雷公藤干扰肾上腺核受体SF-1调控的DHEA合成转化诱导卵巢早衰的机制及“肾主生殖”理论研究

Tripterygium wilfordii is effective, but the incidence of induced premature ovarian failure is also high, which restricts its application. We found that there is a "adrenal-ovarian" linkage phenomenon in the toxicity process of Tripterygium wilfordii. So whether the adrenal gland is also involved in the toxicity mechanism, no relevant reports have been reported, and this phenomenon is difficult to explain with the related principle with the thalamus-pituitary-ovarian axis of the "kidney reproductive" theory. It has been found recently that the adrenal gland plays an important role in supporting ovarian function through DHEA synthesis and transformation and the nuclear receptor SF-1 is the core regulator of this process. The changes of specific indicators in the linkage phenomenon suggest that Tripterygium wilfordii has an interference effect on SF-1 regulation. Therefore, we believe that Tripterygium wilfordii can induce premature ovarian failure by interfering adrenal nuclear receptor SF-1 rugulation of the DHEA synthesis and transformation, and in the theory of "kidney reproductive" the related principle with "adrenal-ovarian" axis should also exist. In this study a combination of pharmacological toxicology, targeted lipidomics and molecular biology methods is to be used, to synthesize the correlation of the adrenal-ovarian relationship in the premature ovarian failure induced by Triptolide, the main effects and toxic components Tripterygium wilfordii, and then focusing layer by layer, with a mode of “the intermediate product-key enzyme-nuclear receptor regulation“ ,to analyze the interference mechanism of Triptolide for the synthesis and transformation of DHEA regulated by receptor SF-1 , and to discuss the related theoretical principles, in order to provide a some reference for ensuring the safe use of Tripterygium wilfordii, and provide a new attempt for elucidating the connotation of the theory of“kidney governing reproduction”.

雷公藤疗效确切，但诱导卵巢早衰发生率高，制约了其应用。我们发现，雷公藤该毒性过程中存在“肾上腺-卵巢”联动现象，肾上腺是否也参与了该毒性机制，未见相关报道，且该现象难以用“肾主生殖”理论中“下丘脑-垂体-卵巢轴”相关原理解释。研究发现，肾上腺通过DHEA合成转化发挥支持卵巢功能的重要作用，核受体SF-1是该过程核心调控因子，联动现象具体指标变化提示雷公藤对SF-1调控具备干扰作用。因此，我们认为雷公藤可干扰肾上腺核受体SF-1调控的DHEA合成转化诱导卵巢早衰，“肾主生殖”理论中还存在“肾上腺-卵巢”轴相关原理。本研究拟以靶向脂质组学串联多种方法，在确证该“肾上腺-卵巢”病变关联关系基础上，从DHEA合成转化中间产物-关键酶-核受体调控逐层聚焦，解析雷公藤干扰肾上腺SF-1调控的DHEA合成转化的机制，探讨相关理论原理。为保证雷公藤安全使用提供支撑，也为阐发肾主生殖内涵做一个有益尝试。

本项目按照研究计划，先后完成了雷公藤诱导卵巢早衰与其对卵巢及肾上腺DHEA合成转化干扰作用的关联性研究，完成了雷公藤对卵巢及肾上腺DHEA等雌激素前体合成转化的靶向脂质组学与转录组学研究，完成了雷公藤对卵巢与肾上腺核受体SF-1调控的DHEA等雌激素前体合成转化干扰机制的体外与体内研究等内容。研究发现，雷公藤主要成分TP诱导卵巢早衰过程中存在潜在的肾上腺-卵巢的关联互动机制：①TP主要在卵巢诱导产生对E2合成转化的抑制，而肾上腺可代偿性的补充E2的前体物质DHEA与T；②TP在卵巢对SF-1调控的STAR以及HSD17B7的抑制可能是其抑制E2合成的主要来源，而其对P-CREB的抑制可能是该作用的核心机制；③同步出现的肾上腺SF-1调控的STAR、CYP11A1及HSD17B7的显著激活可能是其调控DHEA与T发挥对卵巢代偿作用的主要来源，而对P-C-JUN的激活可能是该作用的核心机制。以上发现，不仅为解析雷公藤的生殖毒性提供了重要支撑，同时还为阐释与探讨肾主生殖理论中“肾-胞宫”轴的理论内涵提供了新的支持。