Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, PR China.
Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, PR China.; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, PR China.
Sci Total Environ. 2023 Nov 20;900:166441. doi: 10.1016/j.scitotenv.2023.166441. Epub 2023 Aug 19.
Salinomycin (SAL) has caused widespread pollution as a feed additive and growth promoter in livestock such as pigs, exerting a negative impact on public health. The toxicity mechanism of SAL has been widely studied in chickens, but the underlying mechanisms of SAL-induced toxicity to pigs and the ecosystem remain undefined. In this study, we explored the potential damage of SAL in IPEC-J2 cells to identify the effects of excessive SAL on the interplay between mitophagy and oxidative stress. The results showed that a concentration-dependent response was observed for SAL in altering cellular morphology and inducing cell death in IPEC-J2 cells, including the induction of cell cycle arrest and lactic dehydrogenase (LDH) release. Meanwhile, we found that excessive SAL led to oxidative damage by activating the Nrf2/Keap1/HO-1 pathway, accompanied by reactive oxygen species (ROS) elevation and the reduction of antioxidant enzyme activity. We also found that PINK1/Parkin-dependent mitophagy was activated by SAL exposure, particularly with mitochondrial membrane potential reduction. Interestingly, SAL-induced oxidative damages were prevented after the autophagy inhibitor 3-methyladenine (3-MA) treatment, and mitophagy was alleviated following ROS scavenger (N-acetylcysteine, NAC) treatment. Overall, our findings showed that SAL stimulated oxidative stress and mitophagy in IPEC-J2 cells resulting in cellular injury, and there was a strong connection between SAL-induced oxidative stress and mitophagy. Targeting ROS/PINK1/Parkin-dependent mitophagy and oxidative stress could be a novel protective mechanism in SAL-induced cell damage.
萨利霉素（SAL）作为一种饲料添加剂和生长促进剂在猪等家畜中广泛使用，造成了广泛的污染，对公共健康产生了负面影响。SAL 在鸡中的毒性机制已得到广泛研究，但 SAL 对猪和生态系统的毒性的潜在机制仍不清楚。在这项研究中，我们探讨了 SAL 对 IPEC-J2 细胞的潜在损伤，以确定过量 SAL 对自噬和氧化应激相互作用的影响。结果表明，SAL 以浓度依赖的方式改变 IPEC-J2 细胞的形态并诱导细胞死亡，包括细胞周期停滞和乳酸脱氢酶（LDH）释放。同时，我们发现过量的 SAL 通过激活 Nrf2/Keap1/HO-1 通路导致氧化损伤，伴随着活性氧（ROS）的升高和抗氧化酶活性的降低。我们还发现，SAL 暴露激活了 PINK1/Parkin 依赖性的线粒体自噬，特别是伴随着线粒体膜电位的降低。有趣的是，自噬抑制剂 3-甲基腺嘌呤（3-MA）处理后可预防 SAL 诱导的氧化损伤，ROS 清除剂（N-乙酰半胱氨酸，NAC）处理后可减轻线粒体自噬。总的来说，我们的研究结果表明，SAL 刺激 IPEC-J2 细胞中的氧化应激和线粒体自噬，导致细胞损伤，SAL 诱导的氧化应激和线粒体自噬之间存在很强的联系。靶向 ROS/PINK1/Parkin 依赖性的线粒体自噬和氧化应激可能是 SAL 诱导细胞损伤的一种新的保护机制。
