Infertility is a widespread problem: worldwide, one in eight couples fails to fulfill their desire to have children within a year, or even at all. In half of the cases, this is due to fertility disorders that come from the male. However, it is difficult to identify the genetic causes of such fertility disorders in humans. Researchers lack data on semen quality and molecular markers from sufficiently large cohorts of healthy men of reproductive age.
Therefore, the path to a better understanding of what genes and mechanisms control male fertility lies through suitable laboratory animals, in this case bulls.
A research team led by Hubert Pausch, professor of animal genomics at ETH Zurich, studied young bulls to investigate in detail which genes are active in different tissues of the animals' reproductive organs and how this affects their fertility. His study was recently published in the journal Nature Communications.
For this research, researchers from the Institute of Agricultural Sciences used samples of testicles, epididymis and vas deferens from 118 recently slaughtered bulls of reproductive age. The animals were not sacrificed specifically for the research.
One thing the scientists characterized using these biopsies were the bulls' transcriptomes; in other words, all the messenger RNAs present in each type of tissue, which represent gene transcripts. This allowed the team to discover which genes are active in which of the three tissues. Based on that knowledge, they created corresponding transcriptome profiles for the bulls. They then compared these profiles with those of humans and mice.
Many genes involved
Through this research, the team discovered a large number of genes and their variants associated with fertility in bulls. It is likely that most of the genes found are also relevant to male fertility in humans. In evolutionary terms, the regulation of male fertility is “highly conserved,” explains Xena Mapel, first author of the study. This means that the genes responsible for reproduction function similarly in all mammals.
“These genes are closely related to poor fertility in bulls,” says Mapel. “These subfertile bulls do not appear during conventional ejaculate analysis. However, they can be reliably detected with our new marker genes.”
Unusual animal model
Although cattle are an unusual choice of animal model, they are ideal for these types of studies. On the one hand, the genes of breeding bulls are well known, and on the other hand, breeding organizations obtain ejaculate from the animals twice a week as part of their normal operations. This is analyzed in detail before it is diluted and used to inseminate hundreds of cows, or discarded if the quality of the ejaculate is poor.
The cohort of bulls analyzed here also has the great advantage that all animals are similar in age. “This cohort is very homogeneous. If we were to do a comparable study in men, we would have to rely on volunteer donors, potentially from all possible age groups. This would give us data that is very difficult to compare.”
Data on young male fertility are collected annually from Swiss conscripts in the armed forces, but these data can hardly be used for such analyses. “We do not know what influences the men were exposed to before taking the fertility test, which will be different for each test subject. Additionally, it is virtually impossible to obtain tissue samples from their reproductive tract, as this would involve an invasive medical examination. procedure.”
Findings that will benefit livestock farmers
It is not yet clear how the new findings will be incorporated into human fertility research, but they are already paving the way for better diagnostics to identify the corresponding genes and their variants in breeding bulls. That means livestock breeders will likely be the first to benefit from the findings, as they will help minimize financial losses from failed artificial inseminations.
Currently, each bull's ejaculate is tested for quality before use and the calves' genomes are analyzed; however, some infertile bulls still escape. If a breeder inseminates cows with semen from an infertile bull, the cows will not become pregnant. And since each insemination costs 80 Swiss francs, this can soon eat up a breeder's budget: a typical Swiss dairy farm spends several thousand Swiss francs a year artificially inseminating its herd of cows. But it doesn't end there: unsuccessfully inseminated cows usually cause more problems for farmers, as they do not give birth to calves and no longer produce milk, so the farmer has to replace them. And that costs money.
Artificial insemination is currently a standard in beef and dairy cattle breeding, as well as pig breeding. In Switzerland, around 800,000 cows are artificially inseminated each year. Natural matings, when a bull naturally mates with a cow, occur very rarely. “Raising a bull is not easy. Most farmers do not have space for such a large animal,” says Pausch.