zearalenone and Liver-Neoplasms

The secondary metabolites produced by fungi known as mycotoxins, are capable of causing mycotoxicosis (diseases and death) in human and animals. Contamination of feedstuffs as well as food commodities by fungi occurs frequently in a natural manner and is accompanied by the presence of mycotoxins. The occurrence of mycotoxins' contamination is further stimulated by the on-going global warming as reflected in some findings. This review comprehensively discussed the role of mycotoxins (trichothecenes, zearalenone, fumonisins, ochratoxins, and aflatoxins) toward gut health and gut microbiota. Certainly, mycotoxins cause perturbation in the gut, particularly in the intestinal epithelial. Recent insights have generated an entirely new perspective where there is a bi-directional relationship exists between mycotoxins and gut microbiota, thus suggesting that our gut microbiota might be involved in the development of mycotoxicosis. The bacteria-xenobiotic interplay for the host is highlighted in this review article. It is now well established that a healthy gut microbiota is largely responsible for the overall health of the host. Findings revealed that the gut microbiota is capable of eliminating mycotoxin from the host naturally, provided that the host is healthy with a balance gut microbiota. Moreover, mycotoxins have been demonstrated for modulation of gut microbiota composition, and such alteration in gut microbiota can be observed up to species level in some of the studies. Most, if not all, of the reported effects of mycotoxins, are negative in terms of intestinal health, where beneficial bacteria are eliminated accompanied by an increase of the gut pathogen. The interactions between gut microbiota and mycotoxins have a significant role in the development of mycotoxicosis, particularly hepatocellular carcinoma. Such knowledge potentially drives the development of novel and innovative strategies for the prevention and therapy of mycotoxin contamination and mycotoxicosis.

Topics: Aflatoxins; Animals; Carcinoma, Hepatocellular; Climate Change; Fumonisins; Fungi; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Liver Neoplasms; Mycotoxicosis; Mycotoxins; Ochratoxins; Trichothecenes; Zearalenone

Topics: Aflatoxins; Animal Feed; Animal Husbandry; Animals; Food Contamination; Humans; Kidney; Liver; Liver Neoplasms; Mycotoxins; Ochratoxins; Species Specificity; Trichothecenes; Zearalenone

Dietary exposure of Hong Kong adults to mycotoxins and their metabolites including aflatoxins (AFs), ochratoxin A (OTA), fumonisins (FNs), deoxynivalenol (DON), acetyldeoxynivalenols (AcDONs) and zearalenone (ZEA) was estimated using the Total Diet Study (TDS) approach to assess the associated health risk to the local people. Sixty commonly consumed food items, collected in four seasons, were sampled and prepared as consumed. These mycotoxins were primarily found at low levels. The highest mean levels (upper bound) were: AFs, 1.50 µg kg(-)(1) in legumes, nuts and seed; OTA, 0.22 µg kg(-)(1) in sugars and confectionery; FNs, 9.76 µg kg(-)(1) in cereals and their products; DON and AcDONs, 33.1 µg kg(-)(1) in cereals and their products; and ZEA, 53.8 µg kg(-)(1) in fats and oils. The estimated dietary exposures of Hong Kong adults to the mycotoxins analysed were well below the respective health-based guidance values, where available. For AFs, the upper-bound exposure for high consumers is 0.0049 µg kg bw(-)(1) day(-)(1), which was estimated to contribute to about 7.7 (< 1%) of liver cancer cases when compared with 1222 liver cancer cases per year in Hong Kong. The percentage contributions of the estimated 95th percentile dietary exposures (lower and upper bound) to the health-based guidance values of individual mycotoxins were: ochratoxin A, 3.6-9.2%; fumonisins, 0.04-8.5%; deoxynivalenol and acetyldeoxynivalenols, 21.7-28.2%; and zearalenone 3.3-34.5%. The findings indicate that dietary exposures to all the mycotoxins analysed in this study were unlikely to pose an unacceptable health risk to the Hong Kong population.

Topics: Adult; Aflatoxins; Diet; Environmental Exposure; Food Contamination; Fumonisins; Hong Kong; Humans; Liver Neoplasms; Maximum Allowable Concentration; Mycotoxins; Nutrition Surveys; Ochratoxins; Seasons; Surveys and Questionnaires; Trichothecenes; Zearalenone

Mycotoxin zearalenone (ZEN) is a secondary metabolite produced by some Fusarium species that contaminate a large variety of grains and feedstuffs worldwide. ZEN has been associated with a wide variety of adverse health effects including hepatotoxic, hematologic, immunotoxic and genotoxic. In order to better understand the mechanism of ZEN toxicity, a proteomic approach was applied to characterize cellular responses of hepatocarcinoma cells (HepG2) to ZEN exposure. Protein extracts from cultured HepG2 cells treated with 100 µm ZEN for 8 h, as well as extracts from control cells. The screening method applied to compare the proteome was based on the stable isotope approach of isobaric tagging for relative and absolute quantification (iTRAQ). This study identified 982 proteins, among which peptides and their corresponding proteins were identified and quantified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Ingenuity pathways analysis software was then used to determine the biological functions and canonical pathways associated with the ZEN-responsive proteins.

Topics: Carcinogenicity Tests; Carcinogens; Carcinoma, Hepatocellular; Cell Line, Tumor; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Liver Neoplasms; Mass Spectrometry; Mycotoxins; Peptides; Proteins; Proteome; Software; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Zearalenone

Mycotoxins, secondary metabolites produced by moulds, have been shown to cause diverse toxic effects in animals and are also suspected of disease causation in humans. The present study compares the molecular mechanisms of the toxicity of zearalenone (ZEN), T-2 toxin and ochratoxin A (OTA) in human hepatoma cells HepG2. The three mycotoxins-induced a caspase-dependent mitochondrial apoptotic pathway. The mitochondrial alterations include: bax relocalisation into the mitochondrial outer membrane, loss of the mitochondrial transmembrane potential, PTPC opening, and cytochrome c (but not AIF) release. In the presence of ZEN and T-2 toxin, reactive oxygen species (ROS) level was highly increased at an early stage even before mitochondrial alterations were observed, whereas OTA-induced only O(2)(-) generation among total ROS. This ROS production appears as a consequence of mitochondrial alterations. HepG2 cell treatment with the p53 inhibitor pifithrin-alpha (PFT) and western blot analysis suggested that both ZEN and OTA, but not T-2 toxin, trigger a p53-dependent apoptotic pathway. These results clearly point to a central role of mitochondria in the apoptotic process induced by ZEN, T-2 toxin and OTA and provide new insights into the molecular mechanisms by which these mycotoxins might promote hepatotoxicty.

Topics: Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; DNA Fragmentation; Enzyme Activation; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Ochratoxins; Reactive Oxygen Species; T-2 Toxin; Tumor Suppressor Protein p53; Zearalenone

To study whether zearalenone (ZEA), a fungal estrogen, can transcriptionally up-regulate the expression of cytochrome 450 3A4 (CYP3A4) transcription by activating human steroid hormone and xenobiotic receptor (SXR).. Transient cotransfection reporter gene assays were performed with human SXR expression plasmid and a reporter plasmid containing the SXR in the CYP3A4 gene promoter in HepG(2) cells.. The transcriptional induction of CYP3A4 by ZEA with a dose, time-dependent manner. ZEA at the concentrations of 0.01, 0.10, 1.00 and 10.00 micromol/L, respectively, could induce CYP3A4 with (1.50 +/- 0.21), (1.66 +/- 0.27), (3.04 +/- 0.82) and (3.96 +/- 1.16) folds, as compared with 0.1% DMSO. Results from a time-dependent study show that 1.00 and 10.00 micromol/L of ZEA for 12 to 48 hours could enhance the transcription of CYP3A4 with (3.69 +/- 1.34) and (5.18 +/- 1.50) folds, and 10.00 micromol/L of ZEA for 48 hours could induce the CYP3A4 gene expression (5.18 +/- 1.50) folds, as compared with 0.1% DMSO by activating human SXR.. ZEA could induce the expression of the CYP3A4 gene transcription through activating SXR, possibly by affecting the other substrates of the CYP3A4, especially affecting the metabolism of drugs in the body.

Topics: Carcinoma, Hepatocellular; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Genes, Reporter; Humans; Liver Neoplasms; Transcription, Genetic; Tumor Cells, Cultured; 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