五味子乙素调控AhR-Nrf2/ARE信号通路及在预防苯并芘致人早孕胎盘绒毛膜滋养细胞损伤中的作用

Benzo[a]pyrene (BaP) is one of the group of polycyclic aromatic hydrocarbons (PAHs) and is recognized as one of the most carcinogenic PAH species. BaP exposure has been associated with missed abortion, birth defects and other adverse pregnancy outcomes. Nuclear factor erythroid-2 related factor 2(Nrf2) has been identified as the key regulatory factor against oxidative stress. AhR-Nrf2 and Nrf2/ARE pathway play an important role in the cellular defense against oxidative stress damage and genetic mutation caused by BaP. Traditional Chinese drug Five-Seed Procreating Pill has been found to improve fertility in humans. The principal component of the drug, Schizandrin, can activate Nrf2 and has been proven to be a safer and more efficient antioxidant than ginseng and mythic fungus. From our previous studies, we found that Schizandrin B increased the expression levels of antioxidant gene mediated by Nrf2/ARE. In this study, we plan to use HTR-8/SVneo cells and SD rats to examine the protective effect of Schizandrin B on reproductive health through the regulation of the AhR-Nrf2/ARE pathway. We will use molecule biology methods including siRNA, western blot and comet experiments at cell, gene and protein level. The results will elucidate the mechanism of Schizandrin B against fertility toxicity caused by PAHs and will help develop new and safe drugs in clinical applications to minimize the adverse environmental impact of PAHs.

环境污染物苯并(a)芘（BaP）可诱导胚胎停育和出生缺陷等不良妊娠结局，寻找新型安全的保护药物及分子靶标是国内外关注的热点。转录因子NF-E2相关因子2(Nrf2)是抗氧化应激的中枢调节者，芳香烃受体(AhR)-Nrf2和Nrf2/抗氧化反应元件(ARE)通路在干预BaP导致的氧化应激损伤和基因突变中发挥重要作用。传统中药五子衍宗丸可以提高生育能力，其君药五味子可以活化Nrf2，具有比人参、灵芝更安全有效的抗氧化作用。我们发现五味子乙素可增加Nrf2/ARE下游抗氧化损伤靶基因的表达。本课题拟从细胞、基因和蛋白水平，以HTR-8/SV neo细胞和SD大鼠为载体，利用基因沉默、蛋白印迹、彗星实验等分子生物学方法确证五味子乙素通过调控AhR-Nrf2/ARE信号通路实现生殖保护的作用，阐明中药抗多环芳烃类环境污染物生殖毒性的机制，为临床开发出强效、新型、安全的环境污染物防护剂奠定科学基础。

环境污染物苯并(a)芘（BaP）对胚胎及胎盘具有损伤作用，寻找新型安全的保护药物及分子靶标是国内外关注的热点。转录因子NF-E2相关因子2(Nrf2)是抗氧化应激的中枢调节者，芳香烃受体(AhR)-Nrf2和Nrf2/抗氧化反应元件(ARE)通路在干预BaP导致的氧化应激损伤和基因突变中发挥重要作用。传统中药五味子具有比人参、灵芝更安全有效的抗氧化作用，并可以活化Nrf2。本课题以HTR-8/SV neo细胞和SD大鼠为载体，利用基因沉默、蛋白印迹、彗星实验等分子生物学方法证实了五味子乙素可以通过激活调控AhR-Nrf2/ARE信号通路实现其生殖保护的作用，同时五味子乙素可以通过抗氧化、抗DNA损伤和抑制凋亡途径有效抑制BaP所致的胚胎及HTR细胞的毒性作用，研究结果可为临床开发强效、新型、安全的环境污染物防护剂提供了科学的理论基础。