孕期咖啡因暴露所致子代肾上腺功能异常的跨代遗传效应及分子机制

Caffeine intake during pregnancy can cause adrenal developmental toxicity and increased metabolic disease susceptibility after birth. However, the mechanism has not yet been elucidated. Literature suggests that epigenetic change of imprinting gene H19 plays an important role in the dysplastic trans-generational effect of offspring induced by adverse environmental exposure during pregnancy. We have previously demonstrated that caffeine exposure during pregnancy can cause intrauterine growth retardation (IUGR) fetal maternal glucocorticoid (GC) over-exposure, adrenal hypoplasia and .susceptible to metabolic disease in adulthood. Recently, we found the adrenal function maintain abnormal and showed trans-generational inheritance effect, it could be speculated that the mechanism may be related to the H19 imprint area high methylation and low expression induced by maternal GC over-exposure. Therefore, this project aims to investigate the potential interactions among a series of events in vitro and in vivo basing on the previous research, including “high level of GC - GR overexpression - suppressed CTCF and enhanced DNMTs expression - H19 hypermethylation and suppressed expression - enhanced let 7 and suppressed StAR expression - trans-generational effect of low adrenal function”. Meanwhile, the intrauterine imprinting mechanism of adrenal dysfunction induced by maternal high GC maternal GC could be elucidated. The role of H19 as an early molecular targets for adrenal dysfunction will be validated. This project has important theoretical and practical significance for guiding prenatal care and reducing the IUGR fetal origin disease.

妊娠期摄入咖啡因可引起肾上腺功能异常及子代出生后代谢性疾病易感，其发生机制尚未阐明。文献提示，印记基因H19的表遗传修饰在孕期不良环境所致子代发育异常的跨代遗传效应中具有重要作用。本室前期研究发现，孕期咖啡因暴露可致宫内发育迟缓（IUGR）胎儿母源性糖皮质激素（GC）过暴露、肾上腺发育不良；近期结果显示其子代肾上腺功能持续异常，存在跨代遗传效应，其机制可能与高GC导致的H19印记区域高甲基化及低表达有关。本项目拟在前期研究基础上，在整体和细胞水平，探讨“高GC-GR高表达-CTCF低表达/DNMTs高表达-H19高甲基化及低表达-let7高表达/StAR低表达-肾上腺低功能的跨代遗传效应”之间的内在联系，阐明母源性高GC诱导IUGR肾上腺发育异常的跨代遗传现象及宫内印记机制，确证H19是肾上腺发育毒性的分子靶标。本项目对于实施贯彻优生优育国策和减少胎源性疾病发生，具有重要理论和现实意义。

有报道指出妊娠期摄入咖啡因可引起肾上腺功能异常及子代出生后代谢性疾病易感，其发生机制尚未阐明。文献表明，印记基因H19的表遗传修饰在孕期不良环境所致子代发育异常的跨代遗传效应中具有重要作用。本室前期研究发现，孕期咖啡因暴露可致宫内发育迟缓（IUGR）、胎儿母源性糖皮质激素（GC）过暴露、肾上腺发育不良；近期结果显示其子代肾上腺功能持续异常，存在跨代遗传效应，其机制可能与高GC导致的H19印记区域高甲基化及低表达有关。本项目在前期研究基础上，在整体和细胞水平，探讨“高GC-GR高表达-CTCF低表达/DNMTs高表达-H19高甲基化及低表达-let7高表达/StAR低表达-肾上腺低功能的跨代遗传效应”之间的内在联系。通过研究发现PCE暴露的雌性子代大鼠肾上腺功能障碍，存在跨代遗传效应，具体表现在F1/F2/F3代雌性大鼠肾上腺Star表达以及血CORT改变。细胞水平证实皮质醇通过促进GR活化入核，一方面降低CTCF表达并抑制CTCF结合与H19结合，另一方面增加DNMT3a表达并促进DNMT3a与H19结合，双向调节导致H19启动子区高甲基化和低表达，后者最终导致肾上腺StAR表达降低。本课题阐明母源性高GC诱导IUGR肾上腺发育异常的跨代遗传现象及宫内印记机制，确证H19是肾上腺发育毒性的分子靶标。本项目对于实施贯彻优生优育国策和减少胎源性疾病发生，具有重要理论和现实意义。