College of Life Science, Yangtze University, Jingzhou, 434025, China.
Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic.
Arch Toxicol. 2020 Nov;94(11):3645-3669. doi: 10.1007/s00204-020-02899-9. Epub 2020 Sep 10.
T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.
T-2 毒素是毒性最强的单端孢霉烯族毒素之一，具有免疫毒性、神经毒性和生殖毒性等多种毒性作用。近年来，人们发现了一些新的代谢产物，包括 3'，4'-二羟基-T-2 毒素和 4'，4'-二羟基-T-2 毒素。细胞色素 P4503A4（CYP3A4）和羧酸酯酶参与 T-2 毒素的代谢，3'-羟基-T-2 毒素和 HT-2 毒素是其主要的初级产物。T-2 毒素的修饰形式，如 T-2-3-葡萄糖苷，通过 JAK/STAT 信号通路而不是 MAPK 发挥其免疫毒性作用。T-2-3-葡萄糖苷是由肠道微生物水解相应的母体真菌毒素和其他代谢物产生的，这导致了毒性的增强。越来越多的证据表明，自噬、缺氧诱导因子和外泌体参与了 T-2 毒素诱导的免疫毒性。自噬促进了 T-2 毒素诱导的免疫抑制，凋亡和自噬之间存在复杂的相互作用。最近有报道称，这种毒素与“免疫逃避”活性有关；这种活性始于细胞内部，使病原体能够逃避宿主的免疫反应。此外，T-2 毒素有可能引发细胞缺氧，这与缺氧诱导因子的激活和外泌体的释放有关，从而导致免疫毒性。基于一系列人类暴露研究的数据，游离 T-2 毒素、HT-2 毒素和 HT-2-4-葡萄糖苷应被视为尿液中人类 T-2 毒素的生物标志物。本综述重点介绍了与 T-2 毒素及其修饰形式的代谢、免疫毒性和人类暴露评估相关的新发现。特别是讨论了 T-2 毒素的免疫毒性机制及其修饰形式的毒性机制，以及人类 T-2 毒素生物标志物。这项工作将有助于更好地了解 T-2 毒素及其修饰形式的免疫毒性机制。
