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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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Parents' childhood socioeconomic circumstances are associated with their children's asthma outcomes
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Zhang, Z., Li, N., Chen, R., Lee, T., Gao, Y.-X., Yuan, Z., Nie, Y., & Sun, T. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100333 · Cited by 51
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Epigenetic Mechanisms Involved in Huntington's Disease Pathogenesis
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Epigenetic Changes Associated with Different Types of Stressors and Suicide
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Chokroborty-Hoque, A., Alberry, B., & Singh, S. M. (2014) · Frontiers in Pediatrics · doi:10.3389/fped.2014.00090 · Cited by 52
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Cocaine triggers epigenetic alterations in the corticostriatal circuit
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Bayles, R., Baker, E. K., Jowett, J. B. M., Barton, D., Esler, M., El‐Osta, A., & Lambert, G. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083223 · Cited by 43
“However, while the magnitude of differences in methylation in this study may be considered small, methylation changes of a similar scale in the hypomethylated promoters of three stress-related genes in mice have been associated with significant changes in gene expression [27].”
BackgroundExploring epiallele stability in a population-epigenetic model
Geoghegan, J. L., & Spencer, H. G. (2012) · Theoretical Population Biology · doi:10.1016/j.tpb.2012.09.001 · Cited by 42
“Additionally, the degree to which DNA is methylated appears to be directly proportional to the level of gene transcription inhibition and is therefore highly correlated with the phenotype of an individual (Franklin et al., 2010; Waterland et al., 2007).”
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Yeshurun, S., Rogers, J., Short, A. K., Renoir, T., Pang, T. Y., & Hannan, A. J. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.05.014 · Cited by 43
“Furthermore, maternal separation combined with unpredictable stress (MSUS) transgenerationally modified offspring affective behavior (Franklin et al., 2010) and social behavior (Franklin et al., 2011), possibly via small noncoding RNA (sncRNA) changes in the sperm (Gapp et al., 2014).”
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“While previous studies focused on stress in the F1 generation and its transgenerational effects (Franklin et al., 2010; Yao et al., 2014), there has been little investigation of the effects of recurrent, multigenerational prenatal stress (MPS) resembling a population living in a continuously…”
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“Moreover, CRF-related epigenetic modifications induced by maternal separation are found in first and second generation male and female offspring (Franklin et al., 2010).”
BackgroundEpigenetics in the Neoliberal “Regime of Truth”
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“Rodents’ exposure to various traumatic events early in life, such as early separation from their mothers or certain forms of abuse, have led to persistent effects on the epigenome of the rodents.(14) This evidence suggests a significant influence of family environment on epigenetic programming and health.”
Environmental Alterations of Epigenetics Prior to the Birth
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“Another study looked at early life stress and its transmissible impacts and provided evidence that stress-induced epigenetic memory is retainable across generations (Franklin et al., 2010).”
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“These can affect offspring of both sexes (Carone et al., 2010), solely/predominantly females (Ng et al., 2010), or solely/predominantly males (Drake and Walker, 2004; Franklin et al., 2010).”
BackgroundEffect of Early Life Stress on the Epigenetic Profiles in Depression
Li, M., Fu, X., Xie, W., Guo, W., Li, B., Cui, R., & Yang, W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00867 · Cited by 41
“Moreover, subtypes of ELS, gender, exposed timing, and duration matter in the role of ELS in depression (Cecil et al., 2016; McCoy et al., 2016; Frodl et al., 2017; Reus et al., 2017).”
BackgroundThe body keeps the score: The neurobiological profile of traumatized adolescents
Laricchiuta, D., Panuccio, A., Picerni, E., Biondo, D., Genovesi, B., & Petrosini, L. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105033 · Cited by 51
The epigenetics of animal personality
van Oers, K., van den Heuvel, K., & Sepers, B. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105194 · Cited by 41
DNA Methylation as a Mechanism of Nutritional Plasticity: Limited Support From Horned Beetles
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“For instance, methylation is, among other epigenetic modifications, thought to be important in the development of metabolic syndromes and other mechanisms by which organisms anticipate future nutritional environments (Gluckman et al., 2009; Li et al., 2010).”
Casier, K., Boivin, A., Carré, C., & Teysset, L. (2019) · Cells · doi:10.3390/cells8091108 · Cited by 37
“Maternal separation Mouse/Sperm, brain DNA methylation [41] Fear conditioning Mouse/Sperm DNA methylation [42]”
BackgroundDNA methylation from germline cells in veterans with PTSD
Mehta, D., Pelzer, E. S., Bruenig, D., Lawford, B., McLeay, S., Morris, C. P., Gibson, J. N., Young, R. M., Voisey, J., McLeay, S., et al. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.06.001 · Cited by 37
Dias, B. G., & Ressler, K. J. (2014) · BioEssays · doi:10.1002/bies.201400105 · Cited by 37
Memory and Self–Neuroscientific Landscapes
Markowitsch, H. J. (2013) · ISRN Neuroscience · doi:10.1155/2013/176027 · Cited by 43
“Recently, we have, however, accumulating evidence for major interplays between genetics and learning: the new field of “epigenetics” [73–78] refers to heritable changes in gene expression which do not change the DNA sequence, but still may be transmittable transgenerationally [79, 80].”
BackgroundDon't worry; be informed about the epigenetics of anxiety
Nieto, S. J., Patriquin, M. A., Nielsen, D. A., & Kosten, T. A. (2016) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2016.05.006 · Cited by 42
“The sperm of these males have increased DNA methylation in MeCP2 and decreased DNA methylation of Crfr2 (Franklin et al., 2010) and these epigenetic changes are also found in the sperm and cortex of their offspring (Franklin et al.”
BackgroundMitchell, E. J., Klein, S. L., Argyropoulos, K. V., Sharma, A., Chan, R., Toth, J. G., Barboza, L., Bavley, C. C., Bortolozzi, A. A., Chen, Q., et al. (2016) · Nature Communications · doi:10.1038/ncomms11492 · Cited by 38
Kubota, T. (2016) · Current Zoology · doi:10.1093/eep/dvw017 · Cited by 40
Maternal Separation and the Risk of Drug Abuse in Later Life.
Delavari, F., Sheibani, V., Esmaeili‐Mahani, S., & Nakhaee, N. (2016) · PubMed · Cited by 40
Non-genetic inheritance via the male germline in mammals
Baxter, F., & Drake, A. J. (2019) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2018.0118 · Cited by 41
The Role of Stress in Obsessive-Compulsive Disorder: A Narrative Review
Raposo-Lima, C., & Morgado, P. (2020) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000274 · Cited by 37
Hill, K. T., Warren, M. R., & Roth, T. L. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.001 · Cited by 38
Ancestral experience as a game changer in stress vulnerability and disease outcomes
Metz, G. A. S., Ng, J. W. Y., Kovalchuk, I., & Olson, D. M. (2015) · BioEssays · doi:10.1002/bies.201400217 · Cited by 36
“Other studies revealed that the consequences of adverse early experiences can propagate across two generations of themale lineage to affect the risk of anxietylike and depression-like behaviors [15, 36].”
BackgroundThe emerging role of RNA in the regulation of gene transcription in human cells
Morris, K. V. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.02.017 · Cited by 38
Adding ‘epi-’ to behaviour genetics: implications for animal domestication
Jensen, P. (2015) · Journal of Experimental Biology · doi:10.1242/jeb.106799 · Cited by 40
“In mice, early maternal separation has been found to change the DNA methylation profile in the sperm of affected males (Franklin et al., 2010).”
BackgroundXu, X., Weber, D. N., Burge, R., & VanAmberg, K. (2015) · NeuroToxicology · doi:10.1016/j.neuro.2015.12.009 · Cited by 38
Zaidan, H., Ramaswami, G., Golumbic, Y. N., Sher, N., Malik, A., Barak, M., Galiani, D., Dekel, N., Li, J. B., & Gaisler‐Salomon, I. (2018) · BMC Genomics · doi:10.1186/s12864-017-4409-8 · Cited by 39
Epigenetic Mechanisms of Paternal Stress in Offspring Development and Diseases
Xu, X., Miao, Z., Sun, M., & Wan, B. (2021) · International Journal of Genomics · doi:10.1155/2021/6632719 · Cited by 39
(Epi)Genetic Mechanisms Underlying the Evolutionary Success of Eusocial Insects
Sieber, K. R., Dorman, T., Newell, N., & Yan, H. (2021) · Insects · doi:10.3390/insects12060498 · Cited by 38
Morin, E. L., Howell, B. R., Feczko, E., Earl, E., Pincus, M., Reding, K., Kovacs-Balint, Z. A., Meyer, J. S., Styner, M., Fair, D., et al. (2020) · Development and Psychopathology · doi:10.1017/s0954579420001133 · Cited by 37
Inheritance of environment-induced phenotypic changes through epigenetic mechanisms
Tando, Y., & Matsui, Y. (2023) · Current Zoology · doi:10.1093/eep/dvad008 · Cited by 40
“…expression of several micro RNAs (miRNAs) in F1 sperm and in F2 serum and hippocampus, but not in F2 sperm, although F3 mice also show similar abnormal behaviors as F1 and F2 mice [64], suggesting that the MSUS-induced changes of miRNAs in F1 may be converted to other epigenetic marks in F3 mice.”
BackgroundReversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress
Aoued, H. S., Sannigrahi, S., Doshi, N. K., Morrison, F. G., Linsenbaum, H., Hunter, S. C., Walum, H., Baman, J., Yao, B., Jin, P., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.07.028 · Cited by 38
Gapp, K., Parada, G. E., Groß, F., Corcoba, A., Kaur, J., Grau, E., Hemberg, M., Bohacek, J., & Miska, E. A. (2021) · iScience · doi:10.1016/j.isci.2021.102870 · Cited by 34
Lack of Social Support Raises Stress Vulnerability in Rats with a History of Ancestral Stress
Faraji, J., Soltanpour, N., Lotfi, H., Moeeini, R., Moharreri, A., Roudaki, S., Hosseini, S. A., Olson, D. M., Abdollahi, A. A., Soltanpour, N., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-05440-8 · Cited by 36
Hao, G., Youssef, N. A., Davis, C. L., & Su, S. (2017) · International Journal of Cardiology · doi:10.1016/j.ijcard.2017.12.063 · Cited by 37
“[4] For example, mice that were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14 showed differential methylation in several candidate genes.[5] Subsequent studies in humans also identified differential methylation of NR3C1 gene promoter not only in postmortem hippocampal tissue among…”
BackgroundAmbeskovic, M., Babenko, O., Ilnytskyy, Y., Kovalchuk, I., Kolb, B., & Metz, G. A. S. (2019) · Scientific Reports · doi:10.1038/s41598-019-42691-z · Cited by 36
Nestler, E. J. (2011) · Scientific American · doi:10.1038/scientificamerican1211-76 · Cited by 36
Epigenetic plasticity following early stress predicts long‐term health outcomes in rhesus macaques
Kinnally, E. L. (2014) · American Journal of Physical Anthropology · doi:10.1002/ajpa.22565 · Cited by 36
Przybycien–Szymanska, M. M., Rao, Y. S., Prins, S. A., & Pak, T. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089320 · Cited by 38
“[1,4,5,6,50,51,52] and alcohol is both a drug of abuse and a physiological stressor, since it potently activates the hypothalamopituitary adrenal (HPA) axis [14,15,18,53].”
BackgroundEnvironmental risk factors for autism spectrum disorders
Liu, L., Zhang, D. X., Rodzinka-pasko, J. K., & Li, Y. (2016) · Der Nervenarzt · doi:10.1007/s00115-016-0172-3 · Cited by 39
Epigenetic Programming Effects of Early Life Stress: A Dual-Activation Hypothesis
Lux, V. (2018) · Current Genomics · doi:10.2174/1389202919666180307151358 · Cited by 40
“report, among other epigenetic modifications, an increase of Mecp2 DNA methylation and a decrease of mRNA expression in the cortex of the offspring of mice exposed to a maternal separation and maternal stress paradigm [28].”
BackgroundThe Epigenetics of Early Life Adversity: Current Limitations and Possible Solutions
Barnett-Burns, S., Almeida, D. M., & Turecki, G. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2018.01.008 · Cited by 35
Tomasi, J., Lisoway, A. J., Zai, C. C. H., Harripaul, R., Müller, D. J., Zai, G. C., McCabe, R. E., Richter, M. A., Kennedy, J. L., & Tiwari, A. K. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.09.002 · Cited by 36
Lux, V., Non, A. L., Pexman, P. M., Stadler, W., Weber, L. A. E., & Krüger, M. (2021) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2021.672740 · Cited by 45
“Here, one line of research focuses on epigenetic modifications as relatively stable intermediate level, coordinating genetic constitution, and environmental signals, as indicated by animal studies (Weaver et al., 2004; Murgatroyd et al., 2009; Franklin et al., 2010).”
BackgroundKim, S., Deng, Q., Fleisher, B. M., & Li, S. (2013) · World Development · doi:10.1016/j.worlddev.2013.08.007 · Cited by 40
“Second-generation outcomes examined include birth weight, height, cardiovascular diseases, test scores, and other markers (Currie & Moretti, 2007; Drake & Walker, 2004; Drake et al., 2005; Emanuel, Kimpo, & Moceri, 2004; Franklin et al., 2010; Pembrey, 2010).”
The epigenome and postnatal environmental influences in psychotic disorders
Pishva, E., Kenis, G., van den Hove, D., Lesch, K., Boks, M. P., van Os, J., & Rutten, B. P. F. (2014) · Social Psychiatry and Psychiatric Epidemiology · doi:10.1007/s00127-014-0831-2 · Cited by 36
“This field has re-opened the Lamarckian concept of heritability of acquired traits and has received significant attention, particularly because rodent studies have provided suggestive evidence that the dramatic impact of maternal separation was persistent in some of the abnormal behaviors and in methylation changes ac…”
BackgroundUnderstanding the epigenetics of neurodevelopmental disorders and DOHaD
Kubota, T., Miyake, K., Hariya, N., & Mochizuki, K. (2015) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174415000057 · Cited by 35
“In other words, chronic maternal separation altered behaviors and DNA methylation of the promoter of several genes in the germline of maternally separated mice; the altered epigenetic changes were then observed in the brains of the offspring along with altered gene expression, including decreases in the expression of…”
BackgroundInfluential
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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