Men who carry the same infertility-related genetic changes do not always experience the same degree of fertility problems. A new mouse study suggests diet could be one piece of that puzzle.
Researchers found that a Western-style diet substantially worsened fertility in mice already predisposed to infertility because they lacked a functioning gene called M1ap. The study offers early evidence that genes and diet may work together to influence reproductive health, rather than acting completely independently. But the research was conducted in mice and does not show that diet has the same effect in men or that changing what someone eats can reverse genetically linked infertility.
The study, published in Human Reproduction, focused on M1AP, a gene involved in sperm development. Damaging variants in the human version of the gene are a known cause of male infertility, but their effects vary. Some men with these variants have very low sperm counts, while others produce no sperm at all.
Researchers wanted to know whether something beyond the genetic change itself might help explain those differences.
To test the idea, they compared mice with and without functioning M1ap. Beginning at weaning, the animals ate either a standard control diet or a Western-style diet containing more fat and sugar. Researchers then measured fertility by mating the males with female mice and recording how many offspring were produced.
The clearest differences showed up in litter size.
Genetically normal mice eating the control diet produced an average of 8.25 pups per litter. When those mice ate the Western-style diet, the average fell to 5.2 pups.
Mice lacking M1ap already had much lower fertility, averaging 2.5 pups per litter on the control diet. But when those genetically susceptible mice also ate the Western-style diet, average litter size dropped to just 0.37 pups.
The pattern extended beyond the number of offspring. In mice with the genetic defect, the Western-style diet also worsened some measures of sperm development and movement. It did not, however, make every sperm measure worse, underscoring that the interaction was more complicated than a broad decline across all aspects of reproductive function.
“Our study suggests that environmental or lifestyle factors, such as diet, may contribute to those differences in disease severity,” study co-senior author Jessica Dunleavy of the University of Melbourne said in a news release.
The researchers also looked at whether age would similarly worsen fertility in mice lacking M1ap. It did not. Older genetically susceptible mice remained subfertile, but their fertility was not significantly worse than that of younger mice with the same genetic alteration.
That result supports what the researchers describe as a possible “two-hit” effect. A genetic susceptibility may establish an underlying fertility problem, while certain lifestyle or environmental factors could potentially make that problem more severe.
“While genetics may establish a reduced baseline of fertility and a predisposition to infertility, lifestyle factors likely influence how severe the infertility is, and ultimately the capacity to father children,” Dunleavy said.
Whether that same relationship exists in people remains unknown.
The mice in the study were specifically engineered to lack M1ap, and the researchers studied one genetic cause of infertility in one animal model. Human fertility is influenced by many genetic, medical, environmental and lifestyle factors, so the findings cannot be assumed to apply broadly to men experiencing infertility.
The study also did not test whether improving diet could restore fertility. The researchers raise that possibility as an area for future study, but they acknowledge that human research is needed before dietary changes can be recommended as a way to improve fertility in men with these genetic variants.
It is also difficult to separate the diet itself from the broader changes it caused in the animals. The Western-style diet increased body weight, fat mass and liver weight in the mice, meaning the researchers were studying an overall dietary and metabolic shift rather than the effects of one nutrient such as sugar or fat.
The next step will be determining whether similar gene-diet interactions occur in humans and whether they help explain why men with comparable genetic fertility risks can have very different outcomes.
“Ultimately, understanding these interactions will support a more personalized approach to fertility care in the future,” said study co-senior author Moira O’Bryan.
The research was supported by a Society for Reproductive Biology Career Development Award, Australia’s National Health and Medical Research Council, the Australia-Germany Joint Research Co-operation Scheme and the German Research Foundation through its Clinical Research Unit “Male Germ Cells.”