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Early Life Stress in Both Mice and Men Reduces the Levels of Same Sperm miRNAs Implicated in the Transmission of Stress Induced Phenotypes Across Generations

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Studies in mice have shown that offspring of highly stressed males display stress-associated behaviors even if they never experienced significant stress themselves or interacted with their fathers. One mechanism for this non-Mendelian type of inheritance has been shown to be through stress-induced changes in sperm miRNA content that influences future offspring. Thus, at least in mice, sperm miRNA content and stress-induced behaviors are the consequence of both their own stressful experiences as well as those of their fathers that are transmitted to them through changes in their father’s sperm miRNAs. However, the molecular mechanisms underlying how these sperm miRNAs function in this context have not been revealed.

David Dickson an MD/PhD student in the Neuroscience Program followed up on previous studies in the lab demonstrating that male mice exposed to chronic social instability stress during adolescence transmit stress associated behaviors to their female offspring across at least three generations via the male lineage. He has identified multiple members of the miR34/449 family of miRNAs as potential mediators of this phenomenon in mice because: 1) they function together to promote brain development, 2) their levels are severely reduced not only in sperm of stressed males but also in their sons and grandsons, who each transmit stress phenotypes to their daughters and 3) these reductions in sperm miRNAs are maintained in early embryos derived from them. To test whether a similar phenomenon occurs in men, miRNA array analysis was performed on sperm from men who filled out the Adverse Childhood Experience (ACE) questionnaire, which reveals, through 10 yes or no questions, the degree of their abusive and/or dysfunctional family experience. ACE scores of 4 or more significantly elevate risks of physical and psychological disorders in adulthood, such as depression. Remarkably, the same miRNA family identified in mice described above showed the strongest correlation with ACE score (inverse). This was the first study to demonstrate sperm miRNA changes in response to stress in humans, and raised the possibilities that sperm miRNA content could be a biomarker for early abuse as well as elevated susceptibility of offspring to psychiatric disorders. Expanded clinical studies are under way to test these possibilities. Experiments in mice are also under way to test whether, and how, reduced levels of miRNAs 34/449 alter early development to produce stress phenotypes in female offspring and recapitulate reduced levels of these sperm miRNA in male offspring.

Dickson DA, Paulus JK, Mensah V, Lem J, Saavedra-Rodriguez L, Gentry A, Pagidas K, Feig LA. 2018. Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Transl Psychiatry 8: 101. Abstract