地塞米松作为合成类糖皮质激素（GCs），广泛用于多种妊娠子代相关疾病，但治疗剂量下可引起子代宫内发育迟缓及出生后多种疾病易感。然而，其毒性发生机制尚未阐明。已知肾上腺所分泌的GCs与胎儿组织成熟及出生后命运密切相关。我们近期发现，孕期地塞米松暴露的子代大鼠出生前、后肾上腺局部甾体合成功能皆呈高敏感性变化，进一步发现，地塞米松可上调早期生长反应因子（Egr1）、下调GCs屏障酶11βHSD2表达，同时抑制NR4A1/StAR信号。综合文献我们推测，地塞米松可能通过激活Egr1诱导11βHSD2启动子区表遗传修饰异常/低表达，破坏胎肾上腺细胞GCs屏障，加剧胞内地塞米松蓄积及NR4A1/StAR信号相关甾体合成功能抑制。本项目旨在证实孕期地塞米松暴露所致子代肾上腺局部高敏感性，阐明其宫内表遗传编程机制，为指导孕期合理用药，解析国际“DOHaD”学说，并探寻疾病早期防治策略，提供理论和实验依据。

As synthetic glucocorticoids (GCs), dexamethasone has been widely used to treat diseases during pregnancy, however, a therapeutic dose of dexamethasone treatment induces intrauterine growth retardation (IUGR) and increased susceptibility to a multiple diseases after birth. To date, the underlying mechanism remains unclarified. GCs secreted by adrenal is closely associated with the maturation of fetal tissues and postnatal fate. Recently, we found a local hypersensitivity of adrenal steroidogenesis function before and after birth in prenatal dexamethasone-exposed offspring rats, furthermore, dexamethasone not only up-regulated early growth response factor 1 (Egr1) expression levels but also down-regulated GCs barrier enzyme 11β-hydroxysteroid dehydrogenases (11βHSD2) expression while suppressing NR4A1/StAR signaling in fetal adrenal. Basing on literatures, we hypothesized that dexamethasone may induce aberrant epigenetic modification in 11βHSD2 promoter region thereby lowering the gene expression via activating Egr1 and the impaired GCs barrier of fetal adrenal cells further aggravate the accumulation of intracellular dexamethasone, which finally suppresses the NR4A1/StAR signaling-associated steroidogenesis. The aim of this project is to elucidate the local hypersensitivity of adrenal gland in prenatal dexamethasone-exposed offspring and the corresponding epigenetic programming mechanisms. This work will provide theoretical and experimental basis for guiding rational medication during pregnancy and addressing the international theory of "developmental origin of health and diseases (DoHaD)" as well as exploring the strategy for prevention and treatment.