Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

TLDR

Animal studies show that variations in early maternal care alter offspring HPA stress responses through epigenetic regulation of the glucocorticoid receptor gene. This study examined whether prenatal maternal mood influences methylation of the human GR gene (NR3C1) in newborns and predicts HPA reactivity at three months. Cord blood mononuclear cells from infants of depressed mothers (treated or untreated) and non‑depressed controls were analyzed by bisulfite pyrosequencing for NR3C1 exon 1F methylation, and infant HPA function was assessed at 3 months via salivary cortisol before and after a non‑noxious stressor and at a late‑afternoon baseline. Higher maternal depression/anxiety in late pregnancy increased NR3C1 methylation at an NGFI‑A binding site, which in turn was associated with elevated cortisol stress responses at 3 months, independent of SRI exposure and maternal mood.

Abstract

Background: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal (HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. Objective: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age 3 months were examined. Methods: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n=33), infants of depressed non treated mothers (n=13) and infants of non depressed/non treated mothers (n=36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at 3 months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. Results: Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age, and pre and postnatal maternal mood. Conclusions: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.