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An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment

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Abstract

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.

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Abbreviations

AhR:

Aryl hydrocarbon receptor

AKNA:

AT-hook transcriptionfactor

Akt:

Serine/threonine protein kinase

ARE:

Antioxidant response element

CREB:

CAMP-response clement-binding protein

CYP450:

Cytochrome P450

DAS:

Diacetoxyscirpenol

DRP-1:

Dynamin-related protein 1

DON:

Deoxynivalenol

D3G:

Deoxynivalenol-3-glucoside

ECM:

Extracellular matrix

EIF2AK2:

Double-stranded RNA-activated protein kinase

ERK:

Etracellular signaling kinase

FXR:

Farnesoid X receptor

GH:

Growth hormone

GSTs:

Glutathione S-transferase

Hck:

Hemopoietic cell kinase

HIFs:

Hypoxia-inducible factors

HT-2:

HT-2 toxin

HT-2-β-Glc:

HT-2–3-β-glucoside

HT-2-3Glc:

HT-2–3-glucoside

HT2-3-GlcA:

HT-2–3-glucuronide

HT2-4-GlcA:

HT-2–4-glucuronide

IAPs:

Inhibitors of apoptosis proteins

IFN-γ:

Interferon-γ

ILVs:

Intraluminal vesicles

IRE1α:

Inositol requiring enzyme 1α

JAK:

Janus kinase

JNK:

C-jun amino-terminal kinase

LITAF:

Lipopolysaccharide-induced TNF factor

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloprotein

MT:

Methytransferase

mTORC2:

Mammalian target of rapamycin 2

MVEs:

Multivesicular endosomes

MyD88:

Myeloid differentiation factor 88

NATs:

Arylamine N-acetyltransferase

NEO:

Neosolaniol

NEO-3Glc:

Neosolaniol-3-glucoside

NF-Y:

Nuclear factor-Y

NOX:

NADPH oxidases

Nrf1:

Nuclear respiratory factor 1

Nrf2:

Nuclear erythroid 2-related factor 2

PKR:

RNA-activated protein kinase R

PRRSV:

Porcine reproductive and respiratory syndrome virus

RASSF4:

Ras association domain family 4

RIPK2:

Recombinant receptor interacting serine threonine kinase 2

ROS:

Reactive oxygen species

RSR:

Ribotoxic stress response

sEVs:

Small extracellular vesicles

SOCS1:

Suppressors of cytokine signaling members 1

StAR:

Steroidogenic acute regulatory protein

STAT:

Signal transducers and activators of the transcription

SULT:

Sulfotransferase

T-2:

T-2 toxin

T-2-α-Glc:

T-2–3-α-glucoside

T-2-β-Glc:

T-2–3-β-glucoside

T-2-3Glc:

T-2–3-glucoside

T2-3-GlcA:

T-2–3-glucuronide

TBK1:

TANK-binding kinase 1

TGF-β:

Transforming growth factor-β

TLR:

Toll-like receptors

UGT:

Uridine diphosphate glucuronyl transferase

XBP1:

X-box binding protein 1

XRE:

Xenobiotic-responsive element

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Acknowledgements

This research was supported by the National Key R & D Program (2016YFD0501207; 2016YFD0501009; 2018YFC1603005), National Natural Science Foundation of China (31972741; 31572576; 31572575), China Postdoctoral Science Foundation (2016T90477), PAPD, the Fundamental Research Funds for the Central Universities (2662020DKPY020), and Excellence Project UHK.

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  1. Qinghua Wu and Zihui Qin contributed equally to this work.

Authors and Affiliations

  1. College of Life Science, Yangtze University, Jingzhou, 434025, China

    Qinghua Wu, Li You & Yingying Zhao

  2. MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Zihui Qin & Wenda Wu

  3. Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic

    Qinghua Wu, Kamil Kuca, Kamil Musilek, Zofia Chrienova, Eugenie Nepovimova, Patrik Oleksak & Wenda Wu

  4. National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China

    Aimei Liu & Xu Wang

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Wu, Q., Qin, Z., Kuca, K. et al. An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment. Arch Toxicol 94, 3645–3669 (2020). https://doi.org/10.1007/s00204-020-02899-9

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