Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: A meta-analysis
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Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.
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There is consistent evidence for a link between pregnancy stress (including perceived stress, anxiety, depression, and natural disasters) and increased DNA methylation of NR3C1 in newborns.
“There is now consistent evidence for a link between pregnancy stress (including perceived stress, anxiety, depression, and natural disasters) and increased DNA methylation of NR3C1 in newborns [55,56], even though the studies have been quite heterogeneous in terms of the type of exposure and tissue investigated (i.e., cord blood, peripheral blood, placenta, buccal swabs).”
From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [55]
The Results ('Eligibility of studies and specific CpG sites to be metaanalyzed'; page unavailable) report increased offspring NR3C1 methylation after prenatal stress, but the significant association is limited to CpG site 36, not the other sites tested. The studies pooled anxious-depressive symptoms and exposure to violence, not natural disasters; the Discussion also notes that one study assessed children rather than newborns. Thus the claim is broader than this paper's finding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNR3C1 has been linked to prenatal stress.
“Notwithstanding, NR3C1 has been linked to prenatal stress [140] and is the most studied gene to date related to abuse and neglect [141].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [140]
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- Authors
- Palma-Gudiel, H., Córdova-Palomera, A., Eixarch, E., Deuschle, M., & Fañanás, L.
- Affiliations
- Hospital Sant Joan de Déu Barcelona (ES)
- University of Mannheim (DE)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Corresponding author
- Fañanás, L
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2015-09
- Volume
- 10
- Issue
- 10
- Pages
- 893-902
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC4844196
- OpenAlex
- W1851806939
- Cited by
- 240
- References
- 65
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 22 · 2023: 29 · 2022: 18 · 2021: 21 · 2020: 25 · 2019: 22 · 2018: 30 · 2017: 27 · 2016: 12
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epigenetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universitat Pompeu Fabra
- University of Reading
- Generalitat de Catalunya (2014SGR1636)
- Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya
- Ministerio de Ciencia e Innovación (PIM2010ERN-00642, SAF2008-05674-C03-01)
- Centro de Investigación Biomédica en Red de Salud Mental
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- prenatal stress, maternal psychosocial stress, glucocorticoid receptor, NR3C1, DNA methylation, promoter methylation, CpG sites, developmental programming, hypothalamic-pituitary-adrenal axis, pregnancy
- MeSH terms
- Female, Humans, Male, Pituitary-Adrenal System, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Receptors, Glucocorticoid, Stress, Psychological, CpG Islands, DNA Methylation, Epigenesis, Genetic
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