The early caregiving environment can have lasting effects on child mental health. Animal models suggest that glucocorticoid receptor gene (NR3C1) DNA methylation plays a mediating role in linking more responsive caregiving to improved behavioral outcomes by its impact on the stress regulatory system. In this longitudinal study, we examined whether children’s NR3C1 methylation levels mediate an effect of maternal sensitivity in infancy on levels of child internalizing and externalizing behavior in a community sample. Maternal sensitivity of 145 mothers was rated at infant age 5 weeks, 12 months, and 30 months by observing mother–infant interactions. Buccal DNA methylation was assessed in the same children at age 6 years and maternal-reported internalizing and externalizing behavior was assessed at age 6 and 10 years. Higher sensitivity at age 5 weeks significantly predicted lower DNA methylation levels at two NR3C1 CpG loci, although methylation levels at these loci did not mediate an effect of maternal sensitivity on levels of child internalizing and externalizing behavior. Overall, the study provides evidence that maternal sensitivity in early infancy is associated with DNA methylation levels at loci involved in stress regulation, but the significance of this finding for child mental health remains unclear.

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).

Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.

Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.