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PubMed2005

Efficient decontamination of zearalenone, the mycotoxin of cereal pathogen, by transgenic yeasts through the expression of a synthetic lactonohydrolase gene.

Zearalenone (ZEN), an estrogenic mycotoxin produced by several Fusarium species, is converted to a non-estrogenic product by a detoxifying enzyme of Clonostachys rosea. Previously, we investigated whether recombinant Saccharomyces cerevisiae carrying this detoxification gene, zhd101, can remove 2 microg ml(-1) of ZEN in a liquid culture. Although the transgenic yeasts eliminated most of the ZEN, they also converted a significant amount to a poor substrate, beta-zearalenol, which remained in the medium. In this study, we synthesized a codon-optimized zhd101 gene and investigated whether the transgenic yeast strain can overcome the problem of insufficient detoxification of ZEN. Importantly, within 48 h of incubation at 28 degrees C or 8 h of incubation at 37 degrees C, the transgenic yeasts completely eliminated 2 microg ml(-1) of ZEN in the medium without accumulating even a trace amount of beta-zearalenol. The result suggests that incomplete ZEN detoxification attributed to the action of an endogenous yeast beta-reductase can be overcome by simply increasing the expression of the detoxifying gene.

Amino Acid Sequence↗

PubMed2005

Effect of the mycotoxin, ochratoxin A, on hormone-stimulated ion transport in a cultured cell model of the renal principal cell.

The mycotoxin ochratoxin A (OTA) is a common contaminant of many foodstuffs and, consequently, is present in a large proportion of tested populations of humans and commercial animals. The predominant effects of OTA are manifested in the kidney where the severity varies from salt wasting to renal carcinoma formation in a concentration-dependent fashion. The MDCK-C7 renal cell culture model responds to various hormones known to regulate electrolyte and fluid balance and was used as a model to study the chronic effects of an acute exposure to low dose OTA. The natriferic hormones aldosterone and insulin-like growth factor 1 (IGF1) both stimulate Na(+) flux in a reabsorptive direction via activation of the epithelial Na(+) channel (ENaC). In contrast, anti-diuretic hormone (ADH) stimulates three separate and temporally distinct ion transport responses, one of which is Na(+) reabsorption. Treatment of MDCK-C7 cells with OTA (100 nM) for 48 h selectively and irreversibly inhibits hormone-stimulated Na(+) reabsorption via ENaC. This effect was retained for 48 cell passages after the removal of the toxin and mimics the OTA-induced salt-wasting that has been documented in clinical studies. These studies indicate that the effect of the toxin is genomic and therefore, likely to be long lasting in exposed animals and humans.

Animals↗

PubMed2006

Mycotoxins in Australia: biocontrol of aflatoxin in peanuts.

The major mycotoxin problem in Australia is the formation of aflatoxins in peanuts by Aspergillus flavus and A. parasiticus. This is controlled by good farm management practice, segregation into grades on aflatoxin content at intake to shelling facilities, colour sorting and aflatoxin assays. A second problem is the potential presence of ochratoxin A in grapes and grape products, resulting from infection by Aspergillus carbonarius. Good quality control before and during wine making ensures ochratoxin A is kept to very low levels, but in dried vine fruit, ochratoxin A levels may be higher. Biocontrol by competitive exclusion has been developed as the most promising means of controlling aflatoxins in peanuts. Some details of the process are given, including some basic laboratory experiments.

Aflatoxins↗

PubMed1985

Inhibition of aminoacyl-tRNA synthetases by the mycotoxin patulin.

The effect of patulin on tRNA aminoacylation has been determined. This mycotoxin inhibits the aminoacylation process by irreversibly inactivating aminoacyl-tRNA synthetases. At neutral and alkaline pH-values, the inactivation occurs mainly by modification of essential thiol groups of the protein, whereas at acidic pH, where the effect is the most pronounced, the modification of other amino acid residues cannot be excluded.

Amino Acyl-tRNA Synthetases↗

PubMed1983

Toxicity of T-2 toxin, a Fusarium mycotoxin, to alveolar macrophages in vitro.

The exposure of agricultural workers to dust particulates, which may be contaminated with common fungi and/or their toxic metabolites, is an occupational health concern. To assess the cytotoxic properties of T-2 toxin, rat alveolar macrophages (AM) were exposed to T-2 in tissue culture. Determinations of cell viability, cell number, and viability index indicate that T-2, a trichothecene mycotoxin, is highly toxic to AM. The concentrations of T-2 toxin required to decrease these parameters by 50% at 20 hr were 8.93, 0.33, and 0.89 microM, respectively. The effect of T-2 toxin on AM cell volume was dose dependent, with cultures containing 0.1 microM T-2 being significantly different than controls. The data show that T-2 toxin causes significant AM shrinkage. The amount of chromium released from preloaded AM after 18 hr of incubation was significantly different in culture containing 0.01 microM or greater T-2 toxin. The percentage of chromium released was dose dependent and parallel to the amount of cell death occurring in each culture. Scanning electron microscope examination of AM treated 20 hr with 0.1 microM T-2 toxin demonstrated detachment of pseudopodia, cellular blebing, smoothing of membrane processes, and finally cell lysis. Thus, the data clearly demonstrate that T-2 toxin is cytotoxic for rat alveolar macrophages in vitro and suggest the possibility of a respiratory hazard to agricultural workers.

Animals↗

PubMed1985

Toxicity of the mycotoxin patulin for rat alveolar macrophages.

Agricultural workers are exposed to a variety of organic dusts containing fungi and their secondary metabolites. Patulin, a polyketide lactone mycotoxin produced by several common species of Aspergillus and Penicillium, is found in corn silage. Patulin is toxic in experimental animals and has been reported to be mutagenic, teratogenic, and carcinogenic. The cytotoxicity of patulin was studied in rat alveolar macrophages in vitro. The effects of patulin on membrane integrity were studied by measuring cell volume changes and release of 51Cr. There was a significant release of 51Cr after 1 hr exposure to submillimolar concentrations of patulin. Similarly, there was a significant decrease in ATP in cell cultures exposed to 0.5 mM patulin for 15 min and in cultures exposed to 0.05 mM patulin for 2 hr. There was a significant increase in mean cell volume after 2 hr exposure to 1.0 mM patulin but not after a 1 hr exposure. The effects of patulin on protein and RNA synthesis were studied by monitoring the incorporation of [3H]leucine and [3H]uridine, respectively. Inhibitions of protein and of RNA synthesis were both dose and time dependent. Protein synthesis was the most sensitive cellular parameter studied, with 50% inhibition after 1 hr at ca. 0.002 mM patulin. The data demonstrate that patulin is cytotoxic for rat alveolar macrophages in vitro.

Adenosine Triphosphate↗

PubMed1991

High performance thin layer chromatography ELISAGRAM. Application of a multi-hapten immunoassay to analysis of the zearalenone and aflatoxin mycotoxin families.

A new immunoblot approach called ELISAGRAM was devised that combines the sensitivity and selectivity of competitive ELISA with the capacity of high performance thin layer chromatography (HPTLC) to separate structurally related haptens. The procedure involved (1) separation of haptens by monoclonal antibody, (3) incubation of NC with hapten-enzyme conjugate to identify unreacted antibody binding sites. (4) detection of bound enzyme conjugate with a precipitating substrate and (5) visual or densitometric assessment of inhibition bands indicative of a cross-reacting hapten. The technique was applied to two major mycotoxin families, the zearalenones and aflatoxins (AFs), which are to toxicological significance. Detection limit for zearalenone and alpha-zearalenol in the method was 300 pg/assay. AFB1, AFB2, and AFG1 were detectable at 380 pg/assay and AFG2 was detectable at 1500 pg/assay. Multiple standard curves for the zearalenones and AFs could be constructed using scanning densitometry. Cross-reactivity in ELISAGRAM curves was analogous to that found in competitive ELISA. This procedure should be widely applicable to the simultaneous quantitation and confirmation of multiple haptens with a single cross-reactive antibody.

Aflatoxin B1↗

PubMed1990

Induction of characteristic chromosomal aberrations, particularly X-trisomy, in cultured human lymphocytes treated by ochratoxin A, a mycotoxin implicated in Balkan endemic nephropathy.

Ochratoxin A (OA), a mycotoxin which induces nephropathy and kidney tumours in rats and mice, is a contaminant of food consumed by a population with a high incidence of endemic nephropathy (EN). It was therefore tested in vitro for its ability to induce chromosomal aberrations in human peripheral lymphocytes in a small number of subjects, in the presence or absence of a kidney microsomal metabolic activation system. OA was found to induce aberrations on X chromosomes of similar types to those previously detected in lymphocytes from patients suffering from endemic nephropathy.

Animals↗

PubMed1993

Differential DNA adduct formation and disappearance in three mouse tissues after treatment with the mycotoxin ochratoxin A.

Ochratoxin A (OTA) is a mycotoxin which has been implicated in Balkan endemic nephropathy, a disease characterized by a high incidence of urinary tract tumors. It induces DNA single-strand breaks and has been shown to be carcinogenic in two rodent species. For a better understanding of the OTA genotoxic effect, OTA-DNA adduct formation and disappearance has been measured using the 32P-post-labelling method after oral administration of 2.5 mg/kg of OTA to mice. In kidney, liver and spleen, several modified nucleotides were clearly detected in DNA, 24 h after administration of OTA, but their level varied significantly in a tissue and time dependent manner over a 16-day period. Total DNA adducts reached a maximum at 48 h when 103, 42 and 2.2 adducts per 10(9) nucleotides were found respectively in kidney, liver and spleen, indicating that kidney is the main target of the genotoxicity and likely carcinogenicity of OTA. The major adduct differed between kidney and liver. All adducts disappeared in liver and spleen 5 days after compound administration, whereas some adducts persisted for at least 16 days in the kidney. Some adducts were organ specific. The finding that the adducts are not quantitatively and qualitatively the same in the three organs examined is likely due to differences of metabolism in these organs, leading to different ultimate carcinogens and may also result from differences in the efficiency of repair processes.

Animals↗

PubMed1984

Pharmacokinetics of the mycotoxin penicillic acid in male mice: absorption, distribution, excretion, and kinetics.

The pharmacokinetics of penicillic acid (PA), a carcinogenic mycotoxin, was investigated in male mice. Absorption of PA after po administration of [14C]PA was rapid. Only a small percentage of the radioactivity in the plasma was unchanged PA. After ip or iv administration of [14C]PA (90 mg/kg), blood, liver, kidneys, intestine, lungs, heart, and spleen contained the largest amounts of radioactivity while brain tissue accumulated the least. Over 90% and approximately 60% of the administered radioactivity was excreted in the urine after iv and ip injection, respectively, but essentially no unchanged PA was detected in the urine. Over 25% of the administered radioactivity following an iv dose of [14C]PA (90 mg/kg) was excreted in the bile in 60 min; no unchanged PA was detected in the bile. The excretion of radioactivity in the bile was decreased in diethyl maleate-pretreated mice. Only a small amount of the administered radioactivity was recovered in the feces and as expired CO2. The unchanged PA concentration-time curve in plasma was best fit by three, two, and one compartment open models after iv, ip, and po administration, respectively. Based on these results, it was concluded that metabolism and not excretion of unchanged parent penicillic acid is the major process of elimination of PA from the blood. There are extensive route-dependent differences in the kinetic behavior of PA.

Animals↗

PubMed1983

Effect of T-2 mycotoxin on rat liver mitochondria electron transport system.

The in vitro and in vivo effects of T-2 mycotoxin on electron transport in rat liver mitochondria were investigated. T-2 toxin (2.2 mM) inhibited oxygen consumption by 40% in ADP-coupled and DNP-uncoupled mitochondria using either succinate or pyridine-nucleotide linked substrates. Studies employing known inhibitors of specific sites along the electron transport chain identified site I as the principal site of action of T-2 toxin. In vivo experiments using an LD50 dose of T-2 toxin showed early (10 hr) decreases in succinate and pyruvate plus malate oxidation in liver mitochondria. This observation is supported by in vitro findings and suggests that mitochondria are a possible site of T-2 action.

Animals↗

PubMed1986

Ultrastructural effects of T-2 mycotoxin on rat hepatocytes in vitro.

Cultured rat hepatocytes were treated with several doses of T-2 mycotoxin for either 1 or 12 hr and with or without a 12 hr recovery period. Inhibition of protein synthesis and release of lactate dehydrogenase were measured and correlated with ultrastructural changes, as assessed by transmission electron microscopy. Results indicated that at a dose of 0.01 microgram/ml protein synthesis was inhibited 75% within 1 hr, but recovered to near control levels with or without the continual presence of toxin. At the higher toxin dose of 1.0 microgram/ml hepatocytes were able to recover from a 1 hr, but not a 12 hr, exposure. Cell damage, as assessed by release of lactate dehydrogenase, lagged behind inhibition of protein synthesis. Only at a T-2 concentration of 1.0 microgram/ml for 12 hr followed by a 12 hr recovery period was release of lactate dehydrogenase significantly elevated over control values. Under the same parameters, protein synthesis was inhibited 94%. The ultrastructural appearance of the cell membrane, nucleus, lysosomes, peroxisomes and smooth endoplasmic reticulum remained unchanged. The two organelles which appeared altered by T-2 exposure were the rough endoplasmic reticulum and the mitochondria. Endoplasmic reticulum changes were limited to degranulation of attached ribosomes without dilation of the cisternae. Alterations were seen as early as 1 hr at a T-2 dose of 0.01 microgram/ml. After a dose of 1.0 microgram/ml T-2 for 12 hr some mitochondria displayed one or more non-membrane-bound translucent foci, some of which contained electron-dense cores.

Animals↗

PubMed1986

Quantitative cytophotometric analysis of brain neuronal RNA and protein changes in acute T-2 mycotoxin poisoned rats.

Male Sprague-Dawley rats (200 g) injected intraperitoneally with T-2 toxin, a trichothecene mycotoxin protein synthesis inhibitor, at dosages of 0.75, 1.0, 1.5 and 6.0 mg/kg (1 LD50 = 0.9 mg/kg) were decapitated at 8 hr post-exposure. Data were obtained on changes in neuronal (perikaryal) RNA levels, protein contents and nucleolar volumes in cerebrocortical (layer III) and striatal (caudate-putamen) brain regions using quantitative azure B-RNA and Coomassie-protein cytophotometry and ocular filar micrometry. Correlative observations were made on changes in brain cytomorphology. Reductions in neuronal RNA/protein contents and nucleolar volume were used as indices of impaired perikaryal functioning. At 8 hr after T-2 toxin poisoning the following results were obtained in cerebrocortical and striatal brain compartments: neuronal RNA contents were generally maintained at control values in both brain regions, however, moderate RNA depletion was evidenced in the cerebral cortex with 1.5 mg/kg T-2 and in the striatum with a 6.0 mg/kg dose; neuronal protein levels were suppressed in a dose-dependent fashion within the cerebrocortex, while in the striatum there was no direct correspondence between protein loss and T-2 dosage; neuronal nucleolar volumes were typically maintained at control levels in both neuronal compartments. Microscopic observations revealed no gross evidence of T-2-induced brain cytopathology. These data indicate that T-2 toxin does not elicit direct cytopathic actions in these two brain regions, thus indicating that cerebrocortical and striatal compartments do not represent primary target sites of T-2 toxicant action.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Nuclear lipid peroxidation induced in rat liver by T-2 mycotoxin.

Oral administration to rats of T-2 mycotoxin (1.25 mg/kg) for five days causes an increase in lipid peroxidation (ascorbate-induced as well as NADPH-dependent) in hepatic nuclei, while the activity of liver glutathione-S-transferase (EC. 2.5.1.18) is decreased. The hepatotoxicity could be due to lipid peroxidation induced by depletion of hepatic reduced glutathione and/or production of free radicals.

Animals↗

PubMed1986

Inhibitory effect in vitro of PR toxin, a mycotoxin from Penicillium roqueforti, on the mitochondrial HCO-3-ATPase of the rat brain, heart and kidney.

The effects of PR toxin, a mycotoxin from Penicillium roqueforti, on the mitochondrial HCO3- -ATPase activity of the brain, heart and kidney from male Sprague-Dawley rats were determined by measuring colorimetrically the inorganic phosphate liberated by the ATPase in the presence or absence of bicarbonate ion. The IC50 (the concentration at which 50% of the enzyme activity is inhibited) of PR toxin on the mitochondrial HCO3- -ATPase from brain, heart and kidney were 12.7, 9.2 and 14.8 microM, respectively. The Michaelis-Menten constants (Km) of the enzyme from brain (1.1 mM), heart (1.5 mM) and kidney (2.3 mM) were not changed by PR toxin. Neither neutral nor anionic detergent increased the inhibitory potency of the toxin. It was concluded that of the three tissues tested, HCO3- -ATPase of the heart mitochondria was most sensitive to PR toxin, and that the toxin inhibited the HCO3- -ATPase in a non-competitive and irreversible manner.

Adenosine Triphosphatases↗

PubMed1986

Pharmacokinetics of the trichothecene mycotoxin, T-2 toxin, in swine and cattle.

The pharmacokinetics of the trichothecene mycotoxin, T-2 toxin, were determined in growing gilts and heifers. Following intra-aortal administration in swine and intravenous administration in calves, the disappearance of the parent T-2 toxin followed a 2-compartment open model. Mean elimination phase half-lives were 13.8 and 17.4 min and mean apparent specific volumes of distribution were 0.366 and 0.376 l/kg in swine and calves, respectively. The fraction of T-2 toxin eliminated as parent compound in the urine was negligible. In spite of administration of a lethal oral dose in swine (2.4 mg/kg) and toxic oral doses (up to 3.6 mg/kg) in calves, no parent T-2 toxin was detected in plasma or urine. After intra-aortal administration in swine, tissue concentrations of T-2 toxin were consistently highest in lymphoid organs. Tissue residues of T-2 toxin were rapidly depleted such that, in spite of administration of a potentially lethal intra-aortal dose, no quantifiable T-2 toxin was present in any of the tissues collected at 4 hr after dosing. No T-2 toxin could be detected in liver, even at 1 hr after dosing.

Animals↗

PubMed1988

Cytotoxic effect of T-2 mycotoxin on cells in culture as determined by a rapid colorimetric bioassay.

We developed a colorimetric assay for determining metabolic activity (viability) of cells exposed to toxic agents. This system is based on the ability of mitochondrial enzymes in viable cells to modify a tetrazolium salt into a blue formazan product that can be detected spectrophotometrically at 570 nm. The assay works equally well for mammalian and insect cell lines and at 48 hr color formation is linear over a cell input range of 1.56-50 X 10(4) cells/ml. The inhibitory effects of T-2 mycotoxin on tetrazolium cleavage in L929 cells is comparable to that observed for protein and DNA synthesis (50% inhibition = 6-8 ng/ml). Using this system to analyze the lethal effect of T-2 toxin on cells from various animal species, it was found that bovine cells were the most sensitive (50% inhibition at 2.2 ng/ml) while hamster cells were the most resistant (50% inhibition at 26.2 ng/ml). Murine cells exhibited intermediate sensitivity (50% inhibition at 10.9 ng/ml). Variable toxin susceptibility was also observed among different cell types. Lymphocytes were 3-fold more sensitive to the T-2 inhibitory effects than comparable tissue culture cell lines. These data indicate that the colorimetric assay system could have broad applications in toxicological studies. Further, the observed differences in species sensitivity may provide insight into the primary mechanism of the T-2 toxin-cell interaction that ultimately leads to cell death.

Animals↗

PubMed1994

Hematopoietic alterations after exposure to T-2 mycotoxin.

Adult mice were exposed by oral gavage to 0.75, 1.25, or 1.75 mg/kg body weight T-2 mycotoxin for 5 consecutive days. Thymic atrophy on the 2nd day following cessation of dosing was profound, and was characterized by significant decreases in the total number of cells within all phenotypes defined by CD4 and CD8 cell-surface antigen expression. Further, the distribution of thymocytes within these phenotypes was significantly altered. Increased percentages of CD4-8- (DN) and decreased percentages of CD4+8+ (DP) cells in thymuses from treated animals suggested that T-2 toxin may inhibit thymocyte maturation. In addition to thymus, the bone marrow of treated animals showed a highly significant hypocellularity, indicating that this hematopoietic compartment may also be targeted by T-2 toxin. A trend toward reduced splenic cellularity was additionally observed in exposed animals, but failed to reach significance. A significant decrease in the total number of both B and T-lymphocytes present within the spleen was observed, however. These data, taken together, indicate that effects at multiple hematopoietic compartments involved in the production of T-lymphocytes may contribute to the peripheral T-cell lymphocytopenia and T-cell mediated immunosuppression produced by T-2 toxin.

Administration, Oral↗