College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
Pestic Biochem Physiol. 2024 Jun;202:105935. doi: 10.1016/j.pestbp.2024.105935. Epub 2024 Apr 28.
Imidacloprid (IMI) is a contaminant widespread in surface water, causing serious intestinal damage in the common carp. Melatonin (MT), an endogenous indoleamine hormone, plays a crucial role in mitigating pesticide-induced toxicity. Our previous research has demonstrated that MT effectively reduces the production of intestinal microbial-derived signal peptidoglycan (PGN) induced by IMI, thereby alleviating intestinal tight junction injuries in the common carp. In this study, we performed a transcriptomic analysis to explore the effect of MT on the IMI exposure-induced gut damage of the common carp. The results elucidated that the ferroptosis, mitogen-activated protein kinases (MAPKs), and nucleotide oligomerization domain (NOD)-like signaling pathways were significantly associated with IMI exposure and MT treatment. Meanwhile, the exposure to IMI resulted in the formation of pyroptotic bodies and distinct morphological features of ferroptosis, both mitigated with the addition of MT. Immunofluorescence double staining demonstrated that MT abolished the elevated expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin D (GSDMD) induced by IMI, as well as reduced expression of ferritin heavy chains (FTH) and glutathione peroxidase 4 (GPX4) in gut tissues. Subsequently, we found that the exposure to IMI or PGN enhanced the expression of toll-like receptors (TLR) 2 (a direct recognition receptor of PGN) triggering the P38MAPK signaling pathway, thereby aggravating the process of pyroptosis and ferroptosis of cell models. The addition of MT or SB203580 (a P38MAPK inhibitor) significantly reduced pyroptotic cells, and also decreased iron accumulation. Consequently, these results indicate that MT alleviates IMI-induced pyroptosis and ferroptosis in the gut of the common carp through the PGN/TLR2/P38MAPK pathway.
吡虫啉（IMI）是地表水中广泛存在的污染物，对鲤鱼造成严重的肠道损伤。褪黑素（MT）作为一种内源性吲哚胺激素，在减轻农药诱导的毒性方面起着至关重要的作用。我们之前的研究表明，MT 可有效减少 IMI 诱导的肠道微生物衍生信号肽聚糖（PGN）的产生，从而减轻鲤鱼的肠道紧密连接损伤。在这项研究中，我们进行了转录组分析，以探讨 MT 对 IMI 暴露引起的鲤鱼肠道损伤的影响。结果表明，铁死亡、丝裂原激活蛋白激酶（MAPKs）和核苷酸寡聚化结构域（NOD）样信号通路与 IMI 暴露和 MT 处理显著相关。同时，暴露于 IMI 会导致形成细胞焦亡小体和明显的铁死亡形态特征，而添加 MT 则可以减轻这些变化。免疫荧光双重染色表明，MT 消除了 IMI 诱导的 NOD 样受体热蛋白结构域相关蛋白 3（NLRP3）和 Gasdermin D（GSDMD）表达的上调，以及肠道组织中 ferritin heavy chains（FTH）和 glutathione peroxidase 4（GPX4）表达的下调。随后，我们发现，暴露于 IMI 或 PGN 增强了 Toll 样受体（TLR）2 的表达（PGN 的直接识别受体），从而触发 P38MAPK 信号通路，加重细胞模型的细胞焦亡和铁死亡过程。添加 MT 或 SB203580（P38MAPK 抑制剂）可显著减少细胞焦亡，还可减少铁的积累。因此，这些结果表明，MT 通过 PGN/TLR2/P38MAPK 途径缓解 IMI 引起的鲤鱼肠道细胞焦亡和铁死亡。
