Abstract
Antenatal synthetic glucocorticoid (sGC) treatment is a potent modifier of the hypothalamic-pituitary-adrenal (HPA) axis. In this context, epigenetic modifications are discussed as potential regulators explaining how prenatal exposure to GCs might translate into persistent changes of HPA axis “functioning”. The purpose of this study was to investigate whether DNA methylation and gene expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) may mediate the persistent effects of sGC on cortisol stress reactivity that have been previously observed. In addition, hair cortisol concentrations (hairC) were investigated as a valid biomarker of long-term HPA axis activity. This cross-sectional study comprised 108 term-born children and adolescents, including individuals with antenatal GC treatment and controls. From whole blood, DNA methylation was analyzed by targeted deep bisulfite sequencing. Relative mRNA expression was determined by RT-qPCR experiments and qBase analysis. Acute stress reactivity was assessed by the Trier Social Stress Test (TSST) measuring salivary cortisol by ELISA and hairC concentrations were determined from hair samples by liquid chromatography coupled with tandem mass spectrometry. First, no differences in DNA methylation and mRNA expression levels of the stress-associated genes between individuals treated with antenatal sGC compared to controls were found. Second, DNA methylation and mRNA expression levels were neither associated with cortisol stress reactivity nor with hairC. These findings do not corroborate the belief that DNA methylation and mRNA expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) play a key mediating role of the persistent effects of sGC on HPA axis functioning.
Highlights
Prenatal maternal stress and exposure to antenatal synthetic glucocorticoids can have long-term consequences on major stress response systems and mental health [1, 2]
Following this line of research, the present study aimed to investigate whether DNA methylation (DNAM) profiles and respective changes in the gene expression of stress-related candidate genes (NR3C1, FK506 binding protein 5 (FKBP5), SLC6A4) mediate the persistent effects of synthetic glucocorticoids (sGC) on cortisol reactivity to a standardized laboratory stressor that have been observed previously by our group [4, 5] and others (e.g. Edelmann et al [27])
We had already shown that the pathophysiological pregnancy (PP)/GC group was characterized by higher cortisol levels in response to the Trier Social Stress Test (TSST) both during childhood [4] and late adolescence [5] as compared to controls, whereas no group differences were found with regard to hair cortisol concentrations (hairC) [33]
Summary
Prenatal maternal stress and exposure to antenatal synthetic glucocorticoids (sGC) can have long-term consequences on major stress response systems and mental health [1, 2]. Our group observed increased cortisol stress responses in sGC-treated term-born children compared with untreated controls [4] that persisted into late adolescence [5] Epigenetic modifications such as DNA methylation (DNAM) are discussed as a central mechanism explaining how in utero exposure to GCs might translate into persistent changes of HPA axis functioning [6, 7]. Given the pivotal role of glucocorticoid receptor (GR) signaling in negative feedback regulation of the HPA-axis, respective epigenetic changes may account for permanently altered glucocorticoid levels as it has been suggested by landmark rodent studies [12] Another candidate region constitutes the FK506 binding protein 5 (FKBP5) gene that acts as an important modulator of the HPA axis. FKBP5 provides an ultrashort negative feedback loop for GR signaling by reducing its cortisol binding affinity and impeding
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