Do you take after your dad’s RNA?

Until recently, however, most evidence linking small sperm RNAs to environmental challenges and subsequent effects in offspring has been correlational. Attempts to pin down causality—by injecting RNAs directly into embryos—have often used far higher RNA concentrations than typically found in sperm. In fact, there was no proof that the RNA fragments even make it inside the egg. But though puzzles remain, recent studies show that not only are paternal RNA fragments transferred to a fertilized egg, but also that they are capable of inducing changes in the offspring at the doses found in sperm. Researchers first noticed the intergenerational effects of paternal lifestyle back in the 1960s, but it was decades before they started experimental investigations using animal models. Today, those studying the phenomenon are sure the effects exist but aren’t certain how they are transmitted. The end result, they believe, is adjustments to the activity of genes—a phenomenon known as epigenetics. Such adjustments occur during normal development as tissues and organs adopt their different identities, which require certain genes to be active or to be turned off. Epigenetic changes also occur throughout our lives, due to factors including exposures to certain chemicals, and activities such as smoking—and, maybe, exercise, stress, fatty diets, and more. Such changes can occur in myriad body cells, including those that give rise to sperm. As evidence mounted that sperm somehow transmit environmental information to a male’s children, researchers started probing the epigenetic mechanisms that might be responsible. Several possibilities exist: methyl groups that turn down gene activity when they accumulate on genes, and acetyl groups that attach to the protein spools called histones, around which the DNA wraps. These tend to ramp up activity of nearby genes. But methyl groups aren’t easily passed to the next generation: Fertilized eggs erase most of these marks from both sets of chromosomes before the embryo starts to divide. And mature sperm replaces most histones with its own proteins, limiting transmission of information this way. Today, the idea that small RNAs carry environmental signals has the most direct evidence behind it. Although small RNAs are short-lived, they aren’t actively removed like other epigenetic marks. Somehow, the tiny bits of nucleic acid fluctuate in response to the environment, then find their way into sperm cells. At first, researchers hypothesized that sperm manufacture these microscopic molecules in the testes, where stem cells morph into fledgling spermatozoa that are not yet fertile or able to swim. The problem, though, is that as they develop, sperm whittle down their insides to little more than the nucleus containing the male chromosomes and the mitochondria, cellular powerhouses that fuel the sperm’s odyssey to the egg. New clues emerged in 2016, when Colin Conine and Upasna Sharma, postdocs in the lab of epigeneticist Oliver Rando at the University of Massachusetts’ Chan Medical School, and colleagues, cataloged the molecular makeup of sperm from male mice exposed to low protein diets. Sperm extracted from the testes and the epididymis—a convoluted tube that carries the sperm out of the testes—contain different RNA payloads. And small bubbles found in the walls of the epididymis—called epididymosomes—were found to carry a cargo of RNA fragments matching those found in mature sperm. The team later confirmed their hunch: Sperm take up small RNAs from epididymosomes during their cruise through the winding tube, stockpiling environmental information. Other groups later reported that movement through the epididymis was associated with a reconfiguration of small RNAs in the sperm of rodents exposed to environmental challenges. One group found that chemically activating an animal’s stress response just two weeks before conception—when sperm have already embarked on their epididymal journey—still produces metabolic changes in the offspring. The epididymis connection has grown stronger with time. One 2020 study bred anxious mice by injecting sperm with epididymosomes from stressed rodents. Another 2020 study reproduced traits seen in pups reared from binge-drinking males by injecting epididymosomes from the alcohol-loving mice into sperm from teetotal animals. And in a study published earlier this year, Conine’s team found that epididymosomes also deliver some of the father’s messenger RNA—the molecule that cells use to build proteins—to sperm cells. But in a 2026 study still undergoing peer review, Conine, a developmental biologist now at the University of Pennsylvania, and colleagues injected early embryos with a microRNA known to be elevated in the sperm of mice that consumed more alcohol than others. Those mice sire pups with craniofacial abnormalities associated with paternally derived fetal alcohol syndrome — a phenomenon that has also been documented in people. When the scientists injected young embryos with 200 molecules of the microRNA—an amount typically found in sperm cells—pups developed signs of the syndrome. Conine and colleagues found that the small RNA binds to a group of inhibitory enzymes called Argonaute proteins, which suppresses select genes in the embryo and prompts a cascade of changes in gene activity that adjust the course of development. And when the researchers injected more of the microRNA, there were more developmental changes. Scientists still don’t know what prompts certain small RNAs to accumulate in response to male experiences, or how those molecules yield specific effects in the offspring. One theory suggests that paternal effects may be more general than is currently acknowledged, since most studies tend to focus on a few characteristics. Such widespread changes could be mediated by alterations to the placenta, Rando says. Similarities between mice that experienced poor nutrition in the womb, and those born to fathers with adverse lifestyles, suggests that sperm RNAs may modify placental function, with future consequences on behavior and metabolism, including anxiety, weight changes, and altered sugar control. Whatever the mechanism, there’s enough evidence to rebalance parental responsibility, Teperino says. “Now it’s almost all on women,” he says. “When a couple is planning a family, the doctor gives the woman a list of rules to follow. This is not valid anymore—we need to at least give recommendations to both.”