Mounting evidence from research on nematodes to mice indicate that a father’s environment, such as what he eats or if he is exposed to stress or toxicants, can lead to metabolic and behavioral disorders in his offspring. 

For example, male mice consuming a high-fat diet sire offspring with impaired glucose tolerance and insulin resistance, which are risk factors for diabetes and cardiovascular diseases. Similarly, a mouse father’s exposure to chronic stress can result in an altered stress response in offspring, leading to behavioural defects. 

Despite this wealth of information, the underlying molecular mechanisms of such inter-generational inheritance of father’s environmental effects have remained elusive.

Instead, this influence is passed through tiny regulatory molecules packaged in sperm called small RNAs. The findings have identified a molecular pathway by which sperm acquire small RNA molecules during maturation and use them to guide the earliest stages of embryonic development, shedding light on how non-genetic information carried by sperm can influence development immediately after fertilization.

The team focused on one specific small RNA, tRFValCAC, which becomes highly concentrated in sperm as it matures inside the male reproductive tract. The researchers previously discovered that this molecule is delivered to sperm inside microscopic packages called extracellular vesicles, which are released by cells in the epididymis, where sperm finish developing.

A key finding of this study is that a specific protein acts like a molecular “sorting manager,” binding to tRFValCAC and controlling how much of the molecule gets packed into these vesicles—and ultimately, into sperm. When this protein was reduced, much less of the RNA fragment made it into sperm. “This has opened new avenues of investigation for us,” Sharma said. “We will next investigate how this protein is regulated and which other proteins are involved in packaging small RNAs in sperm.”

Upon fertilization, sperm deposits tRFValCAC to the egg. By blocking the activity of tRFValCAC immediately after fertilization—when the embryo is a single cell—the researchers were able to study its role in embryonic development. They uncovered that this small RNA helps regulate how early embryos turn genes on and off—especially those involved in cell division, chromosome organization, and RNA processing and splicing. Splicing is how genetic messages are edited before being used. 

Understanding how these processes in the father’s sperm unfold is important because they can shape the health of his children in adulthood.

Sharma’s previous studies revealed that the composition and levels of specific small RNAs in sperm are altered by environmental conditions. In this latest study, when her team blocked tRFValCAC in early embryos, the embryos showed disrupted gene regulation, delayed cell division, and were far less likely to reach the blastocyst stage. That stage is a critical milestone needed for successful implantation and pregnancy.

Early embryo development plays a major role in determining long-term health, and disruptions at this fragile stage are increasingly linked to higher risks of some of the most common conditions that have long plagued Americans, such as obesity, diabetes, and cardiovascular diseases. “We revealed that a sperm-enriched small RNA regulates the pace of preimplantation embryonic development,” Sharma said. “Our results support a model in which changes in sperm RNAs caused by a father’s environment, independent of DNA mutations, can reprogram early development and contribute to disease risk in adulthood.”

As Sharma puts it, the most fundamental process for the perpetuation of a species is the transfer of information from parent to offspring via their sperm and egg, or gametes. Although the genetic information in DNA sequence contributes to the majority of heritability in biology, epigenetic information—information beyond the underlying DNA sequence—is also passed on to the offspring.

Epigenetic information regulates how genes are decoded and stored, in the form of chemical modifications on DNA, on proteins bound to DNA, and as small RNAs. Collectively, these are known as epigenetic marks. 

A major implication of the transmission of epigenetic information from parents to offspring is that epigenetic marks can be modulated by environmental conditions. Thus, the environment experienced by parents may influence the development of offspring via alterations to the epigenetic marks in gametes. 

The scientific mysteries of how epigenetic information is established in gametes, how they are modulated by the environment, and how epigenetic marks affect offspring development are what Sharma’s lab seeks to solve. She explained that understanding the mechanism of epigenetic inheritance of paternal environmental effects will help us understand the heritability of common metabolic disorders—and thus, has important implications for public health and policymaking.

This recent study from her lab has made important contributions to understanding the mechanism, but Sharma said much more work is needed to fully understand it. In the long term, this research could lead to medical advancements like early-warning markers for developmental and metabolic risks in future offspring, or new therapeutic targets to improve embryo viability and pregnancy outcomes.

Reference: Liu S, Holmes AD, Gupta A, Katzman S, Sharma U. Epididymal dynamics and preimplantation roles of a sperm-enriched 5′ fragment of tRNA-valine. Cell Reports. 2025;44(10):116366. doi: 10.1016/j.celrep.2025.116366

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