The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
The International Schizophrenia Consortium (2009) · Nature · doi:10.1038/nature08185 · Cited by 4,821
Depression: a new animal model sensitive to antidepressant treatments
PORSOLT, R. D., LE PICHON, M., & JALFRE, M. (1977) · Nature · doi:10.1038/266730a0 · Cited by 4,451
CpG Islands in vertebrate genomes
Gardiner‐Garden, M., & Frommer, M. (1987) · Journal of Molecular Biology · doi:10.1016/0022-2836(87)90689-9 · Cited by 3,417
DNA methylation and human disease
Robertson, K. D. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1655 · Cited by 2,864
Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility
Anway, M. D., Cupp, A. S., Uzumcu, M., & Skinner, M. K. (2005) · Science · doi:10.1126/science.1108190 · Cited by 2,563
Genomic DNA methylation: the mark and its mediators.
Klose, R. J., & Bird, A. P. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.12.008 · Cited by 2,501
Environmental epigenomics and disease susceptibility
Jirtle, R. L., & Skinner, M. K. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2045 · Cited by 2,492
Weber, M., Hellmann, I., Stadler, M. B., Ramos, L., Pääbo, S., Rebhan, M., & Schübeler, D. (2007) · Nature Genetics · doi:10.1038/ng1990 · Cited by 2,297
The link between childhood trauma and depression: insights from HPA axis studies in humans
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.03.008 · Cited by 1,704
Epigenetic inheritance at the agouti locus in the mouse
Morgan, H. D., Sutherland, H. G. E., Martin, D. I. K., & Whitelaw, E. (1999) · Nature Genetics · doi:10.1038/15490 · Cited by 1,476
Epigenetic regulation in psychiatric disorders
Tsankova, N., Renthal, W., Kumar, A., & Nestler, E. J. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2132 · Cited by 1,400
Lasting epigenetic influence of early-life adversity on the BDNF gene
Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.028 · Cited by 1,273
Maternal care, hippocampal synaptogenesis and cognitive development in rats
Liu, D., Diorio, J., Day, J. C., Francis, D. D., & Meaney, M. J. (2000) · Nature Neuroscience · doi:10.1038/77702 · Cited by 1,195
Dynamic DNA methylation programs persistent adverse effects of early-life stress
Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmühl, Y., Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, O. F. X., & Spengler, D. (2009) · Nature Neuroscience · doi:10.1038/nn.2436 · Cited by 1,162
Sex-specific, male-line transgenerational responses in humans
The ALSPAC Study Team, Pembrey, M. E., Bygren, L. O., Kaati, G., Edvinsson, S., Northstone, K., Sjöström, M., & Golding, J. (2006) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201538 · Cited by 1,150
The Dutch Famine and Its Long-Term Consequences for Adult Health
Roseboom, T., de Rooij, S., & Painter, R. (2006) · Early Human Development · doi:10.1016/j.earlhumdev.2006.07.001 · Cited by 1,137
SÁNCHEZ, M. M., LADD, C. O., & PLOTSKY, P. M. (2001) · Development and Psychopathology · doi:10.1017/s0954579401003029 · Cited by 1,003
Cyclical DNA methylation of a transcriptionally active promoter
Métivier, R., Gallais, R., Tiffoche, C., Péron, C. L., Jurkowska, R., Carmouche, R. P., Ibberson, D., Baráth, P., Demay, F., Reid, G., et al. (2008) · Nature · doi:10.1038/nature06544 · Cited by 942
DNA hypomethylation and human diseases
Wilson, A. S., Power, B. E., & Molloy, P. L. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2006.08.007 · Cited by 804
DNA methylation analysis by pyrosequencing
Tost, J., & Gut, I. G. (2007) · Nature Protocols · doi:10.1038/nprot.2007.314 · Cited by 681
Transgeneration memory of stress in plants
Molinier, J., Ries, G., Zipfel, C., & Höhn, B. (2006) · Nature · doi:10.1038/nature05022 · Cited by 675
Research and treatment approaches to depression
Wong, M.-L., & Licinio, J. (2001) · Nature Reviews Neuroscience · doi:10.1038/35072566 · Cited by 656
Rakyan, V. K., Chong, S., Blewitt, M. E., Cuthbert, P. C., Morgan, H. D., Luu, K. V. K., & Whitelaw, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0436776100 · Cited by 642
Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus
Levenson, J. M., Roth, T. L., Lubin, F. D., Miller, C. A., Huang, I.-C., Desai, P., Malone, L. M., & Sweatt, J. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511767200 · Cited by 628
Cryan, J. F., & Mombereau, C. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001457 · Cited by 616
5-HT1A receptor function in major depressive disorder
Savitz, J. B., Lucki, I., & Drevets, W. C. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.01.009 · Cited by 600
Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies
Urdinguio, R. G., Sanchez-Mut, J. V., & Esteller, M. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70262-5 · Cited by 598
Variations in maternal care in infancy regulate the development of stress reactivity
Caldji, C., Diorio, J. C., & Meaney, M. J. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(00)01084-2 · Cited by 588
DNA Methylation Analysis by Pyrosequencing
Busato, F., & Tost, J. (2014) · Springer eBooks · doi:10.1007/978-1-4614-6418-1_799-1 · Cited by 500
Pryce, C. R., Rüedi‐Bettschen, D., Dettling, A. C., Weston, A. A., Russig, H., Ferger, B., & Feldon, J. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.011 · Cited by 430
Self-citationMillstein, R. A., & Holmes, A. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.05.003 · Cited by 406
Stress, genes and the mechanism of programming the brain for later life
de Kloet, E. R., Sibug, R. M., Helmerhorst, F. M., & Schmidt, M. V. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.10.008 · Cited by 370
Epigenetic programming of stress responses through variations in maternal care
FISH, E. W., SHAHROKH, D., BAGOT, R., CALDJI, C., BREDY, T., SZYF, M., & MEANEY, M. J. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1330.011 · Cited by 361
Epigenomics: beyond CpG islands
Fazzari, M. J., & Greally, J. M. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1349 · Cited by 360
Sterba, S. K., Prinstein, M. J., & Cox, M. J. (2007) · Development and Psychopathology · doi:10.1017/s0954579407070174 · Cited by 316
Early life genetic, epigenetic and environmental factors shaping emotionality in rodents
Holmes, A., Guisquet, A. M. L., Vogel, E., Millstein, R. A., Leman, S., & Belzung, C. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.04.012 · Cited by 308
Understanding the potency of stressful early life experiences on brain and body function
McEwen, B. S. (2008) · Metabolism · doi:10.1016/j.metabol.2008.07.006 · Cited by 278
de Kloet, E. R. (2003) · PubMed · Cited by 256
Mammalian cytosine methylation at a glance
Ooi, S. K. T., O’Donnell‐Luria, A., & Bestor, T. H. (2009) · Journal of Cell Science · doi:10.1242/jcs.015123 · Cited by 249
Epigenetic inheritance in the mouse
Römer, I., Reik, W., Dean, W., & Klose, J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00124-2 · Cited by 248
Stress sensitivity and the development of affective disorders
Bale, T. L. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.033 · Cited by 243
Epigenetic germline inheritance
Chong, S., & Whitelaw, E. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.09.001 · Cited by 239
Griebel, G., Belzung, C., Misslin, R., & Vogel, E. (1993) · Behavioural Pharmacology · doi:10.1097/00008877-199312000-00009 · Cited by 239
Sex, trauma, stress hormones and depression
Young, E., & Korszun, A. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.94 · Cited by 235
McGill, B. E., Bundle, S. F., Yaylaoglu, M., Carson, J. P., Christina Thaller, B., & Zoghbi, H. Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608702103 · Cited by 233
Bifulco, A. T., Moran, P. M., Ball, C., Jacobs, C., Baines, R., Bunn, A., & Cavagin, J. (2002) · Journal of Child Psychology and Psychiatry · doi:10.1111/1469-7610.00234 · Cited by 196
Monoamine Oxidase Inhibitors:A Modern Guide to an Unrequited Class of Antidepressants
Stahl, S. M., & Felker, A. (2008) · CNS Spectrums · doi:10.1017/s1092852900016965 · Cited by 191
Nilsson, E. E., Anway, M. D., Stanfield, J., & Skinner, M. K. (2008) · Reproduction · doi:10.1530/rep-07-0542 · Cited by 190
Epigenetic Inheritance and the Intergenerational Transfer of Experience.
Harper, L. V. (2005) · Psychological Bulletin · doi:10.1037/0033-2909.131.3.340 · Cited by 178
Cameron, N. M., Shahrokh, D. K., Corpo, A. D., Dhir, S. K., Szyf, M., Champagne, F. A., & Meaney, M. J. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01725.x · Cited by 171
Bale, T. L., & Vale, W. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-12-05295.2003 · Cited by 169
Behavioural and Neurochemical Consequences of Early Weaning in Rodents
Kikusui, T., & Mori, Y. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01837.x · Cited by 158
Epigenetics in spermatogenesis
Trasler, J. M. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.12.018 · Cited by 150
Pelleymounter, M. A., Joppa, M. A., LING, N. C., & Foster, A. C. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.302.1.145 · Cited by 147
Gamete imprinting: setting epigenetic patterns for the next generation
Trasler, J. M. (2005) · Reproduction Fertility and Development · doi:10.1071/rd05118 · Cited by 128
Kim, H. K., Capaldi, D. M., Pears, K. C., Kerr, D., & Owen, L. D. (2009) · Criminal Behaviour and Mental Health · doi:10.1002/cbm.708 · Cited by 126
Godmann, M., Lambrot, R., & Kimmins, S. (2009) · Microscopy Research and Technique · doi:10.1002/jemt.20715 · Cited by 113
Pelleymounter, M. A., Joppa, M. A., Ling, N., & Foster, A. C. (2004) · Peptides · doi:10.1016/j.peptides.2004.01.008 · Cited by 110
Hinshaw, S. P. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1301.016 · Cited by 103
Marco, E. M., Adriani, W., Llorente, R., Laviola, G., & Viveros, M. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.03.008 · Cited by 97
DNA Methylation: Its Role in Cancer Development and Therapy
Kurkjian, C. D., Kummar, S., & Murgo, A. J. (2008) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2008.08.002 · Cited by 80
Evidence for Transgenerational Transmission of Epigenetic Tumor Susceptibility in Drosophila
Xing, Y., Shi, S., Le, L. X., Lee, C. A., Silver-Morse, L., & Li, W. X. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030151 · Cited by 80
Role of psychological trauma in the cause and treatment of anxiety and depressive disorders
Laugharne, J. D. E., Lillee, A., & Janča, A. (2009) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e3283345dc5 · Cited by 61
Sexual Dimorphism in Non-Mendelian Inheritance
Vigé, A., Gallou‐Kabani, C., & Junien, C. (2008) · Pediatric Research · doi:10.1203/pdr.0b013e318165b896 · Cited by 45
Mani, S. T., & Thakur, M. K. (2005) · Brain Research · doi:10.1016/j.brainres.2005.10.006 · Cited by 39
Risk factors for mental health: Translational models from behavioural neuroscience
Cirulli, F., Laviola, G., & Ricceri, L. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.01.006 · Cited by 24
Singh, K., & Prasad, S. (2008) · Biogerontology · doi:10.1007/s10522-008-9178-y · Cited by 18
Research works printed but not linked: 1
- Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci, 7, 847, 10.1038/nn1276 · DOI · Paper page
Cited by
Sorted by citations
Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice
Gapp, K., Jawaid, A., Sarkies, P., Bohacek, J., Pelczar, P., Prados, J., Farinelli, L., Miska, E., & Mansuy, I. M. (2014) · Nature Neuroscience · doi:10.1038/nn.3695 · Cited by 1,306
Self-citationParental olfactory experience influences behavior and neural structure in subsequent generations
Dias, B. G., & Ressler, K. J. (2014) · Nature Neuroscience · doi:10.1038/nn.3594 · Cited by 1,338
Modabbernia, A., Velthorst, E., & Reichenberg, A. (2017) · Molecular Autism · doi:10.1186/s13229-017-0121-4 · Cited by 809
“Assisted reproductive technology and maternal stress (due to immigration) have also been linked to epigenetic alterations [65, 66], although the importance of such association with respect to ASD is unknown.”
BackgroundRodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S., & Bale, T. L. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.0914-13.2013 · Cited by 814
Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation
Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., & Binder, E. B. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.005 · Cited by 782
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
