YY1-ACE2-MasR介导孕期地塞米松暴露所致子代肝脏发育不良及其表遗传编程机制

Dexamethasone, as a type of the synthetic glucocorticoids (GCs), has been widely used in the treatment of prenatal fetal diseases due to its easy access to the placenta. However, prenatal dexamethasone exposure induces intrauterine growth retardation (IUGR) and increased susceptibility to multiple liver diseases (e.g. non-alcoholic fatty liver disease) in adulthood. Up to now, the underlying mechanism of intrauterine toxicity is still unclear. It is known that fetal exposure to excess glucocorticoids (GCs) can lead to the changes in the development process, and finally to the permanent programming in tissue structure and function. Recently, we found dexamethasone exposure during pregnancy causes fetal liver proliferation and differentiation dysfunction. Furthermore, prenatal dexamethasone exposure not only up-regulated Yin Yang-1 (YY1) expression but also down-regulated ACE2/MasR expression. Basing on literature and our preliminary experiments, we hypothesized that dexamethasone may induce aberrant epigenetic modification through histone acetylation in ACE2 promoter region thereby lowering the gene expression via activating YY1, which finally lead to liver proliferation and differentiation dysfunction. These will be validated in the intrauterine programming and epigenetic mechanisms of YY1-ACE2-MasR signaling mediates the dysplasia of liver in the offspring induced by prenatal dexamethasone exposure. This study is of great theoretical and practical significance for addressing the international theory of "developmental origin of health and diseases (DoHaD)" and guiding the rational use of drugs during pregnancy as well as improving the quality of people's life.

地塞米松作为合成类糖皮质激素（GCs），由于其容易透过胎盘的特性，广泛用于产前胎儿疾病的治疗，但其可致低出生体重和出生后多种肝脏疾病(如非酒精性脂肪肝)易感，其宫内毒性发生机制不明。已知胎儿暴露于过量的GCs会导致发育进程的改变，引起胎组织结构和功能的永久编程。我们近期研究发现，孕期地塞米松暴露可致胎肝增殖和分化功能障碍。进一步发现，孕期地塞米松暴露可上调阴阳子1（YY1）表达而抑制ACE2/MasR的表达。综合文献和预实验，我们推测：地塞米松可能通过激活YY1而诱导ACE2启动子区组蛋白乙酰化修饰异常/低表达，从而抑制MasR，导致肝脏增殖和分化功能障碍。本项目旨在证实YY1-ACE2-MasR介导孕期地塞米松暴露所致子代肝脏发育毒性和其表遗传机制，为解析国际“DOHaD”学说，指导孕期合理用药和提高人口生存质量，都有着重要的理论价值和现实意义。

合成糖皮质激素如地塞米松被广泛用于早产及相关妊娠疾病的治疗，以促进胎儿肺成熟并降低呼吸窘迫综合征的发生。前期研究报道，孕期给予临床治疗剂量下的地塞米松可致子代宫内生长迟缓（IUGR）及出生后成年多种肝脏疾病易感。然而，其宫内编程机制尚未完全阐明。通过本项目研究，我们证实孕期地塞米松暴露（PDE）可激活胎肝细胞糖皮质激素受体（GR），抑制微小RNA-122（miR-122）而增加阴阳子1（YY1）表达，造成血管紧张素转换酶2（ACE2）－Mas受体（MasR）信号通路抑制，最终导致肝脏甘油三酯（TG）合成功能增强及氧化功能减弱。同时，地塞米松作用下miR-122低表达所致的肝细胞TG合成功能增强及氧化功能减弱可一直延续至出生后，导致成年子代非酒精性脂肪肝病（NAFLD）的发生。此外，我们还观察到PDE可致雄性成年子代大鼠胰岛素抵抗及成年后代谢综合征的典型表现。追溯其宫内起源发现，PDE可致雄性胎鼠肝脏发育不良，并且此肝脏发育不良现象可延续至出生后，与血皮质酮和肝脏胰岛素样生长因子-1（IGF1）信号通路持续低编程改变有关。结合体内、外实验，我们证实PDE所致的宫内低水平血皮质酮可通过抑制肝细胞中GR/SP1/p300信号表达和入核，从而降低IGF1启动子区H3K27乙酰化及表达水平，且这种改变具有宫内发育编程效应，能延续至出生后，导致子代肝脏发育不良和成年代谢综合征发生。此外，我们也证实孕期母源性糖皮质激素暴露（如咖啡因暴露）诱导胎鼠肝发育障碍和IUGR后代的追赶生长，其机制与母源性糖皮质过暴露所致肝脏GC-IGF1轴宫内编程改变有关。这些发现对于阐明孕期糖皮质激素暴露对子代肝脏发育毒性的编程机制，更好的理解肝脏发育毒性及其远期危害，为解析胎源性肝脏疾病的发生、发展并探寻成年肝脏疾病的早期防治靶标，提供了重要理论和实验依据。本项目在药理及毒理学权威杂志BIOCHEM PHARMACOL、J ENDOCRINOL、FOOD CHEM TOXICOL等发表第一/通讯作者SCI论文8篇，中文核心3篇，主编出版专著1部，授权/申请专利19项，培养研究生3人。获得云南省大学生新药创制大赛特等奖1项、论文/壁报奖2项。