title: 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.
authors: Department Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada H3G1Y6.
authors: Ariann
authors: A
authors: Crudo
authors: Matthew
authors: M
authors: Suderman
authors: Vasilis G
authors: VG
authors: Moisiadis
authors: Sophie
authors: S
authors: Petropoulos
authors: Alisa
authors: A
authors: Kostaki
authors: Michael
authors: M
authors: Hallett
authors: Moshe
authors: M
authors: Szyf
authors: Stephen G
authors: SG
authors: Matthews
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development / Q000235:genetics; D005333:Fetus / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D006168:Guinea Pigs; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D006657:Histones; D012333:RNA, Messenger; D006854:Hydrocortisone