Guan Haoyue, Cui Yujing, Hua Zixuan, Deng Youtian, Deng Huidan, Deng Junliang
Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
Metabolites. 2025 Mar 1;15(3):165. doi: 10.3390/metabo15030165.
BACKGROUND/OBJECTIVES: Deoxynivalenol (DON), known as vomitoxin, is one of the most common mycotoxins produced by , with high detection rates in feed worldwide. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation and the accumulation of reactive oxygen species. Although it has been demonstrated that DON can induce ferroptosis in the liver, the specific mechanisms and pathways are still unknown. The aim of this experiment was to investigate that DON can induce iron metabolism disorders in the livers of mice, thereby triggering ferroptosis and causing toxic damage to the liver.
Male C57 mice were treated with DON at a 5 mg/kg BW concentration as an in vivo model. After sampling, organ coefficient monitoring, liver function test, histopathological analysis, liver Fe content test, and oxidative stress-related indexes were performed. The mRNA and protein expression of Nrf2 and its downstream genes were also detected using a series of methods including quantitative real-time PCR, immunofluorescence double-labeling, and Western blotting analysis.
DON can cause damage to the liver of a mouse. Specifically, we found that mouse livers in the DON group exhibited pathological damage in cell necrosis, inflammatory infiltration, cytoplasmic vacuolization, elevated relative liver weight, and significant changes in liver function indexes. Meanwhile, the substantial reduction in the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) in the DON group indicated that DON also caused oxidative stress in the liver. Notably, DON exposure increased the levels of Fe and Malondialdehyde (MDA) in the liver, which provides strong evidence for the occurrence of iron metabolism and ferroptosis disorders. Most importantly, mRNA and protein expression of Nrf2, an important pathway for iron metabolism and ferroptosis, along with its downstream genes, heme oxygenase (HO-1), quinone oxidoreductase (NQO1), glutathione peroxidase (GPX4), and solute carrier gene (SLC7a11), were significantly inhibited in the DON group.
Based on our results, the Nrf2 pathway is closely associated with DON-induced iron metabolism disorders and ferroptosis in mouse livers, suggesting that maintaining hepatic iron homeostasis and activating the Nrf2 pathway may be a potential target for mitigating DON hepatotoxicity in the future.
背景/目的：脱氧雪腐镰刀菌烯醇（DON），即呕吐毒素，是由[具体产生菌未给出]产生的最常见的霉菌毒素之一，在全球饲料中检测率很高。铁死亡是一种以脂质过氧化和活性氧积累为特征的新型细胞死亡模式。虽然已经证明DON可诱导肝脏铁死亡，但其具体机制和途径仍不清楚。本实验的目的是研究DON是否能诱导小鼠肝脏铁代谢紊乱，从而引发铁死亡并对肝脏造成毒性损伤。
以5mg/kg体重浓度的DON处理雄性C57小鼠作为体内模型。取样后，进行器官系数监测、肝功能检测、组织病理学分析、肝脏铁含量检测以及氧化应激相关指标检测。还使用定量实时PCR、免疫荧光双标记和蛋白质免疫印迹分析等一系列方法检测Nrf2及其下游基因的mRNA和蛋白表达。
DON可对小鼠肝脏造成损伤。具体而言，我们发现DON组小鼠肝脏表现出细胞坏死、炎症浸润、细胞质空泡化等病理损伤，相对肝脏重量升高，肝功能指标显著变化。同时，DON组谷胱甘肽（GSH）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和总抗氧化能力（T-AOC）水平大幅降低，表明DON也在肝脏中引起了氧化应激。值得注意的是，DON暴露增加了肝脏中铁和丙二醛（MDA）的水平，这为铁代谢和铁死亡紊乱的发生提供了有力证据。最重要的是，DON组中，铁代谢和铁死亡的重要途径Nrf2及其下游基因血红素加氧酶（HO-1）、醌氧化还原酶（NQO1）、谷胱甘肽过氧化物酶（GPX4）和溶质载体基因（SLC7a11）的mRNA和蛋白表达均受到显著抑制。
基于我们的研究结果表明，Nrf2途径与DON诱导的小鼠肝脏铁代谢紊乱和铁死亡密切相关，这表明维持肝脏铁稳态和激活Nrf2途径可能是未来减轻DON肝毒性的潜在靶点。
