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Archives of Toxicology

, Volume 93, Issue 11, pp 3041–3056 | Cite as

T-2 toxin neurotoxicity: role of oxidative stress and mitochondrial dysfunction

  • Chongshan DaiEmail author
  • Xilong Xiao
  • Feifei Sun
  • Yuan Zhang
  • Daniel Hoyer
  • Jianzhong Shen
  • Shusheng TangEmail author
  • Tony VelkovEmail author
Review Article

Abstract

Mycotoxins are highly diverse secondary metabolites produced in nature by a wide variety of fungi. Mycotoxins cause animal feed and food contamination, resulting in mycotoxicosis. T-2 toxin is one of the most common and toxic trichothecene mycotoxins. For the last decade, it has garnered considerable attention due to its potent neurotoxicity. Worryingly, T-2 toxin can cross the blood–brain barrier and accumulate in the central nervous system (CNS) to cause neurotoxicity. This review covers the current knowledge base on the molecular mechanisms of T-2 toxin-induced oxidative stress and mitochondrial dysfunction in the CNS. In vitro and animal data have shown that induction of reactive oxygen species (ROS) and oxidative stress plays a critical role during T-2 toxin-induced neurotoxicity. Mitochondrial dysfunction and cascade signaling pathways including p53, MAPK, Akt/mTOR, PKA/CREB and NF-κB contribute to T-2 toxin-induced neuronal cell death. T-2 toxin exposure can also result in perturbations of mitochondrial respiratory chain complex and mitochondrial biogenesis. T-2 toxin exposure decreases the mitochondria unfolded protein response and dampens mitochondrial energy metabolism. Antioxidants such as N-acetylcysteine (NAC), activation of Nrf2/HO-1 and autophagy have been shown to provide a protective effect against these detrimental effects. Clearly, translational research and the discovery of effective treatment strategies are urgently required against this common food-borne threat to human health and livestock.

Article Highlights

  1. (1)

    This review covers the main signaling pathways and molecular mechanisms of T-2 toxin induced neurotoxicity.

     
  2. (2)

    Oxidative stress and mitochondria dysfunction play a critical role during T-2 toxin induced neurotoxicity.

     
  3. (3)

    Perturbations to the mitochondrial respiratory chain complex and mitochondrial biogenesis occur as a result of T-2 toxin exposure.

     
  4. (4)

    T-2 toxin exposure results in perturbed mitochondria unfolded protein response and mitochondrial energy metabolism.

     
  5. (5)

    T-2 toxin can induce the activation of autophagy and mitophagy which play a protective role.

     

Keywords

T-2 toxin Neurotoxicity Oxidative stress Mitochondrial biogenesis Mitochondrial dysfunction 

Notes

Acknowledgements

S.T. and X.X. were supported by the Key Projects in Chinese National Science and Technology Pillar Program during the 12th Five-Year Plan Period (No. 2015BAD11B03) and the National Key Research and Development Program of China (Project No. 2018YFC1603005).

Compliance with ethical standards

Conflict of interest

The authors declared there was no any conflict of interest.

References

  1. Agrawal M, Bhaskar AS, Lakshmana Rao PV (2015) Involvement of mitogen-activated protein kinase pathway in T-2 toxin-induced cell cycle alteration and apoptosis in human neuroblastoma cells. Mol Neurobiol 51(3):1379–1394.  https://doi.org/10.1007/s12035-014-8816-4 CrossRefPubMedGoogle Scholar
  2. Aksoy A, Yavuz O, Das YK, Guvenc D, Muglali OH (2009) Occurrence of aflatoxin B1, T-2 toxin and zearalenone in compound animal feed. J Anim Vet Adv 8(3):403–407Google Scholar
  3. Arcella D, Gergelova P, Innocenti ML, Steinkellner H, EFS EFSA (2017) Human and animal dietary exposure to T-2 and HT-2 toxin. EFSA J.  https://doi.org/10.2903/j.efsa.2017.4972 CrossRefGoogle Scholar
  4. Arredondo F, Echeverry C, Abin-Carriquiry JA et al (2010) After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult. Free Radic Biol Med 49(5):738–747.  https://doi.org/10.1016/j.freeradbiomed.2010.05.020 CrossRefPubMedGoogle Scholar
  5. Atroshi F, Rizzo A, Biese I, Veijalainen P, Antila E, Westermarck T (1997) T-2 toxin-induced DNA damage in mouse livers: the effect of pretreatment with coenzyme Q(10) and alpha-tocopherol. Mol Aspects Med 18:S255–S258CrossRefGoogle Scholar
  6. Azem A, Oppliger W, Lustig A et al (1997) The mitochondrial hsp70 chaperone system—effect of adenine nucleotides, peptide substrate, and mGrpE on the oligomeric state of mhsp70. J Biol Chem 272(33):20901–20906.  https://doi.org/10.1074/jbc.272.33.20901 CrossRefPubMedGoogle Scholar
  7. Azouzi S, Santuz H, Morandat S et al (2017) Antioxidant and membrane binding properties of serotonin protect lipids from oxidation. Biophys J 112(9):1863–1873.  https://doi.org/10.1016/j.bpj.2017.03.037 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bertero A, Moretti A, Spicer LJ, Caloni F (2018) Fusarium molds and mycotoxins: potential species-specific effects. Toxins.  https://doi.org/10.3390/toxins10060244 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bin-Umer MA, McLaughlin JE, Basu D, McCormick S, Tumer NE (2011) Trichothecene mycotoxins inhibit mitochondrial translation-implication for the mechanism of toxicity. Toxins 3(12):1484–1501.  https://doi.org/10.3390/toxins3121484 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bouaziz C, Abid-Essefi S, Bouslimi A, El Golli E, Bacha H (2006) Cytotoxicity and related effects of T-2 toxin on cultured Vero cells. Toxicon 48(3):343–352.  https://doi.org/10.1016/j.toxicon.2006.06.004 CrossRefPubMedGoogle Scholar
  11. Bouaziz C, Martel C, Sharaf El Dein O et al (2009) Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis. Toxicol Sci 110(2):363–375.  https://doi.org/10.1093/toxsci/kfp117 CrossRefPubMedGoogle Scholar
  12. Capcarova M, Petruska P, Zbynovska K, Kolesarova A, Sirotkin AV (2015) Changes in antioxidant status of porcine ovarian granulosa cells after quercetin and T-2 toxin treatment. J Environ Sci Health Part B-Pestic Food Contam Agric Wastes 50(3):201–206.  https://doi.org/10.1080/03601234.2015.982425 CrossRefGoogle Scholar
  13. Chandel NS (2018) Mitochondria: back to the future. Nat Rev Mol Cell Biol 19(2):76.  https://doi.org/10.1038/nrm.2017.133 CrossRefPubMedGoogle Scholar
  14. Chaudhari M, Jayaraj R, Bhaskar AS, Lakshmana Rao PV (2009) Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells. Toxicology 262(2):153–161.  https://doi.org/10.1016/j.tox.2009.06.002 CrossRefPubMedGoogle Scholar
  15. Chaudhary M, Rao PV (2010) Brain oxidative stress after dermal and subcutaneous exposure of T-2 toxin in mice. Food Chem Toxicol 48(12):3436–3442.  https://doi.org/10.1016/j.fct.2010.09.018 CrossRefPubMedGoogle Scholar
  16. Cid-Castro C, Hernandez-Espinosa D, Moran J (2018) ROS as regulators of mitochondrial dynamics in neurons. Cell Mol Neurobiol 38(5):995–1007.  https://doi.org/10.1007/s10571-018-0584-7 CrossRefPubMedGoogle Scholar
  17. Dai C, Tang S, Deng S et al (2015) Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway. Antimicrob Agents Chemother 59(1):579–585.  https://doi.org/10.1128/AAC.03925-14 CrossRefPubMedGoogle Scholar
  18. Dai C, Li B, Zhou Y et al (2016a) Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells. Food Chem Toxicol 95:52–63.  https://doi.org/10.1016/j.fct.2016.06.025 CrossRefPubMedGoogle Scholar
  19. Dai CS, Tang SS, Velkov T, Xiao XL (2016b) Colistin-induced apoptosis of neuroblastoma-2a cells involves the generation of reactive oxygen species, mitochondrial dysfunction, and autophagy. Mol Neurobiol 53(7):4685–4700.  https://doi.org/10.1007/s12035-015-9396-7 CrossRefPubMedGoogle Scholar
  20. Dai C, Ciccotosto GD, Cappai R et al (2018) Curcumin attenuates colistin-induced neurotoxicity in N2a cells via anti-inflammatory activity, suppression of oxidative stress, and apoptosis. Mol Neurobiol 55(1):421–434.  https://doi.org/10.1007/s12035-016-0276-6 CrossRefPubMedGoogle Scholar
  21. Dai CS, Xiao XL, Li JC et al (2019) Molecular mechanisms of neurotoxicity induced by polymyxins and chemoprevention. ACS Chem Neurosci 10(1):120–131.  https://doi.org/10.1021/acschemneuro.8b00300 CrossRefPubMedGoogle Scholar
  22. De Ruyck K, De Boevre M, Huybrechts I, De Saeger S (2015) Dietary mycotoxins, co-exposure, and carcinogenesis in humans: short review. Mutat Res, Rev Mutat Res 766:32–41.  https://doi.org/10.1016/j.mrrev.2015.07.003 CrossRefGoogle Scholar
  23. Desjardins AE, Hohn TM, McCormick SP (1993) Trichothecene biosynthesis in Fusarium species: chemistry, genetics, and significance. Microbiol Rev 57(3):595–604PubMedPubMedCentralGoogle Scholar
  24. Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD (2019) Modulating NRF2 in disease: timing is everything. Annu Rev Pharmacol Toxicol 59(59):555–575.  https://doi.org/10.1146/annurev-pharmtox-010818-021856 CrossRefPubMedGoogle Scholar
  25. Dohnal V, Jezkova A, Jun D, Kuca K (2008) Metabolic pathways of T-2 toxin. Curr Drug Metab 9(1):77–82CrossRefGoogle Scholar
  26. Doi K, Uetsuka K (2011) Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci 12(8):5213–5237.  https://doi.org/10.3390/ijms12085213 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Drechsel DA, Patel M (2008a) Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radical Biol Med 44(11):1873–1886.  https://doi.org/10.1016/j.freeradbiomed.2008.02.008 CrossRefGoogle Scholar
  28. Drechsel DA, Patel M (2008b) Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease (vol 44, pg 1873. Free Radical Biol Med 45(7):1045.  https://doi.org/10.1016/j.freeadbiomed.2008.07.005 CrossRefGoogle Scholar
  29. Dvorska JE, Pappas AC, Karadas F, Speake BK, Surai PF (2007) Protective effect of modified glucomannans and organic selenium against antioxidant depletion in the chicken liver due to T-2 toxin-contaminated feed consumption. Comp Biochem Physiol C-Toxicol Pharmacol 145(4):582–587.  https://doi.org/10.1016/j.cbpc.2007.02.005 CrossRefPubMedGoogle Scholar
  30. Efeyan A, Comb WC, Sabatini DM (2015) Nutrient-sensing mechanisms and pathways. Nature 517(7534):302–310.  https://doi.org/10.1038/nature14190 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Fairhurst S, Marrs TC, Parker HC, Scawin JW, Swanston DW (1987) Acute toxicity of T2 toxin in rats, mice, guinea pigs, and pigeons. Toxicology 43(1):31–49CrossRefGoogle Scholar
  32. Fang HQ, Cong LZ, Zhi Y, Xu HB, Jia XD, Peng SQ (2016) T-2 toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway. Toxicol Lett 258:259–266.  https://doi.org/10.1016/j.toxlet.2016.06.2103 CrossRefPubMedGoogle Scholar
  33. Fanibunda SE, Deb S, Maniyadath B et al (2019) Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1 alpha axis. Proc Natl Acad Sci USA 116(22):11028–11037.  https://doi.org/10.1073/pnas.1821332116 CrossRefPubMedGoogle Scholar
  34. Fatima Z, Guo P, Huang DY et al (2018) The critical role of p16/Rb pathway in the inhibition of GH3 cell cycle induced by T-2 toxin. Toxicology 400:28–39.  https://doi.org/10.1016/j.tox.2018.03.006 CrossRefPubMedGoogle Scholar
  35. Ferri P, Angelino D, Gennari L et al (2015) Enhancement of flavonoid ability to cross the blood-brain barrier of rats by co-administration with alpha-tocopherol. Food Funct 6(2):394–400.  https://doi.org/10.1039/c4fo00817k CrossRefPubMedGoogle Scholar
  36. Gaige S, Djelloul M, Tardivel C et al (2014) Modification of energy balance induced by the food contaminant T-2 toxin: a multimodal gut-to-brain connection. Brain Behav Immun 37:54–72.  https://doi.org/10.1016/j.bbi.2013.12.008 CrossRefPubMedGoogle Scholar
  37. Galtier P, Paulin F, Eeckhoutte C, Larrieu G (1989) Comparative effects of T-2 toxin and diacetoxyscirpenol on drug-metabolizing enzymes in rat-tissues. Food Chem Toxicol 27(4):215–220.  https://doi.org/10.1016/0278-6915(89)90158-0 CrossRefPubMedGoogle Scholar
  38. Gao Q, Jiang T, Zhao HR et al (2016) Activation of autophagy contributes to the angiotensin II-triggered apoptosis in a dopaminergic neuronal cell line. Mol Neurobiol 53(5):2911–2919.  https://doi.org/10.1007/s12035-015-9177-3 CrossRefPubMedGoogle Scholar
  39. Ghosh C, Hossain M, Solanki J, Dadas A, Marchi N, Janigro D (2016) Pathophysiological implications of neurovascular P450 in brain disorders. Drug Discov Today 21(10):1609–1619.  https://doi.org/10.1016/j.drudis.2016.06.004 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Guo P, Liu A, Huang D et al (2018) Brain damage and neurological symptoms induced by T-2 toxin in rat brain. Toxicol Lett 286:96–107.  https://doi.org/10.1016/j.toxlet.2018.01.012 CrossRefPubMedGoogle Scholar
  41. Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195(1):198–213.  https://doi.org/10.1016/j.bbr.2008.03.020 CrossRefPubMedGoogle Scholar
  42. He MD, Xu SC, Lu YH et al (2011) L-carnitine protects against nickel-induced neurotoxicity by maintaining mitochondrial function in Neuro-2a cells. Toxicol Appl Pharmacol 253(1):38–44.  https://doi.org/10.1016/j.taap.2011.03.008 CrossRefPubMedGoogle Scholar
  43. Hiller DA, Singh V, Zhong M, Strobel SA (2011) A two-step chemical mechanism for ribosome-catalysed peptide bond formation. Nature 476(7359):236–239.  https://doi.org/10.1038/nature10248 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Hu P, Wang M, Chen WH et al (2008) Quercetin relieves chronic lead exposure-induced impairment of synaptic plasticity in rat dentate gyrus in vivo. Naunyn Schmiedebergs Arch Pharmacol 378(1):43–51.  https://doi.org/10.1007/s00210-008-0301-z CrossRefPubMedGoogle Scholar
  45. Huang DY, Cui LQ, Liu XL et al (2018) Protective mechanisms involving enhanced mitochondrial functions and mitophagy against T-2 toxin-induced toxicities in GH3 cells. Toxicol Lett 295:41–53.  https://doi.org/10.1016/j.toxlet.2018.05.041 CrossRefGoogle Scholar
  46. Huebbe P, Wagner AE, Boesch-Saadatmandi C, Sellmer F, Wolffram S, Rimbach G (2010) Effect of dietary quercetin on brain quercetin levels and the expression of antioxidant and Alzheimer’s disease relevant genes in mice. Pharmacol Res 61(3):242–246.  https://doi.org/10.1016/j.phrs.2009.08.006 CrossRefPubMedGoogle Scholar
  47. Hussein HS, Brasel JM (2001) Toxicity, metabolism, and impact of mycotoxins on humans and animals. Toxicology 167(2):101–134.  https://doi.org/10.1016/S0300-483x(01)00471-1 CrossRefPubMedGoogle Scholar
  48. IARC (1993) Monographs on the evaluation of carcinogenic risks to humans: some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. Lyon, France: Int Agency Res Cancer 56:1–599Google Scholar
  49. Ishisaka A, Ichikawa S, Sakakibara H et al (2011) Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radical Biol Med 51(7):1329–1336.  https://doi.org/10.1016/j.freeradbiomed.2011.06.017 CrossRefGoogle Scholar
  50. Islam MT, Mishra SK, Tripathi S et al (2018) Mycotoxin-assisted mitochondrial dysfunction and cytotoxicity: unexploited tools against proliferative disorders. IUBMB Life 70(11):1084–1092.  https://doi.org/10.1002/iub.1932 CrossRefPubMedGoogle Scholar
  51. Jezek J, Cooper KF, Strich R (2018) Reactive oxygen species and mitochondrial dynamics: the yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants.  https://doi.org/10.3390/antiox7010013 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Jornayvaz FR, Shulman GI (2010) Regulation of mitochondrial biogenesis. Essays in Biochem Mitochondrial Funct 47:69–84.  https://doi.org/10.1042/Bse0470069 CrossRefGoogle Scholar
  53. Jovaisaite V, Mouchiroud L, Auwerx J (2014) The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease. J Exp Biol 217(1):137–143.  https://doi.org/10.1242/jeb.090738 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Konigs M, Mulac D, Schwerdt G, Gekle M, Humpf HU (2009) Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture. Toxicology 258(2–3):106–115.  https://doi.org/10.1016/j.tox.2009.01.012 CrossRefPubMedGoogle Scholar
  55. Koppenol WH (1993) The centennial of the fenton reaction. Free Radical Biol Med 15(6):645–651.  https://doi.org/10.1016/0891-5849(93)90168-T CrossRefGoogle Scholar
  56. Kramer BC, Yabut JA, Cheong J et al (2004) Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites. Eur J Neurosci 19(2):280–286.  https://doi.org/10.1046/j.1460-9568.2003.03111.x CrossRefPubMedGoogle Scholar
  57. Kumar MR, Reddy GR (2018) Influence of age on arsenic-induced behavioral and cholinergic perturbations: amelioration with zinc and alpha-tocopherol. Hum Exp Toxicol 37(3):295–308.  https://doi.org/10.1177/0960327117698540 CrossRefPubMedGoogle Scholar
  58. Lakroun Z, Kebieche M, Lahouel A, Zama D, Desor F, Soulimani R (2015) Oxidative stress and brain mitochondria swelling induced by endosulfan and protective role of quercetin in rat. Environ Sci Pollut Res Int 22(10):7776–7781.  https://doi.org/10.1007/s11356-014-3885-5 CrossRefPubMedGoogle Scholar
  59. Lei RH, Jiang N, Zhang Q et al (2016) Prevalence of selenium, T-2 toxin, and deoxynivalenol in Kashin–Beck disease areas in Qinghai Province, Northwest China. Biol Trace Elem Res 171(1):34–40.  https://doi.org/10.1007/s12011-015-0495-0 CrossRefPubMedGoogle Scholar
  60. Lemarie A, Grimm S (2011) Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer. Oncogene 30(38):3985–4003.  https://doi.org/10.1038/onc.2011.167 CrossRefPubMedGoogle Scholar
  61. Leu JIJ, Barnoud T, Zhang G et al (2017) Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function. Oncotarget 8(28):45656–45669.  https://doi.org/10.18632/oncotarget.17321 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Lewis L, Onsongo M, Njapau H et al (2005) Aflatoxin contamination of commercial maize products during an outbreak of acute aflatoxicosis in eastern and central Kenya. Environ Health Perspect 113(12):1763–1767.  https://doi.org/10.1289/ehp.7998 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Limonciel A, Jennings P (2014) A review of the evidence that ochratoxin A is an Nrf2 Inhibitor: implications for nephrotoxicity and renal carcinogenicity. Toxins 6(1):371–379.  https://doi.org/10.3390/toxins6010371 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Liu J, Wang L, Guo X et al (2014a) The role of mitochondria in T-2 toxin-induced human chondrocytes apoptosis. PLoS One 9(9):e108394.  https://doi.org/10.1371/journal.pone.0108394 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Liu JT, Wang LL, Guo X et al (2014b) The role of mitochondria in T-2 toxin-induced human chondrocytes apoptosis. PLoS One.  https://doi.org/10.1371/journal.pone.0108394 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Liu X, Huang D, Guo P et al (2017a) PKA/CREB and NF-kappaB pathway regulates AKNA transcription: a novel insight into T-2 toxin-induced inflammation and GH deficiency in GH3 cells. Toxicology 392:81–95.  https://doi.org/10.1016/j.tox.2017.10.013 CrossRefPubMedGoogle Scholar
  67. Liu XL, Guo P, Liu AM et al (2017b) Nitric oxide (NO)-mediated mitochondrial damage plays a critical role in T-2 toxin -induced apoptosis and growth hormone deficiency in rat anterior pituitary GH3 cells. Food Chem Toxicol 102:11–23.  https://doi.org/10.1016/j.fct.2017.01.017 CrossRefPubMedGoogle Scholar
  68. Loboda A, Stachurska A, Sobczak M et al (2017) Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo. Toxicology 389:42–52.  https://doi.org/10.1016/j.tox.2017.07.004 CrossRefPubMedGoogle Scholar
  69. Lv C, Hong T, Yang Z et al (2012) Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Evid Based Complement Alternat Med 2012:928643.  https://doi.org/10.1155/2012/928643 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426.  https://doi.org/10.1146/annurev-pharmtox-011112-140320 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Ma SJ, Zhao YR, Sun JW, Mu PQ, Deng YQ (2018) miR449a/SIRT1/PGC-1 alpha is necessary for mitochondrial biogenesis induced by T-2 toxin. Front Pharmacol.  https://doi.org/10.3389/fphar.2017.00954 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Mackei M, Matis G, Neogrady Z (2018) The effects of T-2 toxin on animal health, focusing especially on poultry. Magyar Allatorvosok Lapja 140(8):475–483Google Scholar
  73. Maggiorani D, Manzella N, Edmondson DE et al (2017) Monoamine oxidases, oxidative stress, and altered mitochondrial dynamics in cardiac ageing. Oxid Med Cell Longev 2017:3017947.  https://doi.org/10.1155/2017/3017947 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Martinez MC, Andriantsitohaina R (2009) Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid Redox Signal 11(3):669–702.  https://doi.org/10.1089/ars.2007.1993 CrossRefPubMedGoogle Scholar
  75. Meissonnier GM, Laffitte J, Raymond I et al (2008) Subclinical doses of T-2 toxin impair acquired immune response and liver cytochrome P450 in pigs. Toxicology 247(1):46–54.  https://doi.org/10.1016/j.tox.2008.02.003 CrossRefPubMedGoogle Scholar
  76. Moosavi M, Rezaei M, Kalantari H, Behfar A, Varnaseri G (2016) l-carnitine protects rat hepatocytes from oxidative stress induced by T-2 toxin. Drug Chem Toxicol 39(4):445–450.  https://doi.org/10.3109/01480545.2016.1141423 CrossRefPubMedGoogle Scholar
  77. Morris G, Anderson G, Dean O et al (2014) The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol 50(3):1059–1084.  https://doi.org/10.1007/s12035-014-8705-x CrossRefPubMedGoogle Scholar
  78. Mu P, Xu M, Zhang L et al (2013) Proteomic changes in chicken primary hepatocytes exposed to T-2 toxin are associated with oxidative stress and mitochondrial enhancement. Proteomics 13(21):3175–3188.  https://doi.org/10.1002/pmic.201300015 CrossRefPubMedGoogle Scholar
  79. Nakajima K, Masubuchi Y, Ito Y et al (2018) Developmental exposure of citreoviridin transiently affects hippocampal neurogenesis targeting multiple regulatory functions in mice. Food Chem Toxicol 120:590–602.  https://doi.org/10.1016/j.fct.2018.07.051 CrossRefPubMedGoogle Scholar
  80. Nakajima K, Tanaka T, Masubuchi Y et al (2019) Developmental exposure of mice to T-2 toxin increases astrocytes and hippocampal neural stem cells expressing metallothionein. Neurotox Res 35(3):668–683.  https://doi.org/10.1007/s12640-018-9981-4 CrossRefPubMedGoogle Scholar
  81. Nam SM, Ahn SC, Go TH et al (2018) Ascorbic acid ameliorates gestational lead exposure-induced developmental alteration in GAD67 and c-Kit expression in the rat cerebellar Cortex. Biol Trace Elem Res 182(2):278–286.  https://doi.org/10.1007/s12011-017-1086-z CrossRefPubMedGoogle Scholar
  82. Ohta M, Ishii K, Ueno Y (1977) Metabolism of trichothecene mycotoxins. 1. Microsomal deacetylation of T-2 Toxin in animal-tissues. J Biochem 82(6):1591–1598.  https://doi.org/10.1093/oxfordjournals.jbchem.a131854 CrossRefPubMedGoogle Scholar
  83. Pace JG, Watts MR, Canterbury WJ (1988) T-2 mycotoxin inhibits mitochondrial protein synthesis. Toxicon 26(1):77–85CrossRefGoogle Scholar
  84. Pearson JN, Patel M (2016) The role of oxidative stress in organophosphate and nerve agent toxicity. Countermeasures against chemical threats Ii. Ann N Y Acad Sci 1378:17–24.  https://doi.org/10.1111/nyas.13115 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Pelyhe C, Kovesi B, Zandoki E et al (2016) Short-term effects of T-2 toxin or deoxynivalenol on lipid peroxidation and the glutathione system in common carp. Acta Vet Hung 64(4):449–466.  https://doi.org/10.1556/004.2016.042 CrossRefPubMedGoogle Scholar
  86. Poersch AB, Trombetta F, Souto NS et al (2015) Fumonisin B1 facilitates seizures induced by pentylenetetrazol in mice. Neurotoxicol Teratol 51:61–67.  https://doi.org/10.1016/j.ntt.2015.08.007 CrossRefPubMedGoogle Scholar
  87. Raimundo N (2014) Mitochondrial pathology: stress signals from the energy factory. Trends Mol Med 20(5):282–292.  https://doi.org/10.1016/j.molmed.2014.01.005 CrossRefPubMedGoogle Scholar
  88. Ratnaseelan AM, Tsilioni I, Theoharides TC (2018) Effects of mycotoxins on neuropsychiatric symptoms and immune processes. Clin Ther 40(6):903–917.  https://doi.org/10.1016/j.clinthera.2018.05.004 CrossRefPubMedGoogle Scholar
  89. Ravindran J, Agrawal M, Gupta N, Rao PV (2011) Alteration of blood brain barrier permeability by T-2 toxin: role of MMP-9 and inflammatory cytokines. Toxicology 280(1–2):44–52.  https://doi.org/10.1016/j.tox.2010.11.006 CrossRefPubMedGoogle Scholar
  90. Reed JR, Cawley GF, Backes WL (2011) Inhibition of cytochrome P450 1A2-mediated metabolism and production of reactive oxygen species by heme oxygenase-1 in rat liver microsomes. Drug Metab Lett 5(1):6–16CrossRefGoogle Scholar
  91. Rizzo AF, Atroshi F, Ahotupa M, Sankari S, Elovaara E (1994) Protective effect of antioxidants against free radical-mediated lipid-peroxidation induced by don or T-2 toxin. J Vet Med Ser -Zentralblatt Fur Veterinarmedizin Reihe a-Physiol Pathol Clin Med 41(2):81–90.  https://doi.org/10.1111/j.1439-0442.1994.tb00070.x CrossRefGoogle Scholar
  92. Salimian J, Arefpour MA, Riazipour M, Poursasan N (2014) Immunomodulatory effects of selenium and vitamin E on alterations in T lymphocyte subsets induced by T-2 toxin. Immunopharmacol Immunotoxicol 36(4):275–281.  https://doi.org/10.3109/08923973.2014.931420 CrossRefPubMedGoogle Scholar
  93. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462.  https://doi.org/10.1016/j.cub.2014.03.034 CrossRefPubMedPubMedCentralGoogle Scholar
  94. Schothorst RC, van Egmond HP (2004) Report from SCOOP task 3.2.10 “collection of occurrence data of Fusarium toxins in food and assessment of dietary intake by the population of EU member states”. Subtask: trichothecenes. Toxicol Lett 153(1):133–143.  https://doi.org/10.1016/j.toxlet.2004.04.045 CrossRefPubMedGoogle Scholar
  95. Sheng K, Lu X, Yue J et al (2019) Role of neurotransmitters 5-hydroxytryptamine and substance P in anorexia induction following oral exposure to the trichothecene T-2 toxin. Food Chem Toxicol 123:1–8.  https://doi.org/10.1016/j.fct.2018.10.041 CrossRefPubMedGoogle Scholar
  96. Sintov A, Bialer M, Yagen B (1986) Pharmacokinetics of T-2-toxin and its metabolite Ht-2-toxin, after intravenous administration in dogs. Drug Metab Dispos 14(2):250–254PubMedGoogle Scholar
  97. Sintov A, Bialer M, Yagen B (1987) Pharmacokinetics of T-2 tetraol, a urinary metabolite of the trichothecene mycotoxin, T-2 toxin, in dog. Xenobiotica 17(8):941–950.  https://doi.org/10.3109/00498258709044192 CrossRefPubMedGoogle Scholar
  98. Sintov A, Bialer M, Yagen B (1988) Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs. Toxicon 26(2):153–160CrossRefGoogle Scholar
  99. Sudakin DL (2003) Trichothecenes in the environment: relevance to human health. Toxicol Lett 143(2):97–107CrossRefGoogle Scholar
  100. Sun LY, Li Q, Meng FG, Fu Y, Zhao ZJ, Wang LH (2012) T-2 Toxin contamination in grains and selenium concentration in drinking water and grains in Kashin–Beck disease endemic areas of Qinghai Province. Biol Trace Elem Res 150(1–3):371–375.  https://doi.org/10.1007/s12011-012-9469-7 CrossRefPubMedGoogle Scholar
  101. Tan YF, Kuang Y, Zhao RH, Chen B, Wu JW (2011) Determination of T-2 and HT-2 toxins in traditional chinese medicine marketed in China by LC-ELSD after sample clean-up by two solid-phase extractions. Chromatographia 73(3–4):407–410.  https://doi.org/10.1007/s10337-010-1890-5 CrossRefGoogle Scholar
  102. Tang DL, Kang R, Vanden Berghe T, Vandenabeele P, Kroemer G (2019) The molecular machinery of regulated cell death. Cell Res 29(5):347–364.  https://doi.org/10.1038/s41422-019-0164-5 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Tripathi VK, Kumar V, Pandey A et al (2017) Monocrotophos induces the expression of xenobiotic metabolizing cytochrome P450 s (CYP2C8 and CYP3A4) and neurotoxicity in human brain cells. Mol Neurobiol 54(5):3633–3651.  https://doi.org/10.1007/s12035-016-9938-7 CrossRefPubMedGoogle Scholar
  104. Tye KM, Mirzabekov JJ, Warden MR et al (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493(7433):537–541.  https://doi.org/10.1038/nature11740 CrossRefPubMedGoogle Scholar
  105. V Xl, Fielding-Singh V, Iwashyna TJ, Bhattacharya J, Escobar GJ (2017) Reply: the timing of early antibiotics and hospital mortality in sepsis: playing devil’s advocate. Am J Respir Crit Care Med 196(7):935–936.  https://doi.org/10.1164/rccm.201704-0774LE CrossRefGoogle Scholar
  106. Wan D, Wang X, Wu QH et al (2015) Integrated transcriptional and proteomic analysis of growth hormone suppression mediated by trichothecene T-2 toxin in rat GH3 cells. Toxicol Sci 147(2):326–338.  https://doi.org/10.1093/toxsci/kfv131 CrossRefPubMedGoogle Scholar
  107. Wang J, Fitzpatrick DW, Wilson JR (1993) Effect of dietary T-2 toxin on biogenic monoamines in discrete areas of the rat-brain. Food Chem Toxicol 31(3):191–197.  https://doi.org/10.1016/0278-6915(93)90093-E CrossRefPubMedGoogle Scholar
  108. Wang XC, Liu XD, Liu JC, Wang G, Wan KY (2012) Contamination level of T-2 and HT-2 toxin in cereal crops from Aba area in Sichuan Province, China. Bull Environ Contam Toxicol 88(3):396–400.  https://doi.org/10.1007/s00128-011-0478-6 CrossRefPubMedGoogle Scholar
  109. Wang X, Xu W, Fan M et al (2016) Deoxynivalenol induces apoptosis in PC12 cells via the mitochondrial pathway. Environ Toxicol Pharmacol 43:193–202.  https://doi.org/10.1016/j.etap.2016.03.016 CrossRefPubMedGoogle Scholar
  110. Wang H, Zhu J, Li L et al (2017) Effects of Nrf2 deficiency on arsenic metabolism in mice. Toxicol Appl Pharmacol 337:111–119.  https://doi.org/10.1016/j.taap.2017.11.001 CrossRefPubMedGoogle Scholar
  111. Wang J, Yang C, Yuan Z, Yi J, Wu J (2018a) T-2 toxin exposure induces apoptosis in TM3 cells by inhibiting mammalian target of rapamycin/serine/threonine protein kinase(mTORC2/AKT) to promote Ca(2 +)production. Int J Mol Sci.  https://doi.org/10.3390/ijms19113360 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Wang X, Fan M, Chu X et al (2018b) Deoxynivalenol induces toxicity and apoptosis in piglet hippocampal nerve cells via the MAPK signaling pathway. Toxicon 155:1–8.  https://doi.org/10.1016/j.toxicon.2018.09.006 CrossRefPubMedGoogle Scholar
  113. Wang SL, Xia B, Qiao ZL et al (2019) Tetramethylpyrazine attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells through regulating apoptosis, autophagy and oxidative damage. Drug Design Dev Therapy 13:1187–1196.  https://doi.org/10.2147/Dddt.S196172 CrossRefGoogle Scholar
  114. Weekley LB, O’Rear CE, Kimbrough TD, Llewellyn GC (1989) Acute and chronic effects of the trichothecene mycotoxin T-2 on rat brain regional concentrations of serotonin, tryptophan, and tyrosine. Vet Hum Toxicol 31(3):221–224PubMedGoogle Scholar
  115. Weidner M, Huwel S, Ebert F, Schwerdtle T, Galla HJ, Humpf HU (2013a) Influence of T-2 and HT-2 toxin on the blood-brain barrier in vitro: new experimental hints for neurotoxic effects. PLoS One 8(3):e60484.  https://doi.org/10.1371/journal.pone.0060484 CrossRefPubMedPubMedCentralGoogle Scholar
  116. Weidner M, Lenczyk M, Schwerdt G, Gekle M, Humpf HU (2013b) Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. Chem Res Toxicol 26(3):347–355.  https://doi.org/10.1021/tx3004664 CrossRefPubMedGoogle Scholar
  117. Wild CP, Gong YY (2010) Mycotoxins and human disease: a largely ignored global health issue. Carcinogenesis 31(1):71–82.  https://doi.org/10.1093/carcin/bgp264 CrossRefPubMedGoogle Scholar
  118. Wu Q, Dohnal V, Huang L, Kuca K, Yuan Z (2010) Metabolic pathways of trichothecenes. Drug Metab Rev 42(2):250–267.  https://doi.org/10.1080/03602530903125807 CrossRefPubMedGoogle Scholar
  119. Wu J, Jing L, Yuan H, Peng SQ (2011a) T-2 toxin induces apoptosis in ovarian granulosa cells of rats through reactive oxygen species-mediated mitochondrial pathway. Toxicol Lett 202(3):168–177.  https://doi.org/10.1016/j.toxlet.2011.01.029 CrossRefPubMedGoogle Scholar
  120. Wu QH, Huang LL, Liu ZY et al (2011b) A comparison of hepatic in vitro metabolism of T-2 toxin in rats, pigs, chickens, and carp. Xenobiotica 41(10):863–873.  https://doi.org/10.3109/00498254.2011.593206 CrossRefPubMedGoogle Scholar
  121. Wu J, Tu D, Yuan LY, Yuan H, Wen LX (2013) T-2 toxin exposure induces apoptosis in rat ovarian granulosa cells through oxidative stress. Environ Toxicol Pharmacol 36(2):493–500.  https://doi.org/10.1016/j.etap.2013.03.017 CrossRefPubMedGoogle Scholar
  122. Wu QH, Wang X, Wan D, Li J, Yuan ZH (2014a) Crosstalk of JNK1-STAT3 is critical for RAW264.7 cell survival. Cellular Signalling 26(12):2951–2960.  https://doi.org/10.1016/j.cellsig.2014.09.013 CrossRefPubMedGoogle Scholar
  123. Wu QH, Wang X, Yang W et al (2014b) Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch Toxicol 88(7):1309–1326.  https://doi.org/10.1007/s00204-014-1280-0 CrossRefPubMedGoogle Scholar
  124. Wu J, Zhou Y, Yuan ZH et al (2019) Autophagy and apoptosis interact to modulate T-2 toxin-induced toxicity in liver cells. Toxins.  https://doi.org/10.3390/toxins11010045 CrossRefPubMedPubMedCentralGoogle Scholar
  125. Xu J, Pan S, Gan F et al (2018) Selenium deficiency aggravates T-2 toxin-induced injury of primary neonatal rat cardiomyocytes through ER stress. Chem Biol Interact 285:96–105.  https://doi.org/10.1016/j.cbi.2018.01.021 CrossRefPubMedGoogle Scholar
  126. Yang SP, Li YS, Cao XP et al (2013) Metabolic pathways of T-2 toxin in in vivo and in vitro systems of Wistar rats. J Agric Food Chem 61(40):9734–9743.  https://doi.org/10.1021/jf4012054 CrossRefPubMedGoogle Scholar
  127. Yang LC, Yu ZZ, Hou JF et al (2016) Toxicity and oxidative stress induced by T-2 toxin and HT-2 toxin in broilers and broiler hepatocytes. Food Chem Toxicol 87:128–137.  https://doi.org/10.1016/j.fct.2015.12.003 CrossRefPubMedGoogle Scholar
  128. Yang S, Van Poucke C, Wang Z, Zhang S, De Saeger S, De Boevre M (2017a) Metabolic profile of the masked mycotoxin T-2 toxin-3-glucoside in rats (in vitro and in vivo) and humans (in vitro). World Mycotoxin J 10(4):349–362.  https://doi.org/10.3920/Wmj2017.2224 CrossRefGoogle Scholar
  129. Yang SP, De Boevre M, Zhang HY et al (2017b) Metabolism of T-2 toxin in farm animals and human in vitro and in chickens in vivo using ultra high-performance liquid chromatography- quadrupole/time-of-flight hybrid mass spectrometry along with online hydrogen/deuterium exchange technique. J Agric Food Chem 65(33):7217–7227.  https://doi.org/10.1021/acs.jafc.7b02575 CrossRefPubMedGoogle Scholar
  130. Yang JY, Zhang YF, Li YX, Meng XP, Bao JF (2018) l-arginine protects against oxidative damage induced by T-2 toxin in mouse Leydig cells. J Biochem Mol Toxicol 32(10):e22209.  https://doi.org/10.1002/jbt.22209 CrossRefPubMedGoogle Scholar
  131. Yang L, Tu D, Wang N et al (2019) The protective effects of DL-Selenomethionine against T-2/HT-2 toxins-induced cytotoxicity and oxidative stress in broiler hepatocytes. Toxicol In Vitro 54:137–146.  https://doi.org/10.1016/j.tiv.2018.09.016 CrossRefPubMedGoogle Scholar
  132. Ye W, Lin R, Chen X et al (2019) T-2 toxin upregulates the expression of human cytochrome P450 1A1 (CYP1A1) by enhancing NRF1 and Sp1 interaction. Toxicol Lett.  https://doi.org/10.1016/j.toxlet.2019.08.021 CrossRefPubMedGoogle Scholar
  133. Yi YL, Zhao F, Wang N et al (2018) Endoplasmic reticulum stress is involved in the T-2 toxin-induced apoptosis in goat endometrium epithelial cells. J Appl Toxicol 38(12):1492–1501.  https://doi.org/10.1002/jat.3655 CrossRefPubMedGoogle Scholar
  134. Yoon MS (2017) mTOR as a key regulator in maintaining skeletal muscle mass. Front Physiol.  https://doi.org/10.3389/fphys.2017.00788 CrossRefPubMedPubMedCentralGoogle Scholar
  135. Zain ME (2011) Impact of mycotoxins on humans and animals. J Saudi Chem Soc 15(2):129–144.  https://doi.org/10.1016/j.jscs.2010.06.006 CrossRefGoogle Scholar
  136. Zhang Y, Yi B, Ma J et al (2015) Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage. Neurochem Res 40(1):195–203.  https://doi.org/10.1007/s11064-014-1457-1 CrossRefPubMedGoogle Scholar
  137. Zhang J, Zhang H, Liu SL, Wu WD, Zhang HB (2018a) Comparison of anorectic potencies of type A trichothecenes T-2 toxin, HT-2 toxin, diacetoxyscirpenol, and neosolaniol. Toxins.  https://doi.org/10.3390/toxins10050179 CrossRefPubMedPubMedCentralGoogle Scholar
  138. Zhang X, Wang Y, Velkov T, Tang S, Dai C (2018b) T-2 toxin-induced toxicity in neuroblastoma-2a cells involves the generation of reactive oxygen, mitochondrial dysfunction and inhibition of Nrf2/HO-1 pathway. Food Chem Toxicol 114:88–97.  https://doi.org/10.1016/j.fct.2018.02.010 CrossRefPubMedGoogle Scholar
  139. Zhang YF, Yang JY, Meng XP, Qiao XL (2018c) l-arginine protects against T-2 toxin-induced male reproductive impairments in mice. Theriogenology 126:249–253.  https://doi.org/10.1016/j.theriogenology.2018.12.024 CrossRefPubMedGoogle Scholar
  140. Zhao X, Wang R, Xiong J et al (2017) JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2. Toxicol Lett 277:32–40.  https://doi.org/10.1016/j.toxlet.2017.04.011 CrossRefPubMedGoogle Scholar
  141. Zorova LD, Popkov VA, Plotnikov EY et al (2018) Mitochondrial membrane potential. Anal Biochem 552:50–59.  https://doi.org/10.1016/j.ab.2017.07.009 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Veterinary MedicineChina Agricultural UniversityBeijingPeople’s Republic of China
  2. 2.Division of Cardiology, Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleAustralia

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