03.10.23 - Isabelle Mansuy

Abstract: Behavior and physiology in mammals are strongly influenced by life experiences, particularly experiences in childhood. While positive factors favor proper development and good mental and physical health in adulthood, early life adversity and traumatic events increase the risk for psychiatric, metabolic and autoimmune diseases and cancer. Such disorders can affect directly exposed individuals but also their descendants and in some cases across several generations. The biological mechanisms underlying the inheritance of environmentally-induced (acquired) traits are thought to involve factors independent from the DNA sequence in the germline. To study these mechanisms, we developed a mouse model of postnatal stress that induces trauma symptoms across generations ^1–3. The symptoms include increased risk-taking, depressive-like behaviors, cognitive and social deficits, as well as metabolic and cardiovascular dysfunctions in adulthood that persist across life in exposed animals. Further, some symptoms are also manifested by the offspring of exposed individuals, up to the 5th generation i.e. risk-taking behaviors⁴. In humans, comparable symptoms affect people exposed to childhood trauma, suggesting conserved effects across species⁵. 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 symptoms transmission². MiRNAs are also affected in extracellular vesicles in blood and the reproductive tract6. Circulating factors were identified as mediators of some of the 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-offspring⁵. These results suggest the existence of an ensemble of factors and mechanisms that can carry information about past experiences from the periphery to germ cells for the inheritance of acquired traits. 

1. Franklin, T. B. et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68, 408–15 (2010).
2. 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).
3. 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).
4. 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. Epigenetics 8, 024 (2022).
5. van Steenwyk, G. et al. Involvement of circulating factors in the transmission of paternal experiences through the germline. EMBO J. 39, e104579 (2020).
6. 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).