Department of Pharmacology, Wuhan University School of Basic Medical Science, Wuhan, 430071, People's Republic of China.
Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.
Cell Biol Toxicol. 2023 Oct;39(5):2051-2067. doi: 10.1007/s10565-021-09691-0. Epub 2022 Mar 4.
Dexamethasone is widely used to treat pregnancy disorders related to premature delivery. However, lots of researches have confirmed that prenatal dexamethasone exposure (PDE) could increase the risk of offspring multiple diseases. This study was designed to elucidate the epigenetic mechanism of adrenal developmental programming and explore its early warning marker in peripheral blood mononuclear cells (PBMC). We found the adrenal morphological and functional changes of PDE male offspring rats before and after birth, which were mainly performed as the decreased serum corticosterone concentration, steroidogenic acute regulatory (StAR) protein expression, and histone 3 lysine 27 acetylation (H3K27ac) level of steroidogenic factor 1 (SF1) promoter region and its expression. Simultaneously, the expressions of glucocorticoid receptor (GR) and histone acetylation enzyme 5 (HDAC5) in the PDE male fetal rats were increased. In vitro, dexamethasone reduced the expression of SF1, StAR, and cortisol production and still 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 was able to reverse the above roles of dexamethasone. Furthermore, in vivo, we confirmed that H3K27ac levels of SF1 promoter region and its expression in PBMC of the 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 prenatal dexamethasone application decreased H3K27ac of SF1 promoter region and its expression in neonatal PBMC. In conclusion, PDE-caused adrenal insufficiency of male offspring rats was related to adrenal GR activated by dexamethasone in uterus. The activated GR, on the one hand, increased its direct binding to SF1 promoter region to inhibit its expression, on the other hand, upregulated and recruited HDAC5 to decrease H3K27ac level of SF1 promoter region, and strengthened the inhibition of SF1 and subsequent StAR expression.
地塞米松广泛用于治疗与早产相关的妊娠疾病。然而，大量研究证实产前地塞米松暴露（PDE）会增加后代多种疾病的风险。本研究旨在阐明肾上腺发育编程的表观遗传机制，并探索其在外周血单个核细胞（PBMC）中的早期预警标志物。我们发现 PDE 雄性仔鼠出生前后的肾上腺形态和功能发生变化，主要表现为血清皮质酮浓度降低、类固醇生成急性调节蛋白（StAR）蛋白表达降低、以及类固醇生成因子 1（SF1）启动子区域的组蛋白 3 赖氨酸 27 乙酰化（H3K27ac）水平及其表达降低。同时，PDE 雄性胎鼠中糖皮质激素受体（GR）和组蛋白乙酰化酶 5（HDAC5）的表达增加。体外，地塞米松降低了 SF1、StAR 和皮质醇产生的表达，仍增加了 GR 和 HDAC5 的表达、GR 与 SF1 启动子区域的结合以及 GR 和 HDAC5 之间的蛋白相互作用。GR siRNA 或 HDAC5 siRNA 能够逆转地塞米松的上述作用。此外，在体内，我们证实 PDE 组仔鼠出生前后 PBMC 中 SF1 启动子区域的 H3K27ac 水平及其表达降低，与肾上腺中的相同指标呈正相关。同时，在临床试验中，我们证实产前地塞米松应用降低了新生儿 PBMC 中 SF1 启动子区域的 H3K27ac 及其表达。总之，PDE 引起的雄性仔鼠肾上腺功能不全与子宫内地塞米松激活的肾上腺 GR 有关。激活的 GR 一方面增加其直接与 SF1 启动子区域结合以抑制其表达，另一方面上调并募集 HDAC5 以降低 SF1 启动子区域的 H3K27ac 水平，并加强对 SF1 及其后续 StAR 表达的抑制。
