Queues! Security! Lost passports! While many will be currently reminiscing about the fun and frolics enjoyed during old holidays to far-flung exotic destinations, we generally choose to forget the enduring stress of the outward journey. However, a fascinating new study now provides evidence that any stress endured by maturing sperm during their epic voyage is remembered and transmitted to the next generation in a mechanism involving extracellular vesicles released by cells of the reproductive tract.
We’ve previously seen that sperm small non-coding RNAs, such as miRNAs and tRNA fragments, are involved in the programming of offspring development from cues derived from the paternal environment and follow up studies have suggested that extracellular vesicles obtained in the epididymis during sperm maturation may provide this payload of ncRNAs.
In their fascinating new study, a well-traveled but stress-free team of researchers led by Tracy L. Bale (University of Maryland, Baltimore, MD, USA) have built on their previous research to now reveal that extracellular vesicles derived from epithelial cells of the male reproductive tract transmit miRNA-encoded information regarding paternal environmental stress to sperm and impact neurodevelopment in resulting offspring.
So, let’s hear about the epic journey taken by Chan and colleagues, which established the general importance of extracellular vesicular signaling to sperm to the intergenerational transmission of paternal environmental stress:
- Initial studies in a mouse in vivo model, partly confirmed through human sperm analysis, linked previous chronic stress in fathers to persistent alterations in sperm miRNA expression profiles and altered stress responses in offspring
- Fascinatingly, mass spectrometry analysis of mouse epididymal epithelial cells suggests that chronic stress-can induce persistently altered histone modification profiles
- Using a simplified in vitro culture system, the authors demonstrated that treatment with the stress-hormone corticosterone alters the miRNA and protein cargo of sperm-targeting extracellular vesicles derived from caput epididymal epithelial cells
- Alterations to miRNA content persist until long after the end of chronic stress exposure, suggesting that extracellular vesicles can prompt long-lasting programmatic changes in response to stress
- In confirmation, the authors note that human sperm miRNA expression patterns displayed similar stress-induced dynamics
- The team found that offspring generated by sperm incubated with extracellular vesicles derived from previously stressed epididymal epithelial cells show altered neurodevelopment, as evidenced by transcriptional analyses of mice at different developmental stages, and dysregulation of stress responses as adults
Overall, these data suggest that extracellular vesicles can transmit miRNA-encoded information to developing sperm as they pass through the reproductive tract, thereby mediating the intergenerational transmission of information regarding paternal environmental conditions to alter the neurodevelopment of subsequent offspring. The journeymen and journeywomen behind this fascinating study certainly give Odysseus a run for his money when it comes to epic journeys, and their ending surely trumps anything ever written by Homer!
Senior author Tracy Bale shares, “Our study shows that the baby’s brain develops differently if the father experienced a chronic period of stress before conception, but we still do not know the implications of these differences. Could this prolonged higher level of stress raise the risk for mental health issues in future offspring, or could experiencing stress and managing it well help to promote stress resilience? We don’t really know at this point, but our data highlight why further studies are necessary.”
For a voyage of maturation and stress and of epigenetics and discovery, look no further than Nature Communications, March 2020.