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Behavior and physiology in mammals are strongly influenced by life experiences and environmental factors, particularly those encountered in childhood. While positive factors can favor proper development and mental and physical health, adversity and traumatic events increase the risk for psychiatric, cardiometabolic and autoimmune diseases and cancer in adulthood. These complex disorders can affect directly exposed individuals and their descendants, in some cases across generations. The biological mechanisms underlying the inheritance of environmentally-induced (acquired) traits are unlikely to involve changes in the DNA sequence but rather depend on epigenetic processes. To study these mechanisms, we developed a mouse model of traumatic stress in early postnatal life that causes symptoms across generations1–3. The symptoms include increased risk-taking, depressive-like behaviors, cognitive and social deficits, as well as metabolic and cardiovascular dysfunctions that persist across life in exposed animals. Further, some symptoms are manifested by the offspring of exposed individuals e.g. risk-taking behaviors up to the 5th generation in the patriline 4. In humans, childhood trauma also affects mental and physical health, suggesting conserved effects across species5, 6. At a molecular level, exposure is associated with epigenetic changes involving RNA and DNA methylation in somatic cells across the body and in germ cells, with sperm RNA being causally linked to the transmission of symptoms from father to offspring3. MiRNAs are also affected in extracellular vesicles in blood and the reproductive tract7. Circulating factors were identified as mediators of alterations in germ cells. Chronic injection of serum from trauma-exposed mouse males into control males recapitulates metabolic phenotypes in the offspring, suggesting information transfer from serum to germ cells. Pathways involving peroxisome proliferator-activated receptor (PPAR) are causally involved, with pharmacological PPAR activation in vivo affecting sperm transcriptome and metabolic functions in the offspring and grand-offspring6. Together, these findings suggest the existence of an ensemble of factors and mechanisms that can carry information about past experiences from the periphery to germ cells and mediate the inheritance of acquired traits8–11.
- Bohacek, J. et al. Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress. Mol Psychiatry 20, 621–631 (2015).
- Franklin, T. B. et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68, 408–15 (2010).
- Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17, 667–9 (2014).
- Boscardin, C., Manuella, F. & Mansuy, I. M. Paternal transmission of behavioural and metabolic traits induced by postnatal stress up to the 5th generation in mice. Environ Epigenet 8, dvac024 (2022).
- Jawaid, A. et al. Differential microRNAs in human serum and sperm after childhood trauma with potential implications for offspring health. MedRxiv (2025).
- van Steenwyk, G. et al. Involvement of circulating factors in the transmission of paternal experiences through the germline. EMBO J. 39, e104579 (2020).
- Alshanbayeva, A., Tanwar, D. K., Roszkowski, M., Manuella, F. & Mansuy, I. M. Early life stress affects the miRNA cargo of epididymal extracellular vesicles in mouse. Biol Reprod 105, 593–602 (2021).
- Bohacek, J. & Mansuy, I. M. Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat Rev Genet 16, (2015).
- Arzate-Mejia, R. G. & Mansuy, I. M. Remembering through the genome: The role of chromatin states in brain functions and diseases. Transl Psychiatry 13, 122–128 (2023).
- Jawaid, A., Jehle, K. L. & Mansuy, I. M. Impact of parental exposure on offspring health in humans. Trends in Genetics 37, 373–388 (2021).
- Otaru, N. et al. Transgenerational effects of early life stress on the fecal microbiota in mice. Commun Biol 7, 670 (2024).