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Epigenetic Transmission of the Impact of Early Stress Across Generations
Open accessAbstract
Background Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations.Methods To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14.Results We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression.Conclusions These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.
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“Multigenerational early-life stress models demonstrate enduring regulatory and behavioral variation, including depressive-like behaviors and altered responses to environmental novelty (64).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [64]
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“These findings include epigenetic modulation of genes involved in synaptic and stress signaling, including Mecp2, CB1, and CRFR2, with methylation differences observed in both germline and neural tissues (64).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [64]
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“Enduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes (10)(11)(12)(13), in utero effects (14), variations in early postnatal care (15,16), and/or other early life experiences (17) that are influenced by parental exposure (18).”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [12]
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“Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring (10-13), but blood samples will not permit ascertainment of gamete-dependent transmission.”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [12]
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“early-life postnatal adversity in animal models can persistently affect behavior across generations and DNA methylation in the germline.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [163]
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“In rodents, depriving the pups from maternal care for a few hours a day within the first 2–3 weeks since birth increases behavioural measures of anxiety and depression in adulthood, just like early childhood adversity would in humans (Levine and Wiener, 1988; Bremner and Vermetten, 2001; Franklin et al., 2010).”
BackgroundPrenatal programming of stress responsiveness and behaviours: Progress and perspectives
Hamada, H., & Matthews, S. G. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12674 · Cited by 65
Jastreboff, A. M., Chaplin, T. M., Finnie, S., Savoye, M., Stults-Kolehmainen, M., Silverman, W. K., & Sinha, R. (2018) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2018.07.011 · Cited by 57
Epigenetic Variations in Heredity and Evolution
Jablonka, E. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.158 · Cited by 59
Prenatal stress decreases spatial learning and memory retrieval of the adult male offspring of rats
Modir, F., Salmani, M. E., Goudarzi, I., Lashkarboluki, T., & Abrari, K. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.02.040 · Cited by 60
Resilience: Safety in the Aftermath of Traumatic Stressor Experiences
Matheson, K., Asokumar, A., & Anisman, H. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.596919 · Cited by 75
Prions: What Are They Good For?
Si, K. (2015) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100913-013409 · Cited by 57
“…changes can be seen in unicellular fungi and more complex multicellular organisms and encompass alterations in the size, shape, and function of various organs; metabolism; and animal behavior (Franklin et al. 2010, Herb et al. 2012, Lim & Brunet 2013, Seong et al. 2011, Zeybel et al. 2012).”
BackgroundZimmer, C., Larriva, M., Boogert, N. J., & Spencer, K. A. (2017) · Scientific Reports · doi:10.1038/srep46125 · Cited by 54
Braun, K., Bock, J., Wainstock, T., Matas, E., Gaisler‐Salomon, I., Fegert, J. M., Ziegenhain, U., & Segal, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.021 · Cited by 55
“These findings indicate that the effects of stress may be independent of maternal care; indeed, maternal separation leads to changes in CRFR2 methylation in the sperm of separated males and in the frontal cortex of their offspring, implying that epigenetic mechanisms may play a role in transmission (Franklin et al., 2…”
The Effects of Early Life Stress on the Brain and Behaviour: Insights From Zebrafish Models
Eachus, H., Choi, M., & Ryu, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.657591 · Cited by 55
Tarantino, L. M., Sullivan, P. F., & Meltzer-Brody, S. E. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00044 · Cited by 59
“Franklin et al. (2010) have extended these studies to C57BL/6 mice and demonstrated that the stress of chronic and unpredictable early life maternal separation in male offspring alters the profile of DNA methylation in the promoter of several candidate genes including the Mecp2 gene, a…”
BackgroundInfluentialStress and Alterations in Bones: An Interdisciplinary Perspective
Wippert, P., Rector, M., Kuhn, G. A., & Wuertz‐Kozak, K. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00096 · Cited by 65
Psychotherapy and Genetic Neuroscience: An Emerging Dialog
Jiménez, J. P., Botto, A., Herrera, L., Leighton, C., Rossi, J. L., Quevedo, Y., Silva, J. R., Martínez, F. I., Assar, R., Salazar, L. A., et al. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00257 · Cited by 62
“In animal models, it has been observed that chronic and unpredictable maternal separation induced depressive behavior in the offspring during adulthood, changing the profile of DNA methylation, which is transmitted to the next generation with the consequent alteration in gene expression (Franklin et al., 2010).”
BackgroundPsychosocial Stress and Adversity: Effects from the Perinatal Period to Adulthood
Barrero‐Castillero, A., Morton, S. U., Nelson, C. A., & Smith, V. C. (2019) · NeoReviews · doi:10.1542/neo.20-12-e686 · Cited by 60
Genomics and epigenomics of the human glycome
Zoldoš, V., Novokmet, M., Bečeheli, I., & Lauc, G. (2012) · Glycoconjugate Journal · doi:10.1007/s10719-012-9397-y · Cited by 54
“Even still scarce, there are evidences of epialleles passing to offspring and even grand-offspring through germline cells, putting the transgenerational epigenetic inheritance [33–35] in the focus of the epigenetic community.”
BackgroundLiyanage, V. R. B., Zachariah, R. M., & Rastegar, M. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-46 · Cited by 54
“The hypermethylation of this R2 region in mouse brain was associated with MeCP2 downregulation [20], and hence it is possible that the hypomethylation/demethylation of the same R2 region causes Mecp2/MeCP2 upregulation.”
BackgroundResultInfluentialRompala, G. R., Finegersh, A., & Homanics, G. E. (2016) · Alcohol · doi:10.1016/j.alcohol.2016.03.006 · Cited by 53
“Indeed, intergenerational and transgenerational studies have found sex-specific effects of paternal preconception exposures across generations in adult rodents (Franklin et al., 2010; Vassoler, White, et al., 2013).”
BackgroundCallaghan, B. L., Cowan, C. S. M., & Richardson, R. (2016) · Psychological Science · doi:10.1177/0956797616653103 · Cited by 55
“This argument notwithstanding, previous research has demonstrated sexspecific generational inheritance of emotion-related responses (Franklin et al., 2010; H. K. Kim, Capaldi, Pears, Kerr, & Owen, 2009).”
ResultBock, J., Poeschel, J., Schindler, J., Börner, F., Shachar-Dadon, A., Ferdman, N., Gaisler‐Salomon, I., Leshem, M., Braun, K., & Poeggel, G. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0940-4 · Cited by 54
Zaidan, H., & Gaisler‐Salomon, I. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.04.013 · Cited by 55
Stress transgenerationally programs metabolic pathways linked to altered mental health
Kiss, D., Ambeskovic, M., Montina, T., & Metz, G. A. S. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2272-4 · Cited by 52
“Its excretion is upregulated in human subjects with diabetes [62] and high levels of anxiety [63], both of which are common symptoms associated with prenatal stress [15, 64, 65].”
BackgroundThe elusive engram: what can infantile amnesia tell us about memory?
Callaghan, B. L., Li, S., & Richardson, R. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.10.007 · Cited by 51
Maternal overnutrition induces long-term cognitive deficits across several generations
Sarker, G., & Peleg-Raibstein, D. (2018) · Nutrients · doi:10.3390/nu11010007 · Cited by 52
Stenson, A. F., van Rooij, S. J. H., Carter, S. E., Powers, A. D., & Jovanović, T. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113017 · Cited by 53
Epigenetic mechanisms impacted by chronic stress across the rodent lifespan
Dion, A., Muñoz, P., & Franklin, T. B. (2022) · Neurobiology of Stress · doi:10.1016/j.ynstr.2022.100434 · Cited by 54
Self-citationTrans-generational Effects of Early Life Stress: The Role of Maternal Behavior
Schmauss, C., Lee-McDermott, Z., & Ramos-Medina, L. (2014) · Scientific Reports · doi:10.1038/srep04873 · Cited by 52
Metadata
- Authors
- Franklin, T. B., Russig, H., Weiss, I. C., Gräff, J., Linder, N., Michalon, A., Vizi, S., & Mansuy, I. M.
- Affiliations
- University of Zurich (CH)
- Massachusetts Institute of Technology (US)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Mansuy, Isabelle M.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 68
- Issue
- 5
- Pages
- 408-415
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2035616108
- Cited by
- 1,125
- References
- 68
- Citations by year
- 2026: 35 · 2025: 43 · 2024: 39 · 2023: 63 · 2022: 48 · 2021: 63 · 2020: 115 · 2019: 75 · 2018: 96 · 2017: 79 · 2016: 89 · 2015: 88 · 2014: 95 · 2013: 82 · 2012: 66
- FWCI
- 25.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- University of Zürich
- Swiss Federal Institute of Technology
- Swiss National Science Foundation
- National Center for Competence in Research “Neural Plasticity and Repair,”
- Human Frontier Science Program
- Borderline Personality Disorder Research Foundation
- Roche
- European Molecular Biology Organization Young Investigator Program
- Novartis Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- transgenerational transmission, early life stress, maternal separation, chronic unpredictable mild stress, depression-like behavior, DNA methylation, offspring behavior, gene expression
- MeSH terms
- Age Factors, Animals, Behavior, Animal, Mental Disorders, Brain, Female, Humans, Male, Maternal Deprivation, Sex Factors, Stress, Psychological, Gene Expression, DNA Methylation, Models, Animal, Epigenesis, Genetic, Mice
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