Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
Joint International Research Laboratory of Agriculture & Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China.
Cells. 2021 Oct 20;10(11):2818. doi: 10.3390/cells10112818.
Deoxynivalenol (DON) is a common environmental toxin that is secreted by fusarium fungi that frequently contaminates feedstuff and food. While the detrimental effects of DON on human and animal reproductive systems have been well recognized, the underlying mechanism remains poorly understood. Ovarian granulosa cells (GCs), which surround oocytes, are crucial for regulating oocyte development, mainly through the secretion of hormones such as estrogen and progesterone. Using an in vitro model of murine GCs, we characterized the cytotoxic effects of DON and profiled genome-wide chromatin accessibility and transcriptomic alterations after DON exposure. Our results suggest that DON can induce decreased viability and growth, increased apoptosis rate, and disrupted hormone secretion. In total, 2533 differentially accessible loci and 2675 differentially expressed genes were identified that were associated with Hippo, Wnt, steroid biosynthesis, sulfur metabolism, and inflammation-related pathways. DON-induced genes usually have a concurrently increased occupancy of active histone modifications H3K4me3 and H3K27ac in their promoters. Integrative analyses identified 35 putative directly affected genes including Adrb2 and Fshr, which are key regulators of follicular growth, and revealed that regions with increased chromatin accessibility are enriched with the binding motifs for NR5A1 and NR5A2, which are important for GCs. Moreover, DON-induced inflammatory response is due to the activation of the NF-κB and MAPK signaling pathways. Overall, our results provide novel insights into the regulatory elements, genes, and key pathways underlying the response of ovarian GCs to DON cytotoxicity.
脱氧雪腐镰刀菌烯醇（DON）是一种常见的环境毒素，由镰刀菌真菌分泌，经常污染饲料和食物。虽然 DON 对人类和动物生殖系统的有害影响已得到充分认识，但潜在的机制仍知之甚少。卵巢颗粒细胞（GCs）围绕卵母细胞，对于调节卵母细胞的发育至关重要，主要通过分泌雌激素和孕激素等激素来实现。我们使用体外小鼠 GCs 模型，研究了 DON 的细胞毒性作用，并在 DON 暴露后对全基因组染色质可及性和转录组变化进行了分析。我们的结果表明，DON 可诱导细胞活力和生长下降、凋亡率增加以及激素分泌紊乱。总共鉴定出 2533 个差异可及位点和 2675 个差异表达基因，这些基因与 Hippo、Wnt、类固醇生物合成、硫代谢和炎症相关途径有关。DON 诱导的基因通常在其启动子中具有同时增加的活性组蛋白修饰 H3K4me3 和 H3K27ac 的占有率。综合分析确定了 35 个可能受直接影响的基因，包括 Adrb2 和 Fshr，它们是卵泡生长的关键调节剂，并揭示了染色质可及性增加的区域富含 NR5A1 和 NR5A2 的结合基序，这对于 GCs 很重要。此外，DON 诱导的炎症反应是由于 NF-κB 和 MAPK 信号通路的激活。总之，我们的研究结果为卵巢 GCs 对 DON 细胞毒性反应的调控元件、基因和关键途径提供了新的见解。
