Prenatal exposure to maternal depression, neonatal methylation of  human glucocorticoid receptor gene (NR3C1) and infant cortisol stress  responses.
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.
Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. toberlander@cw.bc.ca
Tim F
TF
Oberlander
Joanne
J
Weinberg
Michael
M
Papsdorf
Ruth
R
Grunau
Shaila
S
Misri
Angela M
AM
Devlin
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D003863:Depression / Q000188:drug therapy / Q000235:genetics*; D005091:Exons; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008969:Molecular Sequence Data; D009035:Mothers / Q000523:psychology*; D010913:Pituitary-Adrenal System; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D018687:Antidepressive Agents, Second-Generation; D006854:Hydrocortisone; D011965:Receptors, Glucocorticoid; D017367:Selective Serotonin Reuptake Inhibitors; C497713:NR3C1 protein, human