zearalenone and Chemical-and-Drug-Induced-Liver-Injury

Topics: Aflatoxins; Animals; Chemical and Drug Induced Liver Injury; Cytochalasins; Cytochrome P-450 Enzyme System; Cytoskeleton; Emodin; Energy Metabolism; Humans; Mutagens; Mycotoxins; Neoplasms; Protein Biosynthesis; Rats; Receptors, Estrogen; Zearalenone

Zearalenone is a mycotoxin produced by several species of Fusarium fungi, which contaminates crop and cereal products worldwide. It is widely distributed and can be transported from agricultural fields to the aquatic environment via soil run-off. Zearalenone exposure can cause serious health problems to humans and animals, including estrogenic, immunotoxic, and xenogenic effects. Though its hepatotoxicity has been reported by few studies, the underlying mechanisms are yet to be investigated. This study aimed to comprehensively evaluate the hepatotoxic effects of zearalenone and its molecular mechanism in the zebrafish model system. First, we found zearalenone exposure can cause liver injury, as evidenced by reduced liver size, decreased liver-specific fluorescence, increased aspartate aminotransferase (AST) activity, delayed yolk sac absorption and lipid accumulation. Then, RNA sequencing (RNA-seq) was performed using dissected zebrafish fry liver, which found genes involved in oxidation and reduction were significantly enriched. Quantitative real-time PCR further confirmed the dysregulated expression of several antioxidant enzymes. Additionally, lipid peroxidation was proved by increased malondialdehyde (MDA) production and gene expression at the mRNA level. In contrast to the previous study, apoptosis was likely decreased in response to zearalenone exposure. Last, glucuronidation and amino acid metabolism were also disrupted by zearalenone. Our results revealed the complex mechanism of zearalenone-induced hepatotoxicity, which is a valuable contribution to a more comprehensive understanding of the toxicity of zearalenone.

Topics: Amino Acids; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Lipids; Malondialdehyde; Mycotoxins; RNA, Messenger; Soil; Transcriptome; Zearalenone; Zebrafish

Zearalenone (ZEA) is a secondary metabolite produced by fungi such as Fusarium and Fusarium flavum, which is classified as a mycotoxin. Crops and feed in a humid surrounding are widely polluted by ZEA, which further endangering the healthful aquaculture of poultry and even human health. Up to now, prevention and cure of mycotoxicosis is still a crucial subject of poultry husbandry. Baicalin (BAI) is a flavonoid refined from dried roots of Scutellaria baicalensis possessing the function of hepatoprotective, anti-inflammatory, anti-oxidant, and anti-atherosclerotic efficacies.etc. But whether Baicalin also has a protective effect against ZEA intoxication is unclear. Therefore, the aim of this study was to establish a model of ZEA-induced toxic injury in chicks, and then to investigate the way in which Baicalin plays a protective role in the mechanism of ZEA-induced liver and kidney injury in chicks. The results exhibit that Baicalin could not only significantly decrease aspartate aminotransferase (AST) , alanine aminotransferase (ALT) and creatinine (Cre) levels in serum, but also ameliorate ZEA-induced pathologic changes of liver and kidney. Baicalin could also significantly regulate ZEA-induced the changes of catalase (CAT) , malondialdehyde (MDA) , total sulfhydryl group , except for glutathione peroxidase (GSH-px) , and inhibit the mRNA levels of inflammatory cytokines tumor necrosis factor-α (TNF-α) , interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) with caspase-3 and caspase-11 in the caspase signaling pathway , meanwhile inhibit the cell apoptosis in immunohistochemistry. In summary, we successfully established a model of ZEA-induced liver injury in chicks, and confirm that Baicalin can reduce ZEA-induced liver and kidney injury in chicks. The mechanism of these effects is via inhibiting inflammation, oxidative stress and apoptosis, which also indicates the potential applicability of Baicalin for the prevention and treatment of ZEA-induced toxicity in chicks.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Caspases; Chemical and Drug Induced Liver Injury; Chickens; Cytokines; Disease Models, Animal; Flavonoids; Inflammation Mediators; Kidney; Liver; Oxidative Stress; Signal Transduction; Zearalenone

Zearalenone (ZEN), a mycotoxin is frequently detected in different food products and has been widely studied for its toxicity. However, the underlying mechanisms of hepatotoxic effects, relationship between gut microbiome and liver metabolite mediated hepatotoxicity mechanisms induced by ZEN are still not clear. Here, we reported that the different microscopic changes like swelling of hepatocyte, disorganization of hepatocytes and extensive vacuolar degeneration were observed, and the mitochondrial functions decreased in exposed mice. Results exhibited up-regulation in expression of signals of apoptosis and autophagy in liver of treated mice via mitochondrial apoptotic and autophagy pathway (Beclin1/p62). The diversity of gut microbiome decreased and the values of various microbiome altered in treated mice, including 5 phyla (Chloroflexi, Sva0485, Methylomirabilota, MBNT15 and Kryptonia) and genera (Frankia, Lactococcus, Anaerolinea, Halomonas and Sh765B-TzT-35) significantly changed. Liver metabolism showed that the concentrations of 91 metabolite including lipids and lipid like molecules were significantly changed. The values of phosphatidylcholine, 2-Lysophosphatidylcholine and phosphatidate concentrations suggestive of abnormal glycerophosphate metabolism pathway were significantly increased in mice due to exposure to ZEN. In conclusion, the findings suggest that the disorders in gut microbiome and liver metabolites due to exposure to ZEN in mice may affect the liver.

Topics: Animals; Animals, Outbred Strains; Apoptosis; Autophagy; Chemical and Drug Induced Liver Injury; Gastrointestinal Microbiome; Hepatocytes; Liver; Male; Mice; Mitochondria; Zearalenone

The purpose of this study was to determine the effects of single and combined administrations of deoxynivalenol (DON) and zearalenone (ZEN) on the histology and ultrastructure of pig liver. The study was performed on immature gilts, which were divided into four equal groups. Animals in the experimental groups received DON at a dose of 12 μg/kg body weight (BW) per day, ZEN at 40 μg/kg BW per day, or a mixture of DON (12 μg/kg BW per day) and ZEN (40 μg/kg BW). The control group received vehicle. The animals were killed after 1, 3, and 6 weeks of experiment. Treatment with mycotoxins resulted in several changes in liver histology and ultrastructure, including: (1) an increase in the thickness of the perilobular connective tissue and its penetration to the lobules in gilts receiving DON and DON + ZEN; (2) an increase in the total microscopic liver score (histology activity index (HAI)) in pigs receiving DON and DON + ZEN; (3) dilatation of hepatic sinusoids in pigs receiving ZEN, DON and DON + ZEN; (4) temporary changes in glycogen content in all experimental groups; (5) an increase in iron accumulation in the hepatocytes of gilts treated with ZEN and DON + ZEN; (6) changes in endoplasmic reticulum organization in the hepatocytes of pigs receiving toxins; (7) changes in morphology of Browicz-Kupffer cells after treatment with ZEN, DON, and DON + ZEN. The results show that low doses of mycotoxins used in the present study, even when applied for a short period, affected liver morphology.

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Glycogen; Iron; Liver; Necrosis; Sus scrofa; Trichothecenes; Zearalenone

Topics: Apoptosis; Autophagy; Cell Death; Cell Survival; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Enzymes; Hep G2 Cells; Humans; Liver; Mycotoxins; Reactive Oxygen Species; Zearalenone

Zearalenone (ZEN) can cause serious defects in development and reproduction in humans and animals. Silymarin shows antioxidant and estrogenic effects.. This study was conducted to determine if silymarin can antagonize ZEN-induced hepatic and reproductive toxicities.. Thirty-five 21-d-old female Sprague-Dawley rats (n = 7/diet) were fed a control diet (Ctrl) or Ctrl plus 20 mg ZEN/kg or Ctrl plus 20 mg ZEN/kg with 100, 200, or 500 mg silymarin/kg for 6 wk. Serum, livers, ovaries, and uterus were collected at week 6 for biochemistry, hormone, and redox status and selected gene and protein assays.. The consumption of ZEN decreased (P < 0.05) the final body weight by 17.9%, induced liver injury, increased (P < 0.05) aspartate aminotransferase and alkaline phosphatase activities, and decreased (P < 0.05) total protein and albumin concentrations in serum by 16.7-40.6%. ZEN also caused reproductive toxicity, including decreased (P < 0.05) 17β-estradiol and increased (P < 0.05) follicle-stimulating hormone concentrations in serum by 12.7-46.3% and induced histopathologic alterations in the liver, ovaries, and uterus. Interestingly, these alterations induced by ZEN were alleviated (P < 0.05) by silymarin supplementation at 100, 200, and 500 mg/kg. Moreover, silymarin supplementation at the 3 doses mitigated (P < 0.05) ZEN-induced impairment in hepatic glutathione peroxidase activity, total antioxidant capacity, and malondialdehyde concentration by 17.6-100%. Meanwhile, silymarin supplementation at all doses upregulated (P < 0.05) phospho-ribosomal protein S6 kinase 1 (p-RPS6KB1) and 3β-hydroxysteroid dehydrogenase (HSD3B) by 43.0-121% but downregulated (P < 0.05) AMP-activated protein kinase (AMPK) and 3α-hydroxysteroid dehydrogenase (HSD3A) in the liver relative to the ZEN group by 11.2-40.6%. In addition, silymarin supplementation at all doses elevated (P < 0.05) HSD3B by 1.8- to 2.5-fold and decreased (P < 0.05) estrogen receptor 1 (ESR1), ATP binding cassette (ABC) c1, and Abcc5 in ovaries and the uterus by 10.7-63.2%.. Dietary silymarin supplementation at 100, 200, and 500 mg/kg protected rats from ZEN-induced hepatotoxicity and reproductive toxicity, potentially through improvement in the antioxidant capacity and regulation in the genes related to protein synthesis, ZEN metabolism, hormone synthesis, and ABC transporters in the tissues.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; ATP-Binding Cassette Transporters; Blood Proteins; Chemical and Drug Induced Liver Injury; Dietary Supplements; Estrogen Receptor alpha; Female; Glutathione Peroxidase; Hormones; Hydroxysteroid Dehydrogenases; Liver; Malondialdehyde; Multidrug Resistance-Associated Proteins; Ovary; Phytotherapy; Rats, Sprague-Dawley; Reproduction; Ribosomal Protein S6 Kinases, 70-kDa; Silybum marianum; Silymarin; Uterus; Zearalenone

Although grape-seed proanthocyanidin extract (GSPE) demonstrates strong anti-oxidant activity, little research has been done to clearly reveal the protective effects on the hepatotoxicity caused by zearalenone (ZEN). This study is to explore the protective effect of GSPE on ZEN-induced oxidative damage of liver in Kunming mice and the possible protective molecular mechanism of GSPE. The results indicated that GSPE could greatly reduce the ZEN-induced increase of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. GSPE also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD and GSH-Px. The analysis indicated that ZEN decreased both mRNA expression levels and protein expression levels of nuclear erythroid2-related factor2 (Nrf2). Nrf2 is considered to be an essential antioxidative transcription factor, as downstream GSH-Px, γ-glutamyl cysteine synthetase (γ-GCS), hemeoxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) decreased simultaneously, whereas the pre-administration of GSPE groups was shown to elevate these expressions. The results indicated that GSPE exerted a protective effect on ZEN-induced hepatic injury and the mechanism might be related to the activation of the Nrf2/ARE signaling pathway.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Gene Expression Regulation; Grape Seed Extract; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Proanthocyanidins; Signal Transduction; Superoxide Dismutase; Zearalenone

This study was performed to assess the individual and combined toxic effects of aflatoxin B1 (AFB1), zearalenone (ZEA) and deoxynivalenol (DON) within the liver of mice. A total of 56 4-week-old weanling female mice were divided into seven groups (n = 8). For 2 weeks, each group received an oral administration of either solvent (control), AFB1, ZEA, DON, AFB1 + ZEA, AFB1 + DON or ZEA + DON per day. The results showed that AFB1, ZEA and DON induced liver injury, indicated by elevated relative liver weight, activities of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as well as decreased albumin (ALB) and/or total protein (TP) concentration in the serum. These mycotoxins also decreased hepatic total antioxidant capacity (T-AOC), and/or increased the concentration of malondialdehyde (MDA). Moreover, AFB1 + DON displayed synergistic effects, while AFB1 + ZEA displayed antagonistic effects on those parameters previously described. Furthermore, the apoptotic potential was demonstrated associated with an upregulation of the apoptotic genes Caspase-3 and Bax, along with a downregulation of the antiapoptotic gene Bcl-2 in liver. In conclusion, this study provides a better understanding of the toxic effects of AFB1, ZEA, DON, alone or in combinations on the liver of mice, which could contribute to the risk assessment of these mycotoxins in food and feed.

Topics: Aflatoxin B1; Alanine Transaminase; Animals; Antioxidants; Apoptosis Regulatory Proteins; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Interactions; Female; Growth; Liver Function Tests; Malondialdehyde; Mice; Mycotoxins; Organ Size; Serum Albumin; Trichothecenes; Zearalenone

It was hypothesized that a mycotoxin binder, Grainsure E, would inhibit adverse effects of a mixture of fumonisin B1, deoxynivalenol, and zearalenone in rats. For 14 and 28 days, 8-10 Sprague-Dawley rats were fed control diet, Grainsure E (0.5%), toxins (7 μg fumonisin B1/g, 8 μg of deoxynivalenol/g and 0.2 μg of zearalenone/g), toxins (12 μg of fumonisin B1/g, 9 μg of deoxynivalenol/g, and 0.2 μg of zearalenone/g + Grainsure E), or pair-fed to control for food intake of toxin-fed rats. After 28 days, decreased body weight gain was prevented by Grainsure E in toxin-fed female rats, indicating partial protection against deoxynivalenol and fumonisin B1. Two effects of fumonisin B1 were partly prevented by Grainsure E in toxin-fed rats, increased plasma alanine transaminase (ALT) and urinary sphinganine/sphingosine, but sphinganine/sphingosine increase was not prevented in females at the latter time point. Grainsure E prevented some effects of fumonisin B1 and deoxynivalenol in rats.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diet; Female; Fumonisins; Kidney Diseases; Liver Diseases; Male; Mycotoxins; Rats; Rats, Sprague-Dawley; Trichothecenes; Zearalenone

Raphanus sativus (radish) is a species of crucifer, which includes widely consumed vegetables, distributed in Asia, Africa and Europe. It is a rich source of bioactive molecules including anthocyanins, glucosinolates, isothiocyanates and other flavonoids, and miscellaneous phenolic substances. We have evaluated the hepatoprotection of R. sativus extract against zearalenone, an estrogenic mycotoxin initiating hepatotoxicity in male Balb/c mice.. Animals were divided into seven treatment groups and treated orally each day for twenty eight days as follows: a control, an olive oil group, group I, group II, and group III treated with radish extract alone (5, 10 and 15 mg/kg, respectively), group IV treated with zearalenone (40 mg/kg), and group V treated with zearalenone plus the lowest dose of radish extract.. Administration of zearalenone alone resulted in significant decreases in the levels of alkaline phosphatase, lactate dehydrogenase, alanine and aspartate aminotransferases in the liver, suggesting hepatic damage. Moreover, a marked increase in the level of lipid peroxide and concomitant decrease of glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, glutathione-S-transferase, RNA and DNA concentrations were also observed in the liver tissue of zearalenone-treated mice. Co-treatment with R. sativus extract plus zearalenone succeeded in reversing the condition back to normal levels for all studied parameters.. By itself R. sativus extract did not show any toxic effects and could be considered as a potent hepatoprotectant.

Topics: Animals; Chemical and Drug Induced Liver Injury; DNA; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred BALB C; Phytotherapy; Plant Extracts; Raphanus; RNA; Superoxides; Zearalenone

Zearalenone (ZEN) is a fusarial mycotoxin with several adverse effects in laboratory and domestic animals including mainly estrogenicity. While most ZEN toxic effects have been quite well investigated, little is known regarding its mechanism of toxicity. Our previous investigations have shown the involvement of cytotoxicity, inhibition of macromolecules synthesis as well as genotoxicity. However, there are no available data regarding the involvement of the oxidative stress pathway in ZEN toxicity. In this context, the aim of this study was to find out whether ZEN induces oxidative cell damage. Using human hepatocytes Hep G2 cells, ZEN-induced stress response is monitored at several levels in these cells. ZEN mediated induction of oxidative DNA damage (comet assay using the repair enzymes), modulation of gluthatione (GSH), cytotoxicity (growth inhibition) and the oxidative stress responsive gene Hsp 70 and Hsp 90 were investigated with respect to concentration and time dependency. Hep G2 cells respond to ZEN exposure by loss of cell viability, induction of oxidative DNA damage, GSH depletion and Hsp 70 and Hsp 90 induction already at concentrations, which are not yet cytotoxic. The perturbation of the oxidative status was further confirmed by the significant reduction of the induced oxidative DNA damage as well as stress protein induction when cells were pre-treated with Vitamin E prior to exposure to ZEN. Our study clearly demonstrates that oxidative damage is likely to be evoked as one of the main pathway of ZEN toxicity. This oxidative damage may therefore be an initiating event and contribute, at least in part, to the mechanism of ZEN different genotoxic and cytotoxic effects.

Topics: Antioxidants; Cell Line, Tumor; Cell Survival; Chemical and Drug Induced Liver Injury; Comet Assay; DNA Damage; Glutathione; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Liver; Liver Diseases; Mycotoxins; Oxidative Stress; Statistics, Nonparametric; Vitamin E; Zearalenone

Secondary metabolites, toxic to macro-organisms and micro-organisms, are produced by certain molds and some plant parasitic living fungi. A risk is given for man worldwide by ingestion or apparently also be other routes always undetected. In vivo-effects of the various mycotoxins are different, but mainly the liver is affected, expecially by the intake of smaller amounts of these poisons. Accordingly cirrhosis of the liver or primary liver carcinoma are expected in man as well as in animals and were already proved outside of Europe.

Topics: Aflatoxins; Chemical and Drug Induced Liver Injury; Dairy Products; Dose-Response Relationship, Drug; Environmental Pollution; Food Contamination; Foodborne Diseases; Germany, West; Humans; Liver Neoplasms; Male; Mycotoxins; Nuts; Sterigmatocystin; Zearalenone