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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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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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