Abstract：
Zearalenone (ZEN) is a widespread and transgenerational toxicant that can cause serious reproductive health risks, which poses a potential threat to global agricultural production and human health; its estrogenic activity can lead to reproductive toxicity through the induction of granulosa cell apoptosis. Herein, comparative transcriptome analysis, single-cell transcriptome analysis, and weighted gene co-expression network analysis (WGCNA) combined with gene knockout in vivo and RNA interference in vitro were used to comprehensively describe the damage caused by ZEN exposure on ovarian granulosa cells. Comparative transcriptome analysis and WGCNA suggested that the tumor necrosis factor (TNF)-α-mediated mitogen-activated protein kinase 7 (MAP2K7)/ AKT serine/threonine kinase 2 (AKT2) axis was disordered after ZEN exposure in porcine granulosa cells (pGCs) and mouse granulosa cells (mGCs). In vivo gene knockout and in vitro RNA interference verified that TNF-α-mediated MAP2K7/AKT2 was the guiding signal in ZEN-induced apoptosis in pGCs and mGCs. Moreover, single-cell transcriptome analysis showed that ZEN exposure could induce changes in the TNF signaling pathway in offspring. Overall, we concluded that the TNF-α-mediated MAP2K7/AKT2 axis was the main signaling pathway of ZEN-induced apoptosis in pGCs and mGCs. This work provides new insights into the mechanism of ZEN toxicity and provides new potential therapeutic targets for the loss of livestock and human reproductive health caused by ZEN.
摘要：
玉米赤霉烯酮（ZEN）是一种广泛的跨代毒物，可引起严重的生殖健康风险，其雌激素活性可通过诱导颗粒细胞凋亡导致生殖毒性,对全球农业生产和人类健康构成潜在威胁。在这里，比较转录组分析，单细胞转录组分析，采用加权基因共表达网络分析（WGCNA）结合体内基因敲除和体外RNA干扰，全面描述ZEN暴露对卵巢颗粒细胞的损伤。比较转录组分析和WGCNA表明，ZEN暴露于猪颗粒细胞（pGC）和小鼠颗粒细胞（mGC）后，肿瘤坏死因子（TNF）-α介导的丝裂原活化蛋白激酶7（MAP2K7）/AKT丝氨酸/苏氨酸激酶2（AKT2）轴紊乱。体内基因敲除和体外RNA干扰证实TNF-α介导的MAP2K7/AKT2是ZEN诱导的pGCs和mGCs凋亡的引导信号。此外，单细胞转录组分析表明，ZEN暴露可引起子代TNF信号通路的变化。总的来说,我们得出结论，TNF-α介导的MAP2K7/AKT2轴是ZEN诱导pGCs和mGCs凋亡的主要信号通路。这项工作提供了对ZEN毒性机制的新见解，并为ZEN引起的家畜和人类生殖健康损失提供了新的潜在治疗靶标。
