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Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy
Open accessAbstract
Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPARα (peroxisome proliferator-activated receptor α), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3α (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.
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“exposure to chronic stress in utero increased male, but not female, HPA stress reactivity (e.g., behavioral response to the tail suspension test) 159,162”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [159]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“early gestational stress exposure led to sex differences in expression and methylation of genes in the placenta associated with growth and nutrient transport 159”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [159]
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“prenatal stress has different effects in male vs. female offspring 143,159-161”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [159]
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“Among mice exposed to stress during early, mid and late gestation, male F1 with early gestation prenatal stress exposure demonstrated behavioral indicators of stress responsivity and anhedonia, as well as alterations in GR and corticotrophin-releasing factor (CRF) expression and increased HPA axis responsivity, with corresponding alteration in CRF and nr3c1 gene methylation 159”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [159]
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“These behaviors were transmitted to the next generation through the male germ line.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [159]
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Citations
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
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
The tail suspension test: A new method for screening antidepressants in mice
Steru, L., Chermat, R., Thierry, B., & Simon, P. (1985) · Psychopharmacology · doi:10.1007/bf00428203 · Cited by 3,534
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217
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
CRF and CRF receptors: role in stress responsivity and other behaviors
Bale, T. L., & Vale, W. W. (2004) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121410 · Cited by 1,270
Self-citationA targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei
Leonhardt, H., Page, A. W., Weier, H.-U., & Bestor, T. H. (1992) · Cell · doi:10.1016/0092-8674(92)90561-p · Cited by 1,050
Bale, T. L., Contarino, A., Smith, G. W., Chan, R. K. W., Gold, L. H., Sawchenko, P. E., Koob, G. F., Vale, W. W., & Lee, K. (2000) · Nature Genetics · doi:10.1038/74263 · Cited by 850
Self-citationLucki, I. (1997) · Behavioural Pharmacology · doi:10.1097/00008877-199711000-00010 · Cited by 803
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“In rodents exposed to prenatal stress or multihit early adversity combining prenatal and postnatal stress, males showed greater emotional vulnerability and alterations of gut microbiota than females [25,26].”
BackgroundMechanisms of brain glucocorticoid resistance in stress-induced psychopathologies
Merkulov, V. M., Merkulova, T. I., & Bondar, N. P. (2017) · Biochemistry (Moscow) · doi:10.1134/s0006297917030142 · Cited by 65
The neurobiological effects of stress as contributors to psychiatric disorders: focus on epigenetics
Provencal, N., & Binder, E. B. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.007 · Cited by 64
Monteleone, M. C., Adrover, E., Pallarés, M. E., Antonelli, M. C., Frasch, A. C., & Brocco, M. A. (2014) · Epigenetics · doi:10.4161/epi.25925 · Cited by 64
El Marroun, H., Tiemeier, H., Muetzel, R. L., Thijssen, S., van der Knaap, N. J. F., Jaddoe, V. W. V., Fernández, G., Verhulst, F. C., & White, T. J. H. (2016) · Depression and Anxiety · doi:10.1002/da.22524 · Cited by 62
Yeshurun, S., Short, A. K., Bredy, T. W., Pang, T. Y., & Hannan, A. J. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.11.013 · Cited by 60
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Conradt, E., Adkins, D. E., Crowell, S. E., Raby, K. L., Diamond, L. M., & Ellis, B. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000469 · Cited by 60
Prenatal and postnatal maternal anxiety and amygdala structure and function in young children
Donnici, C., Long, X., Dewey, D., Letourneau, N., Landman, B., Huo, Y., & Lebel, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-83249-2 · Cited by 54
Neuroactive steroids and stress axis regulation: Pregnancy and beyond
Brunton, P. J. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.08.003 · Cited by 48
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Blaze, J., & Roth, T. L. (2017) · Development and Psychopathology · doi:10.1017/s0954579417000128 · Cited by 48
Allard, M., Bergeron, J. D., Baharnoori, M., Srivastava, L. K., Fortier, L., Poyart, C., & Sébire, G. (2017) · Autism Research · doi:10.1002/aur.1647 · Cited by 48
Udo, I. E., Sharps, P., Bronner, Y., & Hossain, M. B. (2016) · Maternal and Child Health Journal · doi:10.1007/s10995-016-1940-1 · Cited by 46
Sarker, G., Berrens, R., von Arx, J., Pelczar, P., Reik, W., Wolfrum, C., & Peleg-Raibstein, D. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0243-2 · Cited by 45
Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria
Silkaitis, K., & Lemos, B. (2014) · Biology of Sex Differences · doi:10.1186/2042-6410-5-2 · Cited by 39
“Male offspring exposed to early prenatal stress (E-PS) displayed behavioral changes and depressive-like phenotype as adults [109].”
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Raposo-Lima, C., & Morgado, P. (2020) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000274 · Cited by 37
Schmidt, M., Lax, E., Zhou, R., Cheishvili, D., Ruder, A. M., Ludiro, A., Lapert, F., Macedo da Cruz, A., Sandrini, P., Calzoni, T., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0348-7 · Cited by 37
Transcriptional regulation of corticotropin-releasing hormone gene in stress response
Zhou, J.-N., & Fang, H. (2018) · IBRO Reports · doi:10.1016/j.ibror.2018.08.003 · Cited by 36
Ambeskovic, 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
Prenatal transportation stress alters genome-wide DNA methylation in suckling Brahman bull calves1,2
Littlejohn, B. P., Price, D. M., Neuendorff, D. A., Carroll, J. A., Vann, R. C., Riggs, P. K., Riley, D. G., Long, C. R., Welsh, T. H., & Randel, R. D. (2018) · Journal of Animal Science · doi:10.1093/jas/sky350 · Cited by 31
Peffer, M. E., Zhang, J. Y., Umfrey, L., Rudine, A. C., Monaghan, A. P., & DeFranco, D. B. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1042 · Cited by 30
Cutuli, D., Berretta, E., Caporali, P., Sampedro-Piquero, P., De Bartolo, P., Laricchiuta, D., Gelfo, F., Pesoli, M., Foti, F., Farioli Vecchioli, S., et al. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.02.015 · Cited by 30
Boschen, K. E., Keller, S. M., Roth, T. L., & Klintsova, A. Y. (2018) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2017.12.009 · Cited by 24
Perinatal stress and methylation of the NR3C1 gene in newborns: systematic review
Chalfun, G., Reis, M. M., de Oliveira, M. B. G., de Araújo Brasil, A., dos Santos Salú, M., da Cunha, A. J. L. A., Prata-Barbosa, A., & de Magalhães-Barbosa, M. C. (2022) · Epigenetics · doi:10.1080/15592294.2021.1980691 · Cited by 22
NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors
Vukojevic, V., Coynel, D., Ghaffari, N. R., Freytag, V., Elbert, T., Kolassa, I.-T., Wilker, S., McGaugh, J. L., Papassotiropoulos, A., & de Quervain, D. J.-F. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008415117 · Cited by 19
Sex Differences in Anxiety and Depression: What Can (and Cannot) Preclinical Studies Tell Us?
Mir, F. R., & Rivarola, M. A. (2022) · Sexes · doi:10.3390/sexes3010012 · Cited by 14
Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders
Tahira, A. C., Barbosa, A. R., Feltrin, A. S., Gastaldi, V. D., de Toledo, V. H. C., de Carvalho Pereira, J. G., Lisboa, B. C. G., de Souza Reis, V. N., dos Santos, A. C. F., Maschietto, M., et al. (2019) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32704 · Cited by 11
Metadata
- Authors
- Mueller, B. R., & Bale, T. L.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Bale, Tracy L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-09-03
- Volume
- 28
- Issue
- 36
- Pages
- 9055-9065
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2731562
- OpenAlex
- W1994740828
- Cited by
- 988
- References
- 52
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 30 · 2023: 36 · 2022: 42 · 2021: 53 · 2020: 63 · 2019: 60 · 2018: 72 · 2017: 73 · 2016: 70 · 2015: 89 · 2014: 85 · 2013: 56 · 2012: 70
- FWCI
- 21.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- University of Pennsylvania
- National Institutes of Health (5t32mh017168-34)
- National Institute of Mental Health (T32 MH-017168)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- prenatal stress, sex differences, anhedonia, corticotropin-releasing factor, glucocorticoid receptor, hypothalamic-pituitary-adrenal axis, DNA methylation, epigenetic programming, placenta, PPARα, IGFBP-1, GLUT4, neurodevelopmental disorders, autism spectrum disorder, schizophrenia, pregnancy timing
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Behavior, Animal, Corticotropin-Releasing Hormone, Emotions, Exploratory Behavior, Female, Food Preferences, Hypothalamo-Hypophyseal System, Male, Mice, Inbred C57BL, Pituitary-Adrenal System, Placenta, Pregnancy, Prenatal Exposure Delayed Effects, Raphe Nuclei, Receptors, Glucocorticoid, Sex Characteristics, Stress, Physiological, Sucrose, Swimming, Tryptophan Hydroxylase, Hindlimb Suspension, Receptor, Serotonin, 5-HT1A, Serotonin Plasma Membrane Transport Proteins, Mice
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