In March 2025, in a preprint uploaded to biorxiv.org, Mansuy and colleagues reported that EVs in mice can transport certain RNAs, metabolites and lipids linked to early-life stress from circulating blood to sperm, with consequences for offspring. The offspring produced by these sperm cells had stress-related metabolic dysfunction as adults and bore the stress signatures in their own sperm RNA. “These changes imply a mechanistic link between sperm RNA modifications and phenotypic features in the offspring,” Mansuy’s team concluded in their paper, which has not yet been peer-reviewed.

Phenotypic Translation

Perhaps the trickiest step to understand is how sperm-borne molecules could influence an adult’s observable traits. In one form of experiment, researchers extract all the sperm RNA from mice that have been raised under stressful or health-altering conditions. Those isolated RNAs are then injected into a zygote. Pups that emerge usually “get the dad’s phenotypes,” Conine said, suggesting that the RNAs alone confer traits from dad to offspring.

But how? During early development, epigenetic processes reign. As one fertilized cell divides into two, and those cells divide again, and so on, one set of DNA instructions is dynamically and repeatedly reprogrammed. The growing body specializes into different cell types and is sculpted into a sequence of increasingly complex forms. It’s possible, then, that early epigenetic alterations to the genome could have significant downstream effects on an adult.

Research out of Conine’s lab, published in 2024, showed that sperm microRNAs alter gene expression in mouse embryos. Experiments like these, he said, support the idea that offspring can inherit paternal traits via the transfer of non-DNA molecular stowaways in sperm.

The recent Cell Metabolism paper took this idea a step further by tracing a mechanism by which this can happen. A team of more than two dozen Chinese researchers focused on the epigenetic transmission of exercise benefits, homing in on a set of microRNAs that reprogram gene expression in the early embryo. These changes ultimately result in skeletal muscle adaptations in adult offspring that enhance exercise endurance. The researchers found that well-exercised mice had more of these microRNAs in their sperm than sedentary mice did. When these microRNAs were transferred into zygotes, the adults they grew into were more physically fit, with more mitochondria in skeletal muscle and higher endurance.

But how did the molecules generate the exercise-positive phenotype? In experiments, the researchers found that the microRNAs suppressed a particular protein, which had the effect of boosting genes related to mitochondrial activity and metabolism.

Intriguingly, the sperm of physically trained male humans also hosted higher levels of many of the same microRNAs than those of untrained cohorts. “This cross-species conservation suggests a potential role for these sperm mi[cro]RNAs in intergenerational exercise adaptations in humans,” the researchers wrote.

The First Draft

The notion that a father’s lived experience can become recorded by his body, transmitted to his gametes and relayed to his offspring is no longer as outlandish as it once seemed. Many researchers in the field are willing to float speculative visions of what could be going on, even as they acknowledge that gaps remain.

“Our hypothesis is that the epididymis ‘sees’ the world and alters the small RNAs it produces in response,” Rando said. “These RNAs are then delivered to the zygote upon fertilization and control early gene regulation and development to shape offspring health and disease.”

Conine speculates that once certain RNAs make their way into the egg, they trigger “a cascade of changes in developmental gene expression that then leads to these phenotypes” of the father showing up in the next generation. Remarkably, this unfolds even though the sheer volume of the sperm’s contents is so much less than an egg’s contents, including the relative amounts of RNA.

The full picture of how paternal experience and behavior might epigenetically influence offspring is not nearly in hand. Researchers are currently piecing the story together, one experiment at a time, rather than proving out every step sequentially in the same set of organisms. One of the gaps is in the characterization of what RNA and perhaps other epigenetic factors do in the zygote to modify genomic activity as it unfolds during development, Mansuy said.

“We are still blind men describing for the first time different parts of the same elephant,” Chen said. “The underlying mechanism is almost certainly an orchestra of a sperm RNA code and factors beyond that.”

Confirming the findings in humans would take enormous effort, but it would be key to turning these findings in mice into “informed medical advice,” Chen said. This would require well-controlled experiments following multiple generations, tracking diet, exercise, aging and environmental exposures, while also using advanced tools to decode sperm-packaged molecules — and then looking for strong correlations between the molecular and phenotypic data.

Even amid the uncertainties, researchers are cautiously moving forward as they learn to believe the results of their own experiments. If they’re right, they will have discovered a new fact of life, Rando said. When he thinks about his two boys, he wonders what he might have done differently when he was younger, before they were born, that might have tweaked his RNA profile in ways that would affect them today.

“We don’t know enough yet to develop guidance like that,” Rando said. “Maybe we will get there.”