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T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1β and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.

During the last decade, the neurotoxicity of the trichothecenes T-2 toxin and deoxynivalenol (DON) has been a major concern, and many important findings have been reported on this topic. Through a summary of relevant research reports in recent years, we discuss the potential neurotoxic mechanisms of T-2 toxin and DON. In neuronal cells, T-2 toxin induces mitochondrial dysfunction and oxidative stress through a series of signalling pathways, including Nrf2/HO-1 and p53. This toxin crosses the blood-brain barrier (BBB) by altering permeability and induces oxidative stress responses, including ROS generation, lipid peroxidation, and protein carbonyl formation. Cellular metabolites (for example, HT-2 toxin) further promote neurotoxic effects. The type B trichothecene DON induces neuronal cell apoptosis via the MAPK and mitochondrial apoptosis pathways. This molecule induces inflammation of the central nervous system, increasing the expression of proinflammatory molecules. DON directly affects brain neurons and glial cells after passing through the BBB and affects the vitality and function of astrocytes and microglia. Exposure to trichothecenes alters brain dopamine levels, decreases ganglion area, and further induces brain damage. In this review, we mainly discuss the neurotoxicity of T-2 toxin and DON. However, our main goal was to reveal the potential mechanism(s) and offer new topics, including the potential of hypoxia-inducible factors, immune evasion, and exosomes, for future research in this context. This review should help elucidate the neurotoxic mechanism of trichothecenes and provides some potential inspiration for the follow-up study of neurotoxicity of mycotoxins., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.