He Weihua, Zhu Zuoyin, Xu Jingru, Huang Chengbao, Wang Jianhua, Wang Qinggong, Zhai Xiaohu, Yang Junhua
Institute of Pet Science and Technology, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou 225300, China.
Institute for Agro-Food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China.
Toxins (Basel). 2025 Jul 30;17(8):381. doi: 10.3390/toxins17080381.
T-2 toxin and HT-2 toxin are commonly found in agricultural products and animal feed, posing serious effects to both humans and animals. This study employed combination index (CI) modeling and metabolomics to assess the combined cytotoxic effects of T-2 and HT-2 on four porcine cell types: intestinal porcine epithelial cells (IPEC-J2), porcine Leydig cells (PLCs), porcine ear fibroblasts (PEFs), and porcine hepatocytes (PHs). Cell viability assays revealed a dose-dependent reduction in viability across all cell lines, with relative sensitivities in the order: IPEC-J2 > PLCs > PEFs > PHs. Synergistic cytotoxicity was observed at low concentrations, while antagonistic interactions emerged at higher doses. Untargeted metabolomic profiling identified consistent and significant metabolic perturbations in four different porcine cell lines under co-exposure conditions. Notably, combined treatment with T-2 and HT-2 resulted in a uniform downregulation of LysoPC (22:6), LysoPC (20:5), and LysoPC (20:4), implicating disruption of membrane phospholipid integrity. Additionally, glycerophospholipid metabolism was the most significantly affected pathway across all cell lines. Ether lipid metabolism was markedly altered in PLCs and PEFs, whereas PHs displayed a unique metabolic response characterized by dysregulation of tryptophan metabolism. This study identified markers of synergistic toxicity and common alterations in metabolic pathways across four homologous porcine cell types under the combined exposure to T-2 and HT-2 toxins. These findings enhance the current understanding of the molecular mechanisms underlying mycotoxin-induced the synergistic toxicity.
T-2毒素和HT-2毒素常见于农产品和动物饲料中，对人类和动物均有严重影响。本研究采用联合指数（CI）建模和代谢组学方法，评估T-2和HT-2对四种猪细胞类型的联合细胞毒性作用，这四种细胞类型分别为猪肠道上皮细胞（IPEC-J2）、猪睾丸间质细胞（PLC）、猪耳成纤维细胞（PEF）和猪肝细胞（PH）。细胞活力测定显示，所有细胞系的活力均呈剂量依赖性降低，相对敏感性顺序为：IPEC-J2 > PLC > PEF > PH。在低浓度下观察到协同细胞毒性，而在高剂量下则出现拮抗相互作用。非靶向代谢组学分析确定了在共暴露条件下四种不同猪细胞系中一致且显著的代谢扰动。值得注意的是，T-2和HT-2联合处理导致溶血磷脂酰胆碱（22:6）、溶血磷脂酰胆碱（20:5）和溶血磷脂酰胆碱（20:4）均一致下调，这表明膜磷脂完整性受到破坏。此外，甘油磷脂代谢是所有细胞系中受影响最显著的途径。醚脂代谢在PLC和PEF中明显改变，而PH表现出独特的代谢反应，其特征为色氨酸代谢失调。本研究确定了在T-2和HT-2毒素联合暴露下四种同源猪细胞类型中协同毒性的标志物以及代谢途径的共同改变。这些发现加深了我们目前对霉菌毒素诱导协同毒性潜在分子机制的理解。
