Effects of Antenatal Synthetic Glucocorticoid on Glucocorticoid Receptor Binding, DNA Methylation, and Genome-Wide mRNA Levels in the Fetal Male Hippocampus

Abstract

The endogenous glucocorticoid (GC) surge in late gestation plays a vital role in maturation of several organ systems. For this reason, pregnant women at risk of preterm labor are administered synthetic glucocorticoids (sGCs) to promote fetal lung development. Animal studies have shown that fetal sGC exposure can cause life-long changes in endocrine and metabolic function. We have previously shown that antenatal sGC treatment is associated with alterations in global DNA methylation and modifications to the hippocampal methylome and acetylome. In this study, we hypothesized that: 1) there are changes in the transcriptional landscape of the fetal hippocampus in late gestation, associated with the endogenous cortisol surge; 2) fetal sGC exposure alters genome-wide transcription in the hippocampus; and 3) these changes in transcription are associated with modified glucocorticoid receptor (GR) DNA binding and DNA methylation. sGC was administered as 2 courses on gestational days (GD) 40, 41, 50, and 51, and the hippocampi of fetal guinea pigs were examined before (GD52) and after (GD65) the endogenous cortisol surge (Term ∼GD67). We also analyzed fetal hippocampi 24 hours and 14 days following maternal sGC injections (n = 3-4/group). Genome-wide modification of transcription and GR DNA binding occurred in late gestation, in parallel with the normal GC surge. Further, sGC exposure had a substantial impact on the hippocampal transcriptome, GR-DNA binding, and DNA methylation at 24 hours and 14 days following the final sGC treatment. These data support the hypothesis that GC exposure in late gestation plays a significant role in modifying the transcriptional and epigenetic landscape of the developing fetal hippocampus and that substantial effects are evident for at least 2 weeks after sGC exposure.

Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition

“…These glucocorticoid-induced changes in DNA methylation have been shown to remain into adulthood and are even transmitted to the next generation. It was also shown that glucocorticoid treatment during pregnancy can modify the transcriptional and epigenetic machinery of the developing fetal hippocampus particularly associated with modified glucocorticoid receptor (GR) DNA-binding and DNA-methylation (108). A study in rats, applying mild or strong stress during mid-gestation demonstrated that PS induced region-specific changes of global DNA-methylation in male and female offspring.…”

Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease

“…18,19 To evaluate the role of the synthetic glucocorticoid, dexamethasone, in modulating DNA modification patterns in immature enterocytes, H4 cells were exposed to dexamethasone for 48 h, and the global pattern of the modification change was examined ( Supplementary Fig. S3).…”

Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes

“…To investigate the direct consequences of excess prenatal glucocorticoid exposure on the epigenetic landscape of brain tissue, Matthews and colleagues exposed pregnant guinea pigs to the synthetic glucocorticoid betamethasone during periods of rapid neurogenesis and brain growth (Days 41–42 and 51–52 of pregnancy, respectively) [61]. DNA and RNA were extracted from offspring hippocampal tissue either on post-natal Day 52 or 65, and microarray analysis with Nr3c1 DNA immunoprecipitation and chip hybridization performed for those genes that demonstrated differential Nr3c1 DNA binding compared to control (unexposed) offspring.…”