H3K27 Acetylation of SF1 in PBMC: A Biomarker for Adrenal Insufficiency of Steroid Synthesis in Male Offspring Induced by Prenatal Dexamethasone Exposure

Dexamethasone is widely used for treating pregnant diseases. However, lots of studies have confirmed that prenatal dexamethasone exposure (PDE) could increase the risk of offspring multiple diseases. The purpose of this study was to elucidate the intrauterine epigenetic mechanism of adrenal developmental programming, and to explore early warning marker in peripheral blood mononuclear cells (PBMC). We found the adrenal morphological and functional changes before and after birth in PDE male offspring rats, which were performed as the decreases of serum corticosterone concentration, steroidogenic acute regulatory (StAR) expression, histone 3 lysine 27 acetylation (H3K27ac) level of steroidogenic factor1 (SF1) promoter region and its expression; meanwhile, the expression of glucocorticoid receptor (GR) and histone acetylation enzyme 5 (HDAC5) in PDE male fetal rats were increased. In vitro , dexamethasone reduced the expression of SF1 and StAR, and cortisol production, but increased the expression of GR and HDAC5, the binding between GR and SF1 promoter region, and protein interaction between GR and HDAC5. GR siRNA or HDAC5 siRNA could reverse the above effects of dexamethasone. Furthermore, in vivo, we confirmed that H3K27ac level of SF1 promoter region and its expression in PBMC of PDE group were decreased before and after birth, showing a positive correlation with the same indexes in adrenal. Meanwhile, in clinical trials, we confirmed that H3K27ac level of SF1 promoter region and its expression were decreased after prenatal dexamethasone application in neonatal PBMC. In conclusion, PDE induced adrenal insufficiency of male offspring rats, which was related to activate adrenal GR by dexamethasone in uterus . The activated GR, on one hand, increased its direct binding to SF1 promoter region to inhibit its expression, on the other hand, up-regulated and recruited HDAC5 to decrease H3K27ac level of SF1 promoter region, and strengthened the inhibition of SF1 and subsequent StAR expression.