Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Pharmacol Res. 2021 Dec;174:105942. doi: 10.1016/j.phrs.2021.105942. Epub 2021 Oct 14.
Dexamethasone is widely used to treat preterm labor and related diseases. However, prenatal dexamethasone treatment (PDT) can cause multiorgan developmental toxicities in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with adrenal developmental programming alterations in offspring. Here, we investigated the effects of PDT on adrenal function in offspring and its intrauterine programming mechanism. A rat model of PDT was established to observe the alterations of adrenal steroidogenesis in offspring. Furthermore, we confirmed the sex differences of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiments. PDT caused a decrease in adrenal steroidogenic function in fetal rats, but it was decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDT offspring were decreased in males and increased in females, suggesting that 11β-HSD2 might mediate sex differences in adrenal function. We further confirmed that dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy of adult PDT offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERβ was proven to be involved in regulating the sex difference in 11β-HSD2 expression. This study demonstrated the sex difference in adrenal steroidogenic function of PDT offspring after birth and elucidated a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.
地塞米松被广泛用于治疗早产及其相关疾病。然而，产前地塞米松治疗（PDT）可导致后代多器官发育毒性。我们之前的研究发现，胎儿起源疾病的发生与后代肾上腺发育编程改变有关。在这里，我们研究了 PDT 对后代肾上腺功能的影响及其宫内编程机制。建立了一个 PDT 的大鼠模型，以观察后代肾上腺类固醇生成的改变。此外，我们结合体内和体外实验，证实了肾上腺类固醇生成的性别差异及其分子机制。PDT 导致胎儿大鼠肾上腺类固醇生成功能下降，但出生后雄性下降，雌性增加。同时，PDT 后代肾上腺 H3K14ac 水平和 11β-羟类固醇脱氢酶 2（11β-HSD2）的表达在雄性中降低，在雌性中升高，提示 11β-HSD2 可能介导肾上腺功能的性别差异。我们进一步证实，地塞米松通过 GR/SP1/p300 通路抑制 H3K14ac 水平和 11β-HSD2 的表达。在成年 PDT 后代大鼠行双侧睾丸切除术或卵巢切除术后，肾上腺 11β-HSD2 表达和类固醇生成功能均降低。使用大鼠原代胎儿肾上腺细胞，证明雄激素受体和雌激素受体β的差异表达参与调节 11β-HSD2 表达的性别差异。本研究表明，PDT 后代出生后肾上腺类固醇生成功能存在性别差异，并阐明了一种性别激素受体依赖性的表观遗传调节机制，用于调节肾上腺 11β-HSD2 编程改变。
