T-2 toxin neurotoxicity: role of oxidative stress and mitochondrial dysfunction
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.
This review covers the main signaling pathways and molecular mechanisms of T-2 toxin induced neurotoxicity.
Oxidative stress and mitochondria dysfunction play a critical role during T-2 toxin induced neurotoxicity.
Perturbations to the mitochondrial respiratory chain complex and mitochondrial biogenesis occur as a result of T-2 toxin exposure.
T-2 toxin exposure results in perturbed mitochondria unfolded protein response and mitochondrial energy metabolism.
T-2 toxin can induce the activation of autophagy and mitophagy which play a protective role.
KeywordsT-2 toxin Neurotoxicity Oxidative stress Mitochondrial biogenesis Mitochondrial dysfunction
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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