The nephrotoxicity of T-2 toxin in mice caused by oxidative stress-mediated apoptosis is related to Nrf2 pathway

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Abstract

T-2 toxin is an inevitable environmental and grain pollutant, which can cause kidney damage, but the mechanism is not clear. In this study, male mice were administered with T-2 toxin at 0, 0.5, 1.0, 2.0 mg/kg body weight (BW) for 28 days. We found that T-2 toxin induced renal structural damage, downregulated BW and kidney coefficient, impaired renal function accompanied by oxidative stress and apoptosis. Meanwhile, T-2 toxin increased nuclear Nrf2 protein expression and the mRNA expressions of its downstream target genes. The correlation analysis indicated that apoptosis and Nrf2 pathway were positively correlated with oxidative stress. These results suggested that the nephrotoxicity of T-2 toxin in mice caused by oxidative stress-mediated apoptosis is related to Nrf2 pathway.

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).

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