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

Epigenetics. Mar-Apr 2008;3(2):97-106. doi: 10.4161/epi.3.2.6034.

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 three months were examined.

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.

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 nontreated 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 three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Second-Generation / therapeutic use
  • Base Sequence
  • CpG Islands
  • DNA Methylation*
  • Depression / drug therapy
  • Depression / genetics*
  • Exons
  • Female
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Humans
  • Hydrocortisone / metabolism*
  • Hypothalamo-Hypophyseal System
  • Infant
  • Leukocytes, Mononuclear / metabolism
  • Molecular Sequence Data
  • Mothers / psychology*
  • Pituitary-Adrenal System
  • Pregnancy
  • Pregnancy Complications / genetics*
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / genetics*
  • Serotonin Uptake Inhibitors / therapeutic use

Substances

  • Antidepressive Agents, Second-Generation
  • NR3C1 protein, human
  • Receptors, Glucocorticoid
  • Serotonin Uptake Inhibitors
  • Hydrocortisone