Prenatal synthetic glucocorticoids (sGC) are administered to pregnant women at risk of delivering preterm, approximately 10% of all pregnancies. Animal studies have demonstrated that offspring exposed to elevated glucocorticoids, either by administration of sGC or as a result of maternal stress, are at increased risk of developing behavioral, endocrine, and metabolic abnormalities. DNA methylation is a covalent modification of DNA that plays a critical role in long-lasting programming of gene expression. Here we tested the hypothesis that prenatal sGC treatment has both acute and long-term effects on DNA methylation states in the fetus and offspring and that these effects extend into a subsequent generation. Pregnant guinea pigs were treated with sGC in late gestation, and methylation analysis by luminometric methylation assay was undertaken in organs from fetuses and offspring across two generations. Expression of genes that modify the epigenetic state were measured by quantitative real-time PCR. Results indicate that there are organ-specific developmental trajectories of methylation in the fetus and newborn. Furthermore, these trajectories are substantially modified by intrauterine exposure to sGC. These sGC-induced changes in DNA methylation remain into adulthood and are evident in the next generation. Furthermore, prenatal sGC exposure alters the expression of several genes encoding proteins that modulate the epigenetic state. Several of these changes are long lasting and are also present in the next generation. These data support the hypothesis that prenatal sGC exposure leads to broad changes in critical components of the epigenetic machinery and that these effects can pass to the next generation.
The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3-4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.
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.
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