fumonisin-b1 and Kidney-Diseases

Radiocontrast nephropathy (RCN) is a major complication after radiographical examination with iodinated contrast media (CM). Although little is known about the mechanism of RCN, a direct toxic action on renal cells and/or decrease in renal blood flow are considered to be implicated in the pathogenesis of the disease/the condition, A large number of vasodilatory agents, including endothelin antagonists, adenosine antagonists, atrial natriuretic peptide, calcium channel blockers, dopamine, dopamine D1 receptor agonist fenoldopam, and prostaglandin E1 have been tried clinically to prevent RCN, however, most of them have failed. Although prophylactic effects of antioxidant N-acetylcysteine have recently been reported by several investigators, only hydration is a universally accepted protocol to prevent it. In our recent in vitro and in vivo study, we have elucidated that CM induced apoptosis of renal tubular cells through the reduction in Bcl-2 expression and the subsequent activation of caspase-9 and caspase-3. Moreover, we found that CM caused an increase in ceramide content in renal tubular cells, which leads to apoptosis by inhibiting the phosphorylation of Akt and cAMP responsive element binding protein (CREB) and the subsequent reduction in Bcl-2 expression. The inhibitor of ceramide synthase, fumonisin B1, reversed both the elevation of ceramide content and renal cell injury induced by CM. On the other hand, a prostacyclin analog beraprost prevented RCN in mice by the increase of endogenous cAMP and subsequent CREB phosphorylation resulted in enhancement of Bcl-2 expression. These findings suggest that ceramide synthesis inhibitor or beraprost is potentially useful for the prophylaxis of RCN.

Topics: Acetylcysteine; Animals; Apoptosis; Ceramides; Contrast Media; Cyclic AMP Response Element-Binding Protein; Enzyme Inhibitors; Epoprostenol; Fumonisins; Humans; Iodine Compounds; Kidney Diseases; Kidney Tubules; Mice; Phosphorylation; Proto-Oncogene Proteins c-bcl-2

In a 196-day feeding trial, 48 male crossbred rabbits (New Zealand × Chinchilla) were randomly assigned and fed varied dietary fumonisin levels of 0.13, 5.0, 7.5 and 10.0 mg fumonisin B(1)/kg diet constituting treatments 1 (control), 2, 3 and 4 respectively. Five animals were randomly selected, stunned and killed per treatment. Relative weight of various visceral organs examined except heart and adrenal gland were significantly (p < 0.05) influenced by the dietary treatments. Liver and spleen weights of rabbits fed 10.0 mg fumonisin per kg were significantly (p < 0.05) lower than those fed control diet and diet 2. Kidney and testes weights were significantly (p < 0.05) lower in rabbits fed control diet and increased with increase in the dietary fumonisin levels. Histological examination of the organs revealed that rabbits fed diets 2, 3 and 4 showed increased severe lesion of approximately 20%, 40% and 60%, respectively, of the total slides examined for each treatment. Forty per cent and 80% of the rabbits fed diets containing 7.5 and 10.0 mg/kg fumonisin, respectively, showed severe necrosis whereas 40%, 60% and 20% of the rabbits fed 5.0, 7.5 and 10.0 mg/kg, respectively, showed mild–moderate liver necrosis/lesions as compared with non-significant lesion observed in the controls. Testicles of rabbits fed diets 3 and 4 showed mild–moderate lesions and sertoli cell degeneration. Tunica mucosa erosion was observed and predominant in the stomach and small intestine of rabbits fed 7.5 and 10.0 mg fumonisin per kg diet. This suggested that fumonisin B(1) above 5.0 mg/kg in rabbit diet is toxic to body organs with potential to induce their hypofunction or total damage.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chemical and Drug Induced Liver Injury; Diet; Dose-Response Relationship, Drug; Enteritis; Fumonisins; Kidney Diseases; Male; Rabbits; Stomach Diseases; Testicular Diseases

Fumonisin B1 (FB1), a worldwide contaminating mycotoxin, can cause global food issue. It has been reported that FB1 is related to chronic kidney disease of unknown etiology. However, the study of FB1-induced nephrotoxicity in vitro is very limited and the mechanism is unknown. Human renal tubule epithelial (HK-2) cells were used in this study. The results showed that FB1 exposure could decrease cell viability, induce cell apoptosis and up-regulate the expression of Kim-1, collagen I, α-SMA and TGF-β1. In addition, autophagy was activated after FB1 exposure, including the conversion of LC3 and up-regulation of ATGs. Furthermore, autophagy inhibitor 3-MA could block FB1-induced abnormalities. And antioxidant enzymes (Gpx1 and Gpx4) were obviously down-regulated and intracellular ROS levels displayed an ascent trend as FB1 exposure concentrations increased. Employing of antioxidant NAC could suppress FB1-induced nephrotoxicity and autophagy. FB1 inhibited the phosphorylation of p70 S6k, a downstream protein of mTORC1. Also, oxidative stress, autophagy and phosphorylation of p70 S6k induced by FB1 was inhibited by MHY1485, an activator of mTOR. But the phosphorylation of AKT, a downstream protein of mTORC2 showed no change with or without MHY1485. Taken together, FB1 induced nephrotoxicity via autophagy mediated by mTORC1 instead of mTORC2 in HK-2 cells.

Topics: Autophagic Cell Death; Autophagy; Cell Line; Cell Survival; Epithelial Cells; Fumonisins; Humans; Kidney Diseases; Kidney Tubules; Mechanistic Target of Rapamycin Complex 1; Oxidative Stress

Nixtamalisation is a widely used food processing method in which whole kernel corn is cooked and steeped in alkaline water. It reduces the amount of fumonisin B1 (FB1) that can be detected after cooking. However, the fate of FB1 during nixtamalisation is not fully understood and potentially toxic reaction products, including matrix-associated "masked" FB1 forms that are not detected by routine analytical methods might remain in nixtamalised corn. To assess how nixtamalisation of whole kernel corn affects fumonisin toxicity, male rats were fed diets containing low, mid or high levels of uncooked (LU, MU, HU) or alkaline cooked (LC, MC, HC) FB1-contaminated corn for 3 weeks. The control diet contained uncontaminated corn only. Apoptotic kidney lesions of the type caused by FB1 were not found in the LC or MC groups. Lesions in the group fed HC were minimal and less severe than those found in the rats fed LU, MU or HU. Furthermore, significantly increased sphinganine and sphingosine concentrations indicative of FB1 exposure were found in the kidneys of the rats given LU, MU or HU. Concentrations were also elevated, but to a lesser extent, in rats fed HC, whereas sphinganine and sphingosine concentrations in rats given LC or MC did not differ from the control group. FB1 concentrations in the LC (0.08 mg kg(-1)), MC (0.13 mg kg(-1)) and HC (0.37 mg kg(-1)) diets were markedly reduced compared with their LU (1.8 mg kg(-1)), MU (3.5 mg kg(-1)) and HU (4.2 mg kg(-1)) counterparts as determined by HPLC (n =  1 analysis/diet). Taken together, the findings show that nixtamalisation is an effective cooking method for reducing the potential toxicity of FB1 contaminated corn.

Topics: Animal Feed; Animals; Biological Assay; Cooking; Diet; Fumonisins; Hydrogen-Ion Concentration; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Sprague-Dawley; Zea mays

Mycotoxic nephropathy was induced in eighteen young pigs by mouldy diets containing 0.5 ppm ochratoxin A (OTA) and/or 10 ppm fumonisin B1 (FB1) for three months. While the most obvious damages provoked by OTA were seen in the kidneys as expressed by the strong degenerative changes in proximal tubules and fibrosis in kidneys, FB1 was found to induce an increase in permeability of vessels mainly in lung, brain, cerebellum or kidneys and slight to moderate degenerative changes in kidneys. Pathomorphological damages in pigs exposed to both mycotoxins simultaneously present a combination of the main lesions provoked by each mycotoxin alone being stronger in their expression. Biochemical investigations as expressed by the increase of serum creatinine, urea and enzyme activity of ASAT/ALAT and by the decrease of serum cholesterol, total protein, albumin and glucose were strongest in pigs exposed to both mycotoxins simultaneously as can be anticipated form the strongest lesions in the kidneys. Both mycotoxins and their combination were found to disturb powerfully humoral immune response in all experimental pigs as expressed by the strong decrease in antibody titer against Morbus Aujesky at days 21 and 35 after vaccination. Having in mind that the feed levels of the both mycotoxins as well as the exposure time and the pathological findings corresponded to those in some spontaneous cases of porcine nephropathy in Bulgaria and South Africa, it can be concluded that the same mycotoxins are involved in the observed field cases of that nephropathy.

Topics: Animal Feed; Animals; Capillaries; Disease Models, Animal; Drug Synergism; Female; Fumonisins; Immunity, Humoral; Intestinal Mucosa; Kidney Diseases; Kidney Tubules, Proximal; Liver; Lung; Lymph Nodes; Male; Ochratoxins; Swine

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

Spontaneous nephropathy in Bulgaria, which is observed frequently during meat inspection and which differs morphologically from the classical description of mycotoxic porcine/chicken nephropathy as made in Denmark, was found to have a multi-mycotoxic aetiology being mainly provoked by a combined effect of ochratoxin A, penicillic acid and fumonisin B1 in addition to a not-yet-known metabolite. Mean contamination levels of ochratoxin A were consecutively low (188.8 and 376.4 microg kg(-1)) in contrast to high contamination levels of fumonisin B1 (5564.1 and 3254.5 microg kg(-1)) and penicillic acid (838.6 and 904.9 microg kg(-1)) for 2006 and 2007, respectively. Some other mycotoxins with lower importance such as citrinin, penitrem A, etc., may also influence clinicopathological picture of this nephropathy. A heavy contamination with Gibberella fujikuroi var. moniliformis (Fusarium verticillioides) and Penicillium aurantiogriseum complex (mainly Penicillium polonicum) was observed in almost all examined feed samples coming from pig and chick farms with nephropathy problems from Bulgaria. In contrast, low contamination with Aspergillus ochraceus, Penicillium verrucosum and Penicillium citrinum was observed in the same feed samples and these species were isolated as very rare components of the mycobiota.

Topics: Animal Feed; Animals; Balkan Nephropathy; Bulgaria; Chickens; Drug Synergism; Food Contamination; Food Microbiology; Fumonisins; Humans; Kidney Diseases; Mycotoxicosis; Mycotoxins; Ochratoxins; Penicillic Acid; Poultry Diseases; Sus scrofa; Swine; Swine Diseases

Quantitative risk analysis permits modifying risk estimates with changes in variables such as exposure. This analysis for exposure to the mycotoxin fumonism describes the magnitude of adverse effects, variability in the population and uncertainty of models as a range of possible outcomes. The most sensitive adverse response in rats, nephrotoxic lesions, was used for the dose-response analysis. Dietary intake of corn products was estimated from a 3-day consumption survey. Levels of corn in each product were estimated by standard methods. Fumonisin levels in corn products were estimated from Food and Drug Administration (FDA) surveillance data and distributions of fumonisin consumption were modelled for each eater in the survey population. Uncertainty for predictions made from each model and uncertainty resulting from model selection were described. Results of the dose-response and exposure analyses were assimilated in a two-dimensional Monte-Carlo simulation. Distributions representing variability and uncertainty were iteratively selected to form an array of estimates of the risk. On the basis of this analysis, current dietary levels of fumonisin would not result in renal lesions even at upper levels of exposure. To avoid toxicity at much higher doses, limiting corn intake would be more effective than would limiting the level of fumonisin in corn.

Topics: Animals; Carboxylic Acids; Carcinogens, Environmental; Diet; Dose-Response Relationship, Drug; Female; Food Contamination; Fumonisins; Humans; Kidney Diseases; Male; Monte Carlo Method; Mycotoxins; Rats; Risk Assessment; Software; United States; Zea mays

Male rats were gavaged with fumonisin B1 (FB1) once daily for 11 consecutive days at doses of 0, 1, 5, 15, 35, and 75 mg FB1/kg body weight. Urine osmolality (at 5-75 mg FB1/kg) and organic ion transport in kidney slices (at 5-75 mg FB1/kg) were reduced. Urinary excretion of protein (at 15-75 mg FB1/kg) and of the enzymes LDH (at 5-75 mg FB1/kg), NAG (at 5-75 mg FB1/kg) and GGT (at 15-75 mg FB1/kg) were increased. These findings were indicative of glomerular and tubular toxicity. Histopathologic changes in the kidney consisted of necrosis of tubular epithelia of variable extent accentuated in the inner cortex. These changes were present at 1 and 5 mg FB1/kg and were more pronounced at 15-75 mg FB1/kg. Serum enzymes indicative of hepatotoxicity (ALT, GGT) were elevated compared to controls at 75 mg FB1/kg only. There were noticeable increases in mitotic figures in hepatocytes at 35-75 mg FB1/kg, while single cell necroses were increasingly numerous from 15-75 mg FB1/kg. The kidneys were considered to be the primary target organs in this study.

Topics: Acetylglucosaminidase; Animals; Creatinine; Fumonisins; gamma-Glutamyltransferase; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Leukocyte Count; Liver; Male; Mycotoxins; Osmolar Concentration; Proteinuria; Rats; Rats, Sprague-Dawley; Transaminases; Urine; Weight Gain

Fumonisins are potent inhibitors of sphingolipid biosynthesis produced by several Fusarium species. Consumption of corn or corn products infected with F. moniliforme, or high levels of fumonisins, is associated with several animal diseases. In a 4-wk feeding study, the concentration of fumonisin B1 that caused nephrotoxicity in Sprague-Dawley rats was much less than that required to cause hepatotoxicity. This retrospective study shows a close correlation between the extent and severity of ultrastructural lesions and the degree of disruption of sphingolipid metabolism. The kidney was more sensitive to fumonisin B1-induced disruption of sphingolipid metabolism than liver with significant elevation of free sphingosine, free sphinganine, and the free sphinganine:free sphingosine ratio in rats fed 15, 50 and 150 micrograms/g fumonisin B1. Accumulation of free sphinganine and elevation of the free sphinganine:free sphingosine ratio in urine closely reflected the changes that occurred in kidney. The accumulated sphinganine and elevation of the free sphinganine:free sphingosine ratio was associated with accumulation of cells in urine. Thus, urine rather than serum is the fluid of choice for detecting elevated free sphingoid bases generated as a consequence of fumonisin-induced kidney damage.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diet; Female; Fumonisins; Kidney; Kidney Diseases; Liver; Male; Microscopy, Electron; Mycotoxins; Rats; Rats, Sprague-Dawley; Sphingolipids; Sphingosine

Currently there is no convenient bioassay to determine the potential toxicity of corn naturally contaminated with Fusarium moniliforme. A short-term bioassay would be useful for future investigations aimed at isolating as yet unidentified toxins produced by this fungus. Two groups of five male Sprague-Dawley rats were each fed one of two F. moniliforme contaminated corn samples, designated CS-1 and CS-2, that were associated with separate field cases of equine leukoencephalomalacia (ELEM). A control group, also consisting of five male rats, was fed uncontaminated seed corn. All animals survived to the end of the study and there were no apparent differences in appearance or behaviour among groups. Weight loss and irregular food consumption occurred in all groups and probably resulted from nutritional deficiencies inherent in the corn diets. Hepatocellular degeneration, necrosis and hyperplasia as well as biliary hyperplasia were found in the test groups only and were attributed to F. moniliforme. Serum transaminase and alkaline phosphatase activities in animals fed CS-1 and CS-2 for 4 wk were significantly increased compared with the controls, while serum bilirubin concentration was increased only in the CS-1 group. Tubular nephrosis was also present in the renal cortex of all animals fed CS-1 and CS-2. These effects may have been related to fumonisins B1 and B2, recently discovered metabolites of F. moniliforme, that were found in both CS-1 and CS-2. Short-term studies of this type may be useful in screening naturally-contaminated grains and other materials for hepatotoxic metabolites produced by F. moniliforme.

Topics: Animals; Carcinogens, Environmental; Encephalomalacia; Food Contamination; Fumonisins; Fusarium; Horse Diseases; Horses; Kidney Diseases; Liver Diseases; Male; Mycotoxins; Rats; Rats, Inbred Strains; Zea mays