientists.
Using RNA sequencing, Oatley and colleagues examined genes expressed in sperm-producing cells in mice, cattle, and pigs to see if they could find a gene critical to sperm function.
Through extensive cross-referencing of different data sets, they reduced their first list of 10,183 genes down to 1 candidate gene. Arrdc5 encodes an α-arrestin molecule called AARDC5, short for arrestin-domain-containing 5 protein.
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 α-arrestins in mammals, is highly expressed in mouse sperm ducts, and genetic inactivation of its coding gene, Arrdc4, impairs sperm movement. But besides this one previous study, little else 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. So the team aimed to determine if this gene could play a key role in the creation and function of sperm.
Sperm from genetically modified mice lacking the ARRDC5 protein had an abnormal shape and could not properly fertilize eggs in the lab, Oatley and his colleagues found.
Normally, sperm can move through a female's reproductive system with the help of a tail-like structure called a flagellum. They go through a process called capacitation, which lets them attach themselves to an egg from a female. The sperm head fuses with the egg, and the genetic material from the male is delivered to the egg.
Electron microscopy showed the sperm from ARRDC5-deficient mice had shorter tails, and 98 percent had defects in the head and midpiece, which made them move slower than the sperm of normal mice.
Importantly, female mice lacking the ARRDC5 protein still had normal pregnancies when paired with healthy male mice, which suggests ARRDC5 only affects male fertility.
Male contraceptive drugs have been making headlines for a few years now, but progress has been disappointingly slow. In the meantime, women are mostly responsible for contraception, and that's not without its downsides.
A genetic approach that targets only 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 step from experiments in the lab to real-life use.
"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."
The researchers have filed a provisional patent for a male contraceptive pill based on this gene discovery, although much more research is needed to see how it works in humans.
"Although our findings clearly show that ARRDC5 is an essential regulator of sperm morphogenesis, the mechanism of action is undefined," the authors write in their paper.
"Filling this gap in knowledge will be important for understanding how genetic deficiency could lead to infertility as well as targeting the molecule for male contraceptive development."
The research has been published in Nature Communications.