Liu Qingxiu, Wang Leli, An Lei, Liu Yafei, Qu Honglei, Huang Shimeng, Zhao Lihong, Yin Yulong, Ma Qiugang
State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
Centre of Healthy Animal Husbandry, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan 410125, China.
J Agric Food Chem. 2024 Dec 25;72(51):28390-28399. doi: 10.1021/acs.jafc.4c07623. Epub 2024 Nov 28.
A study aimed to investigate the signaling pathway of zearalenone (ZEA) leading to the apoptosis of ovarian granulosa cells (GCs) and explore the potential of vitamin E (VE) in alleviating ZEA-induced apoptosis of GCs. We constructed an apoptosis model for GCs based on exposure to the environmental toxin ZEA. Transcriptome analysis revealed that ZEA induced endoplasmic reticulum stress by activating the ATF4-Chop pathway. The addition of inhibitors targeting the estrogen receptor (ER) demonstrated that ZEA activates the ATF4-Chop pathway through ER-beta. As a strong antioxidant, VE is thought to mitigate ZEA-induced toxicity. Interestingly, molecular docking analysis at the PERK active site of the endoplasmic reticulum stress revealed a high binding capacity of VE. VE supplementation reduced apoptosis in GCs and decreased the expression of p-eIF-2α, ATF4, and Chop. Mouse tests also demonstrated that VE supplementation effectively mitigated ovarian dysfunction induced by ZEA, as evidenced by increased body weight gain, reduced oxidative stress, and decreased cell death. In summary, the present study demonstrates that ZEA activates the PERK-eIF-2α-ATF4-Chop pathway through ERβ, leading to endoplasmic reticulum stress and apoptosis of GCs. Conversely, VE inhibits the PERK/eIF-2α/ATF4/Chop signaling pathways, mitigating endoplasmic reticulum stress and improving ZEA-induced reproductive toxicity.
一项研究旨在探究玉米赤霉烯酮（ZEA）导致卵巢颗粒细胞（GCs）凋亡的信号通路，并探索维生素E（VE）缓解ZEA诱导的GCs凋亡的潜力。我们基于暴露于环境毒素ZEA构建了GCs的凋亡模型。转录组分析显示，ZEA通过激活ATF4-Chop通路诱导内质网应激。添加针对雌激素受体（ER）的抑制剂表明，ZEA通过ER-β激活ATF4-Chop通路。作为一种强抗氧化剂，VE被认为可减轻ZEA诱导的毒性。有趣的是，在内质网应激的PERK活性位点进行的分子对接分析显示VE具有高结合能力。补充VE可减少GCs凋亡，并降低p-eIF-2α、ATF4和Chop的表达。小鼠试验还表明，补充VE可有效减轻ZEA诱导的卵巢功能障碍，表现为体重增加、氧化应激减轻和细胞死亡减少。总之，本研究表明，ZEA通过ERβ激活PERK-eIF-2α-ATF4-Chop通路，导致内质网应激和GCs凋亡。相反，VE抑制PERK/eIF-2α/ATF4/Chop信号通路，减轻内质网应激并改善ZEA诱导的生殖毒性。
