The nephrotoxicity of T-2 toxin in mice caused by oxidative stress-mediated apoptosis is related to Nrf2 pathway
Graphical abstract
Introduction
T-2 toxin is produced by the Fusarium genus as a secondary metabolite (Li et al., 2011) and widely found in cereals of many countries (Wang et al., 2010). Ingestion of food or feed contaminated by T-2 toxin will cause damage to human and animal tissues and organs (Wu et al., 2010). According to international regulations, the daily tolerable intake of T-2 toxin should be less than 100 ng/kg body weight (BW) (Weidner et al., 2012). The global report of Biomin in 2018 showed that among 8721 kinds of agricultural products from 75 countries, the detection rate of T-2 toxin was as high as 23%, the average detection amount was 25 mg/kg (Schmidt et al., 2018). T-2 toxin can remain in animal tissues, meat, eggs, and milk, and threaten human health through the food chain, which can be a risk factor for causing fatal alimentary toxic aleukia and Kaschin-Beck Disease in human (Lei et al., 2016; Wu et al., 2014). Previous studies have shown that T-2 toxin is toxic to kidney (Rahman et al., 2016), however, the specific mechanism is still uncertain.
Oxidative stress is one of the toxic mechanisms of mycotoxins. Researches showed T-2 toxin caused the renal oxidative stress of rat (Rahman et al., 2016), rabbit (Liu et al., 2020), broiler chicken (Wan et al., 2016), and common carp (Matejova et al., 2017). Excessive reactive oxygen species (ROS) can trigger apoptosis, and it is confirmed that oxidative stress is a upstream activator of apoptosis signal cascade (Chan et al., 2006; Wen-Hsiung, 2006). T-2 toxin initiated mitochondrial apoptosis through oxidative stress, and then led to damage of murine embryonic stem cells (Fang et al., 2012). T-2 toxin caused oxidative stress and apoptosis of human renal tubular epithelial cells (Lei et al., 2017). However, it is not clear whether apoptosis is related to oxidative stress in renal injury caused by T-2 toxin.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor, which maintains cell redox balance by regulating related antioxidant genes to alleviate ROS-induced tissue damage (Itoh et al., 2003). Nrf2 is normally degraded in cytoplasm through a linker with Keap1 as a ubiquitination factor. Whereas, excessive ROS dissociates Nrf2 and Keap1 complex by activating tyrosine kinases, which leads to the increase of Nrf2 into nucleus, then activates the expression of cytoprotective gene (Soraya and Mozafar, 2017). In addition, the activation of Nrf2 can alleviate acute and chronic kidney disease (Nezu et al., 2017). However, there is no studies have linked oxidative stress, apoptosis and the Nrf2 signaling pathway in nephrotoxicity of T-2-treated mice. Therefore, the aim of our study was to investigate whether T-2-induced kidney damage in mice was associated with apoptosis mediated by oxidative stress and the regulation of Nrf2 signaling pathway.
Section snippets
Animals and experimental design
Forty-eight male Kunming mice (six weeks old) were divided into the control group (CG) and three T-2 toxin treatment groups. The mice were treated with T-2 toxin (≥99.8%, Qingdao Pribolab Pte. Ltd, China) at doses of 0.5 (low-dose group, LG), 1.0 (medium-dose group, MG), or 2.0 (high-dose group, HG) mg/kg BW by oral gavage for 28 d (Yang et al., 2019). T-2 toxin was dissolved in distilled water contained 4% v/v ethanol (Wan et al., 2015). The CG was administered with distilled water. To
T-2 reduced the BW and kidney coefficient
Compared to the CG, the BW was decreased in the MG and HG (P < 0.05, P < 0.01, Fig. 1A), the kidney coefficient was decreased in all T-2-treated mice (P < 0.05, P < 0.01, Fig. 1B).
T-2 caused kidney histopathological lesions
H&E staining showed that the complete glomerular and tubular morphology, intact cell membrane and normal nuclear staining were observed in the CG. Several tubules rupture were observed in the LG, a large number of renal tubule epithelial cells rupture, the nuclei abscission, degradation of renal tubule epithelial
Discussion
T-2 toxin, a widespread pollutant in the environment, poses a threat to public health (Makowska et al., 2018). Although the toxicity of T-2 toxin has aroused widespread concern, the nephrotoxicity of T-2 toxin lacks systematic study and the mechanism has not been elucidated. Thus, we report the interference of T-2 toxin on renal histopathology and ultrastructure, the renal function, oxidative stress markers, apoptosis key factors, and Nrf2 pathway, as well as the correlation of oxidative
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by Youth Program of National Natural Science Foundation (31902332), Natural Science Foundation of Heilongjiang Province (C2018020) and the “Young Talent” Project of Northeast Agricultural University (18QC44).
References (49)
- et al.
CdSe quantum dots induce apoptosis in human neuroblastoma cells via mitochondrial-dependent pathways and inhibition of survival signals
Toxicol. Lett.
(2006) - et al.
Renal toxicity through AhR, PXR, and Nrf2 signaling pathway activation of ochratoxin A-induced oxidative stress in kidney cells
Food Chem. Toxicol.
(2018) - et al.
Immunoperoxidase localization of T-2 toxin
Toxicol. Appl. Pharmacol.
(1984) - et al.
Astragaloside suppresses apoptosis of the podocytes in rats with diabetic nephropathy via miR-378/TRAF5 signaling pathway
Life Sci.
(2018) - et al.
Effect of T-2 toxin-contaminated diet on common carp (Cyprinus carpio L.)
Fish Shellfish Immunol.
(2017) - et al.
Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy
Lab. Invest.
(2004) - et al.
Hispidulin alleviates high-glucose-induced podocyte injury by regulating protective autophagy
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
(2018) - et al.
Spermatogenesis disorder caused by T-2 toxin is associated with germ cell apoptosis mediated by oxidative stress
Environ. Pollut.
(2019) - et al.
T-2 toxin induces apoptosis via the Bax-dependent caspase-3 activation in mouse primary Leydig cells
Toxicol. Mech. Methods
(2017) Protective effect of curcumin against experimentally induced aflatoxicosis on the renal cortex of adult male albino rats: a histological and immunohisochemical study
Int. J. Clin. Exp. Pathol.
(2014)
T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway
APOPTOSIS -OXFORD-
Targeting apoptosis pathways in cancer therapy
CA A Cancer J. Clin.
BCL-2 family members and the mitochondria in apoptosis
Genes Dev.
Aflatoxin B 1 disrupts blood-testis barrier integrity by reducing junction protein and promoting apoptosis in mice testes
Food Chem. Toxicol.
Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles
Gene Cell.
Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture
Toxicology
Prevalence of selenium, T-2 toxin, and deoxynivalenol in kashin–beck disease areas in qinghai Province, northwest China
Biol. Trace Elem. Res.
Cellular responses to T-2 toxin and/or deoxynivalenol that induce cartilage damage are not specific to chondrocytes
Sci. Rep.
T-2 toxin, a trichothecene mycotoxin: review of toxicity, metabolism, and analytical methods
J. Agric. Food Chem.
T-2 toxin, a trichothecene mycotoxin: review of toxicity, metabolism, and analytical methods
J. Agric. Food Chem.
Protective effect of organic selenium on oxidative damage and inflammatory reaction of rabbit kidney induced by T-2 toxin
Biol. Trace Elem. Res.
The impact of T-2 toxin on vasoactive intestinal polypeptide-like immunoreactive (VIP-LI) nerve structures in the wall of the porcine stomach and duodenum
Toxins
Cellular levels of oxidative stress affect the response of cervical cancer cells to chemotherapeutic agents
BioMed Res. Int.
MicroRNA-196a/b mitigate renal fibrosis by targeting TGF-β receptor 2
J. Am. Soc. Nephrol.
Cited by (45)
Multi-Fusarium mycotoxin exposure activates Nrf2 and Ahr pathway in the liver of laying hens
2024, Toxicology LettersHexafluoropropylene oxide trimer acid exposure triggers necroptosis and inflammation through the Wnt/β-catenin/NF-κB axis in the liver
2023, Science of the Total Environment