孕期地塞米松暴露所致子代肾上腺局部高敏感性及其表遗传编程机制

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.

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。

地塞米松作为合成类糖皮质激素，临床广泛用于早产及妊娠相关疾病。然而，临床和动物实验发现，治疗剂量下可引起子代宫内发育迟缓、出生后多器官发育毒性及成年后多种疾病易感。本项目通过系列研究取得以下学术成绩，具体表现在：1)首次发现孕期地塞米松暴露所致子代大鼠出生后肾上腺甾体合成功能异常的性别差异现象；2)阐明孕期地塞米松暴露导致子代大鼠肾上腺功能异常的地塞米松直接作用及其宫内表观遗传编程机制；3)首次阐明孕期地塞米松暴露子代大鼠出生前、后肾上腺功能异常变化的宫内母源性低糖皮质激素暴露介导的“GC-IGF1轴”同向编程机制；4)首次证实孕期地塞米松暴露所致子代出生后肾上腺功能性别差异的宫内起源现象及其肾上腺性激素受体介导的SP1/11-HSD2表观遗传编程机制；5)首次发现孕期地塞米松暴露导致雌性子代肾上腺功能低下的母系多代遗传效应及其H19/let-7c轴互作抑制机制；6)首次提出孕期地塞米松暴露男性(雄性)子代肾上腺功能低下的外周血表观遗传预警标志物—SF1启动子区H3K27ac水平及表达；7)全面证实孕期地塞米松暴露所致子代胎盘、多器官(如肝脏、骨、肾脏、胰腺、睾丸、卵巢、海马、下丘脑)发育毒性、成年多疾病易感现象及其性别差异/多代遗传效应。本项目证实孕期地塞米松暴露所致子代肾上腺的发育编程、稳态改变及相关胎源性疾病易感现象，并阐明肾上腺局部高敏感性、性别差异性及多代遗传效应的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，为探寻胎源性疾病的早期防控策略提供了系统的实验证据、创新的理论体系及研究思路。本项目在国际、国内发育毒理学领域已发表文章67篇，其中SCI收录文章64篇（90%为JCR二区及以上），获湖北省科技进步一等奖2项（分别为第一、第三完成人），获第三届中国出生缺陷干预救助基金会科学技术二等奖（第一完成人），申请国家发明专利16项授权6项，出版《骨与关节疾病的胎儿起源》著作1部。