Centre de Recherche en Reproduction et Fertilité (CRRF), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.
Departamento de Reproducción, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autonoma de Mexico, Mexico City 04510, Mexico.
Toxins (Basel). 2023 Mar 17;15(3):228. doi: 10.3390/toxins15030228.
Deoxynivalenol (DON) is a major mycotoxin present in animal feed and negatively affects growth and reproduction in farm species, including pigs and cattle. The mechanism of DON action involves the ribotoxic stress response (RSR), and it acts directly on ovarian granulosa cells to increase cell death. In ruminants, DON is metabolized to de-epoxy-DON (DOM-1), which cannot activate the RSR but has been shown to increase cell death in ovarian theca cells. In the present study, we determined if DOM-1 acts on bovine theca cells through endoplasmic stress using an established serum-free cell culture model and to assess whether also DON activates endoplasmic stress in granulosa cells. The results show that DOM-1 increased the cleavage of ATF6 protein, increased the phosphorylation of EIF2AK3, and increased the abundance of cleaved mRNA. Activation of these pathways led to an increased abundance of mRNA of the ER stress target genes , , and . Although CHOP is widely associated with autophagy, inhibition of autophagy did not alter the response of theca cells to DOM-1. The addition of DON to granulosa cells partially increased ER stress pathways but failed to increase the abundance of mRNA of ER stress target genes. We conclude that the mechanism of action of DOM-1, at least in bovine theca cells, is through the activation of ER stress.
脱氧雪腐镰刀菌烯醇（DON）是一种存在于动物饲料中的主要霉菌毒素，会对包括猪和牛在内的农场动物的生长和繁殖产生负面影响。DON 的作用机制涉及核糖体毒性应激反应（RSR），它直接作用于卵巢颗粒细胞，增加细胞死亡。在反刍动物中，DON 代谢为脱环氧-DON（DOM-1），它不能激活 RSR，但已被证明会增加卵巢膜细胞的细胞死亡。在本研究中，我们使用已建立的无血清细胞培养模型，确定 DOM-1 是否通过内质网应激作用于牛的膜细胞，并评估 DON 是否也能激活颗粒细胞中的内质网应激。结果表明，DOM-1 增加了 ATF6 蛋白的切割，增加了 EIF2AK3 的磷酸化，并增加了切割的 mRNA 的丰度。这些途径的激活导致 ER 应激靶基因 、 和 的 mRNA 丰度增加。虽然 CHOP 与自噬广泛相关，但自噬的抑制并没有改变膜细胞对 DOM-1 的反应。向颗粒细胞中添加 DON 部分增加了 ER 应激途径，但未能增加 ER 应激靶基因的 mRNA 丰度。我们得出结论，DOM-1 的作用机制，至少在牛的膜细胞中，是通过激活内质网应激。
