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

• Published in: Epigenetics Vol. 3; no. 2; pp. 97 - 106
• Main Authors: Oberlander, Tim F., Weinberg, Joanne, Papsdorf, Michael, Grunau, Ruth, Misri, Shaila, Devlin, Angela M.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.03.2008
• Subjects: Adult; Antidepressive Agents, Second-Generation - therapeutic use; Base Sequence; Binding; Biology; Bioscience; Calcium; Cancer; Cell; CpG Islands; Cycle; Depression - drug therapy; Depression - genetics; DNA Methylation; Exons; Female; Fetal Blood - cytology; Fetal Blood - metabolism; Humans; Hydrocortisone - metabolism; Hypothalamo-Hypophyseal System; Infant; Landes; Leukocytes, Mononuclear - metabolism; Molecular Sequence Data; Mothers - psychology; Organogenesis; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications - genetics; Promoter Regions, Genetic; Proteins; Receptors, Glucocorticoid - genetics; Serotonin Uptake Inhibitors - therapeutic use
• ISSN: 1559-2294; 1559-2308
• DOI: 10.4161/epi.3.2.6034

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.