Driving the Next Generation: Paternal Lifetime Experiences Transmitted via Extracellular Vesicles and Their Small RNA Cargo

Epidemiological studies provide strong evidence for the impact of diverse paternal life experiences on offspring neurodevelopmental disease risk. While these associations are well established, the molecular mechanisms underlying these intergenerational transmissions remain elusive, though recent studies focusing on the influence of paternal experience before conception have implicated germ cell epigenetic programming. Any model accounting for the germline transfer of nongenetic information from sire to offspring must include certain components, such as 1) a vector to carry any signal from the paternal compartment to the maternal reproductive tract and future embryo; 2) a molecular signal, encoded by a paternal experience, to carry this memory and enact downstream responses; and 3) a target cell or tissue to receive the signal and convert it into an effect on embryonic development. We explore the current understanding of the potential processes and candidate factors that may serve as these components. We specifically discuss the growing appreciation for the importance of extracellular vesicles in these processes, beginning with their known role in delivering potential signals, including small RNAs, to sperm, the prototypical vector, during their posttesticular maturation. Finally, we explore the possibility that paternal extracellular vesicles could themselves serve as vectors, delivering signals not only to gametes or the zygote but also to tissues of the maternal reproductive tract to influence fetal development.