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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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Epigenetic marking of sperm by post-translational modification of histones and protamines
Brunner, A. M., Nanni, P., & Mansuy, I. M. (2014) · Epigenetics & Chromatin · doi:10.1186/1756-8935-7-2 · Cited by 181
“Mature sperm was collected from the caudal epididymis of adult 3- to 12-month-old C57BL/6 males as previously described [38].”
Self-citationEpigenetic Inheritance of Disease and Disease Risk
Bohacek, J., & Mansuy, I. M. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.110 · Cited by 180
“…brain are the long-term epigenetic remodeling of the stress axis in response to stressful experiences early in life (Murgatroyd et al, 2009; Franklin et al, 2010), or the cascade of epigenetic events involved in the development of drug addiction (Kumar et al, 2005; Robison and Nestler,…”
BackgroundInfluentialSelf-citationEarly life stress in fathers improves behavioural flexibility in their offspring
Gapp, K., Soldado-Magraner, S., Álvarez-Sánchez, M., Bohacek, J., Vernaz, G., Shu, H., Franklin, T. B., Wolfer, D. P., & Mansuy, I. M. (2014) · Nature Communications · doi:10.1038/ncomms6466 · Cited by 170
“RT–PCR showing MR expression in the hippocampus in F1 MSUS males (controls n1⁄4 7, MSUS n1⁄4 8; t(13)1⁄4 2.”
MethodSelf-citationValor, L. M., Viosca, J., López‐Atalaya, J. P., & Barco, Á. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990382 · Cited by 173
“Extensive correlative evidence supports a role for histone acetylation in memory storage that seems highly conserved through evolution [8-13].”
BackgroundPotential of Environmental Enrichment to Prevent Transgenerational Effects of Paternal Trauma
Gapp, K., Bohacek, J., Grossmann, J., Brunner, A. M., Manuella, F., Nanni, P., & Mansuy, I. M. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.87 · Cited by 172
Self-citationWeber-Stadlbauer, U., Richetto, J., Labouesse, M. A., Bohacek, J., Mansuy, I. M., & Meyer, U. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.41 · Cited by 170
Self-citationKundaković, M., Lim, S. C., Gudsnuk, K. M., & Champagne, F. A. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00078 · Cited by 179
“and may account for the transmission of behavioral and epigenetic effects of MS-rearing across generations (21, 71).”
BackgroundMethodInfluentialLiyanage, V. R. B., & Rastegar, M. (2014) · NeuroMolecular Medicine · doi:10.1007/s12017-014-8295-9 · Cited by 182
“results in altered expression of Mecp2 (Franklin et al. 2010).”
Backgroundde Haan, S. (2020) · Cambridge University Press eBooks · doi:10.1017/9781108685214 · Cited by 178
Inheritable Effect of Unpredictable Maternal Separation on Behavioral Responses in Mice
Weiss, I. C., Franklin, T. B., Vizi, S., & Mansuy, I. M. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00003 · Cited by 172
Self-citationThe neural mechanisms and consequences of paternal caregiving
Feldman, R., Braun, K., & Champagne, F. A. (2019) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0124-6 · Cited by 177
Breton, C. V., Landon, R., Kahn, L. G., Enlow, M. B., Peterson, A. K., Bastain, T. M., Braun, J. M., Comstock, S. S., Duarte, C. S., Hipwell, A. E., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02316-6 · Cited by 177
Gapp, K., van Steenwyk, G., Germain, P. L., Matsushima, W., Rudolph, K. L. M., Manuella, F., Roszkowski, M., Vernaz, G., Ghosh, T., Pelczar, P., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-018-0271-6 · Cited by 195
“First, using the MSUS paradigm, we produced a cohort of mice exposed to traumatic stress in early postnatal life and confirmed their behavioural phenotype in adulthood described previously [2, 10] (Supplementary Figure 1).”
MethodSelf-citationJawahar, M. C., Murgatroyd, C., Harrison, E. L., & Baune, B. T. (2015) · Clinical Epigenetics · doi:10.1186/s13148-015-0156-3 · Cited by 172
Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors
Lehrner, A., Bierer, L. M., Passarelli, V., Pratchett, L. C., Flory, J. D., Bader, H. N., Harris, I. R., Bedi, A., Daskalakis, N. P., Makotkine, I., et al. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.11.019 · Cited by 160
“The effects of paternal stress exposure on offspring in animal models have been primarily attributed to preconception influences on gamete development (Franklin and Mansuy, 2010; Franklin et al., 2010; Rodgers et al., 2013).”
BackgroundInfluentialEpigenetic inheritance and reproductive mode in plants and animals
Anastasiadi, D., Venney, C. J., Bernatchez, L., & Wellenreuther, M. (2021) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2021.08.006 · Cited by 162
The social brain meets the reactive genome: neuroscience, epigenetics and the new social biology
Meloni, M. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00309 · Cited by 169
Sarker, G., Sun, W., Rosenkranz, D., Pelczar, P., Opitz, L., Efthymiou, V., Wolfrum, C., & Peleg‐Raibstein, D. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820810116 · Cited by 163
Schiele, M. A., Gottschalk, M. G., & Domschke, K. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101830 · Cited by 156
Heim, C. M., Entringer, S., & Buss, C. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.12.011 · Cited by 158
“Animal data support the possibility of inter-and trans-generational transmission of ELS-induced behavioral traits mediated by epigenetic modifications through the paternal germ line (Franklin et al., 2010; Gapp et al., 2014; Pang et al., 2017; Rodgers et al., 2015; Zhang et al., 2018).”
BackgroundNorouzitallab, P., Baruah, K., Vandegehuchte, M., Stappen, G. V., Catania, F., Bussche, J. V., Vanhaecke, L., Sorgeloos, P., & Bossier, P. (2014) · The FASEB Journal · doi:10.1096/fj.14-252049 · Cited by 167
Epigenetics for behavioral ecologists
Ledón‐Rettig, C. C., Richards, C. L., & Martin, L. B. (2012) · Behavioral Ecology · doi:10.1093/beheco/ars145 · Cited by 160
Kubota, T., Miyake, K., & Hirasawa, T. (2012) · Clinical Epigenetics · doi:10.1186/1868-7083-4-1 · Cited by 157
“Recent research on animals has shown that behavioral characteristics can be inherited [60].”
BackgroundPaternal Influences on Offspring Development: Behavioural and Epigenetic Pathways
Braun, K., & Champagne, F. A. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12174 · Cited by 157
Nätt, D., Rubin, C., Wright, D., Johnsson, M., Bélteky, J., Andersson, L., & Jensen, P. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-59 · Cited by 155
Peter, C. J., Fischer, L. K., Kundaković, M., Garg, P., Jakovcevski, M., Dincer, A., Amaral, A. C. S., Ginns, E. I., Galdzicka, M. M., Bryce, C. P., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.03.2100 · Cited by 158
“N: 0006-3223 Biologica SEE COMMENTARY exist in the offspring of a parent exposed to malnutrition in infancy, similar to the multigenerational transmission of DNA methylation signatures after maternal separation stress in postnatal mice (8,9).”
BackgroundBekdash, R. A., Zhang, C., & Sarkar, D. K. (2013) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12082 · Cited by 159
Benito, E., Kerimoglu, C., Ramachandran, B., Pena‐Centeno, T., Jain, G., Stilling, R. M., Islam, R., Capece, V., Zhou, Q., Edbauer, D., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.059 · Cited by 159
Timescales of Human Adaptation: The Role of Epigenetic Processes
Kuzawa, C. W., & Thayer, Z. M. (2011) · Epigenomics · doi:10.2217/epi.11.11 · Cited by 151
O’Dea, R. E., Noble, D. W. A., Johnson, S. L., Hesselson, D., & Nakagawa, S. (2016) · Current Zoology · doi:10.1093/eep/dvv014 · Cited by 156
Northstone, K., Golding, J., Smith, G. D., Miller, L. L., & Pembrey, M. E. (2014) · European Journal of Human Genetics · doi:10.1038/ejhg.2014.31 · Cited by 158
Development and the epigenome: the ‘synapse’ of gene–environment interplay
Boyce, W. T., & Kobor, M. S. (2014) · Developmental Science · doi:10.1111/desc.12282 · Cited by 160
Karatekin, C., & Ahluwalia, R. (2016) · Journal of Interpersonal Violence · doi:10.1177/0886260516681880 · Cited by 191
“…& Hartwick, 2012; Bartlett & Easterbrooks, 2012; Kim, 2009; Marshall, Huang, & Ryan, 2011; Widom, Czaja, & DuMont, 2015) and biological level through epigenetic transmission of stressful experiences (Franklin et al., 2010; Neigh, Gillespie, & Nemeroff, 2009; Roth, Lubin, Funk, & Sweatt, 2009).”
Background
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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