Glucocorticoid Programming of the Fetal Male Hippocampal Epigenome

Abstract

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.

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

“…Substantial evidence indicates the importance of epigenetic modifications including DNA methylation in glucocorticoid signaling (Crudo et al, 2013;Sharma et al, 2013;Petropoulos et al, 2014). It has been shown that glucocorticoids repress gene expression by interacting with DNA (cytosine-5)-methyltransferase 3b and methyl CpG binding protein 2 and increasing promoter methylation (Sharma et al, 2013).…”

“…It has been shown that glucocorticoids repress gene expression by interacting with DNA (cytosine-5)-methyltransferase 3b and methyl CpG binding protein 2 and increasing promoter methylation (Sharma et al, 2013). Furthermore glucocorticoid exposure is associated with both methylation and demethylation of promoter and enhancer regions, illustrating a potentially complex regulatory pathway (Crudo et al, 2013;Thomassin et al, 2001). Crudo et al (2012) demonstrated that the endogenous glucocorticoid surge alters the expression of methylation specific genes such as DNA (cytosine-5)-methyltransferase 3b and methyl-CpG-binding domain protein 2 and is instrumental in defining DNA methylation patterns in an organ-specific manner (Crudo et al, 2012).…”

“…Crudo et al (2012) demonstrated that the endogenous glucocorticoid surge alters the expression of methylation specific genes such as DNA (cytosine-5)-methyltransferase 3b and methyl-CpG-binding domain protein 2 and is instrumental in defining DNA methylation patterns in an organ-specific manner (Crudo et al, 2012). The effects of glucocorticoids on methylation patterns are long lasting and are sustained into adulthood and even in subsequent generations (Crudo et al, 2012(Crudo et al, , 2013. In the present study, we found that treatment with dexamethasone was not associated with changes in global DNA methylation.…”

Antenatal Treatment with Glucocorticoids and the Hypotalamic-Pituitary-Adrenal Axis

“…Literature data show similar effects of fetal glucocorticoid overexposure in different species, including mice, rhesus macaques and humans, such as reduced hippocampal volume with a reduced number of pyramidal neurons and pronounced degeneration of neuronal perikarya and dendrites, resulting in a decreased number of synaptic contacts (34,35). Epigenetic changes caused by antenatal treatment with synthetic glucocorticoids that alter genome-wide transcription and modify GR DNA binding in the fetal hippocampus during late gestation have been recently shown in guinea pigs (36).…”

Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

“…Pregnancy and early postnatal environment could cause epigenetic changes in specific genes in offspring, and these changes can be continued to several generations (Lillycrop et al, 2005;Szyf et al, 2008;Weaver et al, 2004). Some studies have demonstrated that prenatal high level of GC exposure can induce epigenetic alteration in male offspring (Crudo et al, 2013), and a possible target of GC programming is the fetal hippocampus. Reports demonstrated that prenatal high level of GC exposure could induce the epigenetic alteration of specific genes, including glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in fetal hippocampus (Crudo et al, 2012;McCabe et al, 2001).…”