Trauma Effects on Men's Sperm miRNA Function in Epigenetic Inheritance

Summary: The negative effects trauma exposure, such as those that promote PTSD, can be passed to offspring. While the environment in which affected parents raise their offspring clearly plays a role, a significant genetic component also exists. However, some of this genetic influence, typically revealed by twin studies, may stem from epigenetic inheritance; as implied by studies in male rodents, where trauma-specific changes in sperm miRNA content can lead to trauma-specific behavioral changes in all offspring. Evidence for epigenetic inheritance in humans is mainly epidemiological, but recent studies have revealed stress-induced sperm miRNA changes consistent with this idea. For example, we found that men with high Adverse Childhood Experiences (ACEs), whose children can be negatively affected, show reduced sperm levels of miR-34/449 family members; mirroring findings in mice exposed to chronic social instability (CSI) stress across generations. In mice, these sperm miRNA changes persist in preimplantation embryos post-fertilization, altering early embryonic gene expression that leads to elevated anxiety and impaired sociability in female offspring as well as reduced levels of sperm miR-34/449 in males. Our new data driving this proposal reveals another example. The degree of men’s exposure to adult trauma, as assessed by the Trauma History Questionnaire (THQ), which measures PTSD risk, correlates with the levels of miRNAs 532, 361, 375, and 491 in their sperm. The highest THQ scores are associated with 4- to 130-fold increases in these levels. In contrast, these miRNA changes do not correlate with ACE scores and miR-34/449 does not correlate with THQ score. Notably, miRNAs-532 and 375 are two of the 9 sperm miRNAs whose enhanced levels in male mice mediate how chronic variable (CV) stress leads to a suppressed HPA axis response in offspring, a trait linked to mental health disorders. This proposal investigates how elevated levels of sperm miRNAs-532,361,375 and 491 in men with high THQ scores might affect their offspring using the mouse model that previously demonstrated how elevated levels of sperm miRNAs transmit the stress-related effects of paternal CV stress across generations. Aim 1 tests how injecting THQ-associated miRNAs, at levels found in sperm of men exposed to high levels of trauma, into mouse zygotes affects the phenotypes of resulting offspring. Aim 2 will begin to reveal how these injected miRNAs lead to phenotypic changes revealed in Aim 1 by i) identifying gene expression changes induced by them in mouse blastocysts, and ii) looking for similarities to those occurring in discarded blastocysts from IVF procedures using men’s sperm with elevated THQ associated miRNAs derived from an ongoing, independently funded project. This study has the potential to: a) provide strong support for using mouse models to understand epigenetic inheritance in humans; and b) drive future research showing that a significant portion of inherited susceptibility to mental health disorders arises from epigenetic inheritance, and how to reverse it before fatherhood. Project Number: 1R21HD121040-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: LARRY FEIG | Institution: TUFTS UNIVERSITY BOSTON, BOSTON, MA | Award Amount: $453,750 | Activity Code: R21 | Study Section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11380412