Liu Changjiang, Qu Jiayuan, Wu Mingzhu, Huang Xu, Li Lianbing
NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, 420 Baohuan Road, Chongqing 400020, China; Medical Research Institute, Southwest University, Chongqing 400715, China.
NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, 420 Baohuan Road, Chongqing 400020, China.
Ecotoxicol Environ Saf. 2021 Dec 1;225:112792. doi: 10.1016/j.ecoenv.2021.112792. Epub 2021 Sep 17.
Cypermethrin (CYP), an extensively-used broad-spectrum pyrethroid pesticide, is regarded as a potential environmental endocrine disruptor with the anti-androgenic characteristic. To explore underlying roles of non-coding RNAs and the Jak/Stat pathway in CYP-mediated testosterone biosynthesis suppression, SD rats and Leydig cells were employed in this work. Results displayed that β-CYP decreased plasma testosterone levels and led to abnormal alterations of testicular histomorphology and ultrastructures. LncRNA XIST and miR-142-5p were co-localized in the cytoplasm of Leydig cells, but the expression of XIST was inhibited by β-CYP while that of miR-142-5p was induced. Then overexpressed miR-142-5p dampened the Jak1/Stat1 pathway by directly targeting Jak1. Transcription factors NFκB and YY1 impeded by β-CYP were positively regulated by the Jak1/Stat1 pathway. Bidirectional Co-IP and ChIP assays demonstrated that NFκB interacted with and modulated YY1 by directly binding to the promoter region of YY1. ChIP, qPCR, and YY1 knockdown/overexpression assays indicated that YY1 acted as a transcriptional activator to directly modulate steroidogenic StAR and 3β-HSD in Leydig cells. Taken together, miR-142-5p sponged by lncRNA XIST directly targets the Jak1/Stat1 pathway, which regulates steroidogenic StAR and 3β-HSD via NFκB and YY1, and ultimately dampens testosterone production in Leydig cells.
氯氰菊酯（CYP）是一种广泛使用的广谱拟除虫菊酯类农药，被认为是一种具有抗雄激素特性的潜在环境内分泌干扰物。为了探究非编码RNA和Jak/Stat信号通路在CYP介导的睾酮生物合成抑制中的潜在作用，本研究使用了SD大鼠和睾丸间质细胞。结果显示，β-CYP降低了血浆睾酮水平，并导致睾丸组织形态和超微结构的异常改变。长链非编码RNA XIST和miR-142-5p共定位于睾丸间质细胞的细胞质中，但XIST的表达受到β-CYP的抑制，而miR-142-5p的表达则被诱导。过表达miR-142-5p通过直接靶向Jak1抑制Jak1/Stat1信号通路。受β-CYP抑制的转录因子NFκB和YY1受到Jak1/Stat1信号通路的正向调控。双向免疫共沉淀和染色质免疫沉淀实验表明，NFκB通过直接结合YY1的启动子区域与YY1相互作用并调节YY1。染色质免疫沉淀、定量PCR和YY1敲低/过表达实验表明，YY1作为转录激活因子直接调节睾丸间质细胞中类固醇生成相关蛋白StAR和3β-HSD。综上所述，lncRNA XIST吸附的miR-142-5p直接靶向Jak1/Stat1信号通路，该信号通路通过NFκB和YY1调节类固醇生成相关蛋白StAR和3β-HSD，最终抑制睾丸间质细胞中睾酮的产生。
