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Epigenetics. 2015;10(10):893-902. doi: 10.1080/15592294.2015.1088630.

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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a Anthropology Unit; Department of Animal Biology, Faculty of Biology; and Instituto de Biomedicina (IBUB); Universidad de Barcelona (UB) ; Barcelona , Spain.
b Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) ; Madrid , Spain.
c Fetal i+D Fetal Medicine Research Center; BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine; Hospital Clínic and Hospital Sant Joan de Deu; IDIBAPS; University of Barcelona ; Barcelona , Spain.
d Centre for Biomedical Research on Rare Diseases (CIBER-ER) ; Madrid , Spain.
e Central Institute of Mental Health; Faculty of Medicine Mannheim; University of Heidelberg ; Heidelberg , Germany.


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.


DNA methylation; HPA axis; NR3C1 gene; epigenetics; glucocorticoid receptor; maternal stress

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