Glucocorticoid receptor signaling in leukocytes after early life adversity

Abstract

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.

Targeted bisulfite sequencing: A novel tool for the assessment of DNA methylation with high sensitivity and increased coverage

“…For NR3C1, we present an assay to analyze DNA methylation of the promoter of exon 1F, most commonly investigated when differential DNA methylation of NR3C1 is of interest. As also observed by others (Elwenspoek et al, 2019;McGowan et al, 2009;Moser et al, 2007), the analyzed NR3C1 stretch was generally unmethylated, with mean DNA methylation values below 1 %. The statistical difference for NR3C1 we observed comparing individuals with BPD and controls has to be handled with caution.…”

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

“…However, results from mechanistic studies in our EpiPath cohort have excluded this. We were able to show that despite an altered HPA axis [25], glucocorticoid signaling and the peripheral HPA-axis stress system were not epigenetically programed [40], implying that the immune system was directly impacted.…”

Childhood Trauma Affects Stress-Related Interoceptive Accuracy

“…The experience of traumatic stress during childhood can permanently alter stress responses (4–8). Chronic activation of the hypothalamic pituitary–adrenocortical (HPA) axis and the sympathetic–adreno–medullary (SAM) axis causes prolonged secretion of stress hormones that induce dysregulation of these interdependent stress axes (9), resulting in adverse effects on psychological and physical health (10).…”