DNA methylation and RASSF4 expression are involved in T-2 toxin-induced hepatotoxicity

Liu, Aimei; Xu, Xiaoqing; Hou, Ren; Badawy, Sara; Tao, Yanfei; Chen, Dongmei; Ihsan, Awais; Wang, Xu; Wu, Qinghua; Zhang, Yuan

doi:10.1016/j.tox.2019.152246

Cited by 25 publications

(12 citation statements)

References 42 publications

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“…Symptoms of acute poisoning include vomiting, hemorrhagic dysfunction, and cardiovascular dysfunction (such as endotoxin shock) [ 6 ], while chronic poisoning symptoms include loss of appetite, weight loss, and oral and esophageal lesions, among others [ 7 ]. According to some studies, T-2 toxin has many toxic effects, include immunotoxicity [ 8 ], reproductive toxicity [ 9 ], hematotoxicity [ 10 ], hepatotoxicity [ 2 ], neurotoxicity [ 11 ], cardiotoxicity [ 12 ], and bone system damage [ 13 ] ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Zhu

et al. 2020

Toxins

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T-2 toxin, the most toxic of the trichothecenes, is widely found in grains and feeds, and its intake poses serious risks to the health of humans and animals. An important cytotoxicity mechanism of T-2 toxin is the production of excess free radicals, which in turn leads to oxidative stress. Betulinic acid (BA) has many biological activities, including antioxidant activity, which is a plant-derived pentacyclic triterpenoid. The protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied. BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus. BA pretreatment also reduced the degree of congestion observed in histopathological tissue sections of the thymus induced by T-2 toxin. Besides, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues. The results indicated that BA could protect the thymus against the oxidative damage challenged by T-2 toxin by activating Nrf2 and suppressing the MAPK signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Zhu

et al. 2020

Toxins

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“…Regarding DNA methylation, DNMT1, DNMT3A and DNMT3B, maintain synergistically the stability of DNA methylation [20]. Most of the changes in DNA methylation are due to chemicals, including mycotoxins, in food and in the environment [20,21]. It was found that 10 mM DON increased the percentage of 5-methylcytosine in DNA from 4.5-9% in Caco-2 cells [59].…”

Section: Donmentioning

confidence: 99%

Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver

Liu

Zhu

et al. 2020

Preprint

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Background Deoxynivalenol (DON) is an inevitable contaminant in animal feed and human food and can lead to decreased appetite and growth retardation in children and piglets, which are often used as models for children. Hepatotoxicity induced by DON is closely related to growth inhibition. Although many molecular mechanisms are related to the liver damage caused by DON, few studies have been done on cytochrome P450 (CYP450s) and DNA methylation, and the role of DNA methylation in growth inhibition of piglets was also unclear. Results In the present study, piglets were randomly assigned to the following three different dietary treatments for 4 weeks: control diet, diet containing 1 mg DON/kg feed, and diet containing 3 mg DON/kg feed. Compared to the control group, elevated alanine aminotransferase activity and globulin level were observed in DON groups; however, aspartate aminotransferase activity was decreased in 3 mg/kg DON group. DON exposure increased the mRNA expression of CYP450s including CYP1A1, CYP1A2, CYP2B22, CYP2C33, CYP2D25, CYP2E1, CYP3A22 and CYP3A39, in which DNA methylation was involved in the regulation of the expression of these enzymes. By estimating the benchmark dose value of the metabolic enzymes, CYP1A1 was found to be the most sensitive metabolic enzyme to evaluate the clinical liver injury caused by DON. DON upregulated the expression of DNA methyltransferases (DNMT1 and DNMT3B) in a dose-dependent manner, thus increasing the level of 5-mC in the whole genome. Notably, DON downregulated the expression of nicotinamide n-methyltransferase, possibly reducing the weight of the piglets. Additionally, 1 mg/kg DON decreased the expression of galanin-like peptide (GALP), while 3 mg/kg DON significantly increased the level of GALP through DNA methylation, thus affecting the appetite of the piglets. DON can significantly reduce the methylation level of insulin-like growth factor 1 (IGF-1) promoter and thus increase its expression. Conclusions Taken together, increased CYP450 expression and DNA methylation are important mechanisms of liver injury and growth inhibition induced by DON, which provide future reference values determination of antagonistic toxicity.

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“…In 2019, a report showed for the first time that DNA methylation is related to the expression of inflammatory factors (TNF-α, IL-6, IL-11, IL-1β and IL-1α) during T-2-induced liver injury in rats (Liu et al 2019a). A series of studies indicated that DNA methylation can silence the expression of Ras association domain family 4 (RASSF4) during T-2 exposure, leading to activation of PI3K-serine/threonine protein kinase (Akt)/ caspase/NF-κB signal pathways as its downstream pathways and causing apoptosis of liver cells (Liu et al 2019b). These findings suggest that DNA methylation is a potential mechanism of T-2-induced hepatotoxicity.…”

Section: Autophagy and Apoptosismentioning

confidence: 99%

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

Qin

Kuča

et al. 2020

Arch Toxicol

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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. Keywords T-2 toxin • Modified T-2 toxin • Metabolism • Immunotoxicity • Human exposure assessments • Biomarkers 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 Qinghua Wu and Zihui Qin contributed equally to this work.

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DNA methylation and RASSF4 expression are involved in T-2 toxin-induced hepatotoxicity

Cited by 25 publications

References 42 publications

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver

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

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