More than Sperm Support

Sarah Robertson, a professor of reproductive immunology and biomedicine at the University of Adelaide in Australia, has been studying the effects of mouse seminal fluid in the female reproductive tract for nearly 20 years. She and her colleagues first realized that, beyond its role of maintaining the integrity and function of sperm, seminal fluid altered the expression of immune genes in the female. Inflammatory cytokines and chemokines became upregulated in the female reproductive tract, possibly as a counterintuitive way of initiating immune tolerance of the sperm and resulting embryos. But Robertson suspected seminal fluid might be doing even more.

To further explore the role of seminal fluid on fertility and offspring health, Robertson’s group removed the seminal vesicles of male mice, then bred them with normal females. The first—and unsurprising—outcome was that most of the matings were unsuccessful; fertilization and implantation rates were reduced. But some of the females did conceive, and that’s when things got interesting.

Embryos fathered by males lacking seminal vesicles were developmentally delayed on average, with blastocysts tending to be smaller and having abnormal cavities. Furthermore, as adults, the male offspring exhibited significant metabolic disturbances, carrying 72 percent more fat than controls and exhibiting altered metabolic profiles, delayed glucose clearance, and a 15 percent increase in systolic blood pressure—all hallmark features of metabolic syndrome. Interestingly, female offspring were relatively unaffected by these metabolic disturbances.

To confirm that it was something different about the environment inside the female that was causing these changes, the researchers flushed the embryos from the reproductive tract after mating and grew them in a culture dish, where they actually seemed to fare better. And when the researchers put normal embryos into the reproductive tracts of females who had mated with males lacking seminal vesicles, they also showed signs of poor development and metabolic syndrome. “We were able to show that the tract did impact the adverse effect on embryos,” Robertson said.

Looking more closely at the female reproductive tracts for clues regarding these impairments, Robertson and her team found that females mated to seminal-vesicle-lacking males were deficient in “the good cytokines,” such as granulocyte-macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and interleukin-6 (IL6). Moreover, the researchers found higher levels the apoptosis-inducing factor TNF-related apoptosis-inducing ligand (Trail), which was suppressed after mating with wild-type males. “The embryos [developing in the absence of seminal fluid] got the wrong signals,” said Robertson, which could explain the altered phenotypes she and her colleagues observed. “We used to think embryos had this kind of autonomous developmental program, and now it seems that in most cases they are really needing to sense information from the tract in order to develop optimally.”

As to why male offspring were predominately affected, Robertson speculated that males are simply more vulnerable to early environmental perturbations. Research has shown that male embryos develop faster and require greater access to glucose, and possibly as a result, “the males always seem to be more vulnerable to any kind of insult,” Robertson said.

While the results are important, they shouldn’t necessarily come as a surprise, said reproductive biologist Susan Suarez of Cornell University, who was not involved in the work. “Why would males have evolved to have all these accessory sex glands and produce all these proteins and lipids and other factors, and not have it be important to reproduction?” But since 1977, when the first baby was born via in vitro fertilization (IVF), researchers—and funding agencies—largely “lost interest in semen,” she added, “because, after all, they could make babies in a dish without any seminal plasma. . . . All you needed was a sperm, and not a very good one at that. But this [study] helps to turn around that lack of interest.”

Moreover, if the results hold true in humans, they could have implications for how IVF and other assisted reproductive technologies are performed, Wolfner said. “This [research] does suggest to me that while the mechanics of fertilization could work fine without the proteins that are normally there, there may be some value in providing seminal plasma to jumpstart the changes that have to happen in the reproductive tract of females to support embryo development.”

J.J. Bromfield et al., “Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring,” PNAS, doi/10.1073/pnas.1305609111, 2014.