Sowing the seeds of stress: maternal exposure to synthetic glucocorticoids impacts sperm miRNA for generations

Maternal health strongly influences fetal outcomes and can impact the physiology of subsequent generations. Exposure to adverse environments during pregnancy can predispose offspring to a spectrum of diseases, a concept known as the Developmental Origins of Health and Disease (DOHaD). While several biological factors mediate the negative impact of adversity on the developing baby and subsequent generations, stress-induced elevations in glucocorticoids are often involved. High maternal (F0) glucocorticoids can alter the development of the fetus (F1) such that when that fetus reaches adulthood, they are predisposed to produce higher concentrations of the glucocorticoid cortisol in response to stress. If female F1 offspring fall pregnant, then the developing fetus (F2) may also be exposed to high maternal glucocorticoids and cause intergenerational transmission of this high cortisol producing phenotype (Cheong et al., 2016). Intriguingly, glucocorticoid-induced intergenerational transmission of perturbed physiology has also been shown to be passed through the paternal lineage, and emerging evidence highlights the importance of the sperm and its pathway to maturation in this process. Synthetic glucocorticoids (sGCs) are frequently used to promote lung development in babies at risk of premature birth. SGCs reduce rates of respiratory distress syndrome and facilitate the survival of many babies that would otherwise not survive. They most significantly benefit babies born extremely preterm (less than 28 weeks). Fortunately, many babies at risk of extreme preterm birth do not birth as early as initially feared. It has been common practice to give such babies repeated doses of sGC if they remained at risk of preterm birth 7 days after the initial treatment and so many babies were given sGC on multiple occasions. While the benefits of sGC treatment surpass the risks of exposure, there is a large body of evidence demonstrating that sGC during fetal development negatively impact a range of physiological systems in adulthood with this being passed to subsequent generations. Recognising the need for deeper understanding of these long-term impacts, the Matthews research team's investigation into sGC exposure offers critical insights. Utilising the guinea pig as a model, the team has shown that exposure to three doses of sGCs during pregnancy can lead to alterations in cortisol concentrations, brain structures and behaviour in adults that were exposed as fetuses (F1). Of most significant interest is that these alterations can be transmitted to F2 and F3 generations through the paternal line (Moisiadis et al., 2017). As these subsequent generations are not impacted in utero by adverse maternal physiology, it suggests that sGC exposure during fetal life may impact sperm of the adult male such that a predisposition to high cortisol concentrations can be passed onto offspring. In the current edition of The Journal of Physiology, Hamada Hirotaka and the Matthews research team at the University of Toronto explore microRNA (miRNA) profiles in testicular germ cells and epididymal spermatogonia in adults across three generations (F1, F2 and F3) after F0 sGC exposure (Hamada et al., 2024). miRNAs are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. It was found that despite direct exposure to sGCs, miRNA expression in testicular germ cells was unchanged. In contrast, dysregulation occurred in four of 12 targeted miRNAs in F1 and F2 male sperm. Interestingly, mi-125b was downregulated in the F1 sperm, with the phenotype persisting into the F2 generation. While it is possible that differences in miRNA expression in sperm but not the germ cells may be due to different methods of measuring miRNA, this result suggests that sGCs have likely affected F1 male physiology, impairing the maturation process from testicular germ cells to epididymal sperm. During sperm maturation, particularly in the epididymis, the cells undergo critical morphological and biochemical changes crucial for acquiring motility and fertilisation capability. These processes are significantly influenced by hormones like testosterone and cortisol. Given that this research team have also previously shown that sGCs induce elevations in cortisol in offspring (Moisiadis et al., 2017), it is likely that elevated cortisol may be the physiological change that is impacting sperm miRNA content in male F1 offspring. These changes in miRNA within the F1 sperm may then influence how the conceived F2 embryo develops, such that F2 offspring also have increased glucocorticoid production and altered sperm miRNA profiles which can be passed onto the third generation. The Matthews research team recently demonstrated in another study that glucocorticoids can indeed impact sperm miRNA directly. Casciaro et al. (2023) provided adult male guineapigs sGC daily throughout the period of spermatogenesis and demonstrated altered miRNA profiles within sperm from the cauda of the epididymis. Hamada et al also highlighted an important association between miR-125b, which was altered across generations in the sperm, and its target gene, Itga8, in the prefrontal cortex of F1 and F2 female offspring. It is possible that miRNA changes in the sperm have altered target genes within cells of the developing conceptus which result in long term changes to offspring physiology. Work from others may provide some additional insight into potential mechanisms involved. A study by Chan et al. (2020) demonstrated that epididymal sperm miRNA that were altered by glucocorticoid exposure, originated from extracellular vesicles (EVs) that were secreted by epididymal epithelial cells. Furthermore, using intracytoplasmic sperm injection, these EVs were delivered to naïve sperm. Fetuses conceived from these sperm exhibited significant transcriptomic changes in the embryonic brain and placenta. Adult offspring also had heightened glucocorticoid productivity. Overall, data from the study by Hamada et al. (2024) provide mechanistic insight into how sGCs may lead to programmed changes to physiology that are transmitted across generations. While sGCs will remain an essential medication for prevention of preterm birth, this study may highlight the need to improve the way in which we use this medication. If sGCs could be delivered in a way in which they reach the fetal lung without affecting the fetal brain and programming offspring to have an altered cortisol response, this may go some way to minimising the intergenerational neuroendocrine changes linked to sGC exposure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors have no conflicts of interest. D.B. and J.C.: conception or design of the work; drafting the work or revising it critically for important intellectual content. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. No funding was obtained for this work. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians.

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