fumonisin-b1 and Liver-Diseases

Topics: Apoptosis; Chemical and Drug Induced Liver Injury; Fibrosis; Fumonisins; Humans; Hydrogen Peroxide; Liver; Liver Diseases; Male; Oxidative Stress

Populations consuming aflatoxin (AF) and fumonisin (FN)-contaminated foods may be at increased risk for hepatocellular carcinoma (HCC) and developmental disorders; consequently, development of intervention strategies to reduce AF/FN-induced liver disease and adverse health effects in humans could be very useful. Calcium montmorillonite clay (NovaSil) has been shown to absorb AF in vitro, in multiple animal models, as well as in human studies. In the present study, we aimed to evaluate whether uniform particle size NovaSil (UPSN) possessed an ability to modulate the co-carcinogenic potentials of aflatoxin B

Topics: Adsorption; Aflatoxin B1; Aluminum Silicates; Animals; Bentonite; Clay; Fumonisins; Humans; Liver; Liver Diseases; Male; Rats; Rats, Inbred F344

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

Fumonisin B(1), a mycotoxin, is an inhibitor of ceramide synthase causing marked dysregulation of sphingolipid metabolism in cells. This mycotoxin causes accumulation of free sphingoid bases (sphingosine and dihydrosphingosine or sphinganine) and their metabolites, important messengers involved in signal transduction leading to either cell survival or death. Free sphingoid bases are known apoptotic molecules whereas sphingosine 1-phosphate is protective. We previously reported that fumonisin B(1) caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT). Fumonisin B(1) also increased inducible nitric oxide synthase (iNOS) expression. In the current study we employed a mouse strain with the targeted deletion of iNOS gene (Nos-KO) to evaluate the role of nitric oxide (NO) on fumonisin B(1)-induced hepatotoxicity. The Nos-KO mice exhibited increased hepatotoxicity after subacute fumonisin B(1) exposure compared to their wild type counterparts, the liver regeneration was lower in Nos-KO compared to that in the WT mice. Increased hepatotoxicity in Nos-KO was not related to the extent of free sphingoid base accumulation after fumonisin B(1) treatment; however, it was accompanied by a lack of fumonisin B(1)-induced SPHK induction. The fumonisin B(1)-induced SPT was unaffected by lack of iNOS gene. Deletion of iNOS gene did not prevent fumonisin B(1)-dependent induction of inflammatory cytokines, namely tumor necrosis factor alpha, interferon gamma and interleukin-12. The lack of fumonisin B(1)-induced SPHK induction in Nos-KO was supported by a similar effect on phosphorylated metabolites of sphingoid bases; the equilibrium between sphingoid bases and their phosphates is maintained by SPHK. We therefore conclude that iNOS induction produced by fumonisin B(1) modulates SPHK activity; the lack of iNOS prevents generation of sphingosine 1-phosphate and deprives cells from its protective effects.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carcinogens, Environmental; Cell Proliferation; Chemical and Drug Induced Liver Injury; Fumonisins; Hepatocytes; In Situ Nick-End Labeling; Interferon-gamma; Interleukin-12; Liver Diseases; Liver Regeneration; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphotransferases (Alcohol Group Acceptor); RNA, Messenger; Sphingosine; Tumor Necrosis Factor-alpha; Weight Loss

Sodium bentonite (SB) was evaluated for its ability to reduce the deleterious effects of fumonisin B1 (FB1) and aflatoxin B1 (AFB1) in broiler diets. It was incorporated into the diets (0.3%) containing 2.5 mg/kg AFB1, 200 mg/kg FB1, or a combination of 2.5 mg/kg AFB1 and 200 mg/kg FB1. Aflatoxin B1 significantly diminished body weight gain, whereas FB1 or the combination of FB1 and SB had no effect. Addition of SB in the diets significantly diminished the inhibitory effects of dietary AFB1. Feeding AFB1 alone caused significant increases in the relative weights of most observed organs. Feeding FB1 alone did not alter relative weights of any organs. In the combined diet (AFB1 plus FB1) relative weights of the liver, kidney, gizzard, and spleen were increased. Addition of SB to the diet containing AFB1 diminished the relative weights of liver, kidney, and spleen. Addition of SB to diets containing AFB1 and FB1 only decreased liver weights. In relation to the control, lower serum levels of total protein, albumin, and globulins were observed for all AFB, containing diets without SB addition, whereas all other treatments were not altered. Livers of birds fed diets containing AFB1 and a combination of AFB1 and FB1 were enlarged, yellowish, friable, and had rounded borders. The histopathology of them, stained with hematoxylin and eosin, showed multifocal and varied cytoplasmatic vacuolization with perilobular location. Incorporation of SB reduced the incidence and severity of the hepatic histopathology changes associated with aflatoxicosis.

Topics: Aflatoxin B1; Animal Feed; Animals; Bentonite; Chemical and Drug Induced Liver Injury; Chickens; Diet; Food Contamination; Fumonisins; Intestinal Absorption; Liver; Liver Diseases; Organ Size; Poultry Diseases

Acute and subacute intraperitoneal doses of fumonisin B(1) (FB(1)) were administered to test the efficacy of the FB(1)-glucose reaction products in detoxifying FB(1) in swine. In the acute study at 11 mumol of FB(1)/kg of body weight, five of six pigs administered FB(1) and four of six pigs administered FB(1)-glucose died from acute pulmonary edema. Analysis of weight gain, serum aspartate aminotransferase and gamma-glutamyltransferase, total cholesterol, and pathological evaluation did not provide evidence of protection against FB(1) toxicity by the FB(1)-glucose reaction products. In the subacute study at 5.5 mumol of FB(1)/kg of body weight, one pig administered FB(1) died from liver damage. Analysis of serum aspartate aminotransferase, gamma-glutamyltransferase, and total bilirubin showed protection against FB(1) toxicity by the FB(1)-glucose reaction products. The levels of sphinganine and sphinganine/sphingosine ratios in serum and liver as well as pathologic findings provided definitive evidence of protection against the FB(1) toxic effects by this detoxification procedure (p < 0.05).

Topics: Animals; Chemical and Drug Induced Liver Injury; Fumonisins; Glucose; Liver Diseases; Pulmonary Edema; Swine; Swine Diseases

Fumonisin B1 (FB1), a mycotoxin produced primarily by Fusarium veticillioides and related fungi, is a carcinogen and causative agent of various animal diseases. Our previous studies indicated the involvement of tumor necrosis factor-alpha (TNFalpha) in FB1-induced hepatotoxicity. Male B6,129 mice (five/group) were injected subcutaneously with vehicle or 2.25 mg/kg/day of FB1 for 5 days and sampled 1 day after the last treatment. FB1 treatment caused an increased expression of TNFalpha, interferon gamma (IFNgamma) and interleukin (IL)-12 p40 in liver without any changes in kidney or spleen, suggesting the localized site of their production. IL-1beta cytokine expression was increased in liver and kidney after FB1 exposure. Cells involved in TNFalpha production after FB1 treatment in liver were identified as Kupffer cells. FB1 increased alanine aminotransferase in plasma and increased apoptotic cells in liver. Selective increase in proinflammatory T helper (Th)1-cytokines (IL-12 and IFNgamma) and TNFalpha with no alteration in Th2-cytokines (IL-4, IL-6 and IL-10) suggest the involvement of IL-12, produced by Kupffer cells, in induction of IFNgamma production by natural killer (NK) cells and/or NK1+ T cells, which can undergo a positive amplification loop with TNFalpha produced by macrophages or other hepatic cells to elicit the toxic reaction.

Topics: Alanine Transaminase; Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Cytokines; Fumonisins; Gene Expression; In Situ Hybridization; In Situ Nick-End Labeling; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Kidney; Kupffer Cells; Liver; Liver Diseases; Male; Mice; Mycotoxins; Spleen; Tumor Necrosis Factor-alpha

Our previous studies have indicated that tumour necrosis factor alpha (TNFalpha) is involved in fumonisin B1 (FB1)-induced toxic responses. To investigate the role of TNFalpha in FB1 toxicity further we employed male transgenic mice expressing human TNFalpha gene (TG) and their wild-type equivalent C57BL/6 (WT). It was hypothesized that TG animals would have enhanced response to FB1. Repeated subcutaneous treatment of animals with 2.25 mg/kg per day of FB1 for 5 days caused minimal changes in body weight, organ weights, blood cell counts, and TNFalpha levels in plasma 1 day after the last injection. The mRNA for TNFalpha in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic TNFalpha expression. Liver and kidney lesions were found in TG after FB1 treatment; however, liver lesions seen in FB1-treated TG were considerably less than those observed in WT. The decreased hepatotoxicity in TG after FB1 treatment correlated with plasma concentrations of alanine aminotransferase and aspartate aminotransferase. Free sphinganine levels increased significantly in both the liver and kidney of WT and TG mice treated with FB1. The increase of free sphinganine in the liver from TG mice was 40% less than in WT mice and paralleled the changes in serum liver enzymes. Regional brain neurotransmitters and their metabolites were increased to a similar extent by FB1 in both WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NFkappaB in liver. The cytosolic NFkappaB was significantly higher in TG compared with WT. Induction of NFkappaB, caused by increased endogenous production of TNFalpha, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NFkappaB in FB1-induced liver damage.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biogenic Amines; Brain; Carboxylic Acids; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Female; Fumonisins; Gene Expression; Kidney; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mycotoxins; Neurotransmitter Agents; NF-kappa B; RNA, Messenger; Sphingolipids; Tumor Necrosis Factor-alpha

Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium moniliforme, a common fungus which occurs naturally on corn, and other Fusarium species. FB1 and other fumonisins are now recognized as having potentially important animal and human health implications. However, few toxicological data are currently available. Male and female B6C3F1 mice and Fischer 344 rats were fed diets containing 0, 1, 3, 9, 27, or 81 ppm FB1 (> or = 98% purity) for 13 weeks. No differences in behavior or appearance, body weight or food consumption between control and FB1-fed groups were found. In mice, hepatopathy and altered serum chemical profiles indicative of hepatotoxicity were found in females fed the 81 ppm diet. No adverse effects were found in female mice fed < or = 27 ppm FB1 or in male mice at any dietary level studied. In rats, nephrosis involving the outer medulla was found in males fed > or = 9 ppm and, to a lesser degree, in females fed 81 ppm FB1, while decreased kidney weight was found in both sexes at dietary levels > or = 9 ppm FB1. Although the liver is a target organ of FB1 in rats, hepatotoxicity was not found in rats fed diets containing up to 81 ppm FB1 for 90 days. Thus, FB1 was toxic to both species following subchronic oral exposure, although significant interspecies differences in the no observed effect levels and organ-specific responses were found.

Topics: Adrenal Glands; Animals; Behavior, Animal; Body Weight; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Cholesterol; Creatinine; Dose-Response Relationship, Drug; Eating; Female; Fumonisins; Kidney; Liver; Liver Diseases; Male; Mice; Mice, Inbred Strains; Mycotoxins; Organ Size; Rats; Rats, Inbred F344; Species Specificity

Three gilts fed a diet containing 100 mg fumonisin B1/kg for 7 days followed by a diet containing 190 mg/kg for 83 days developed nodular hyperplasia of the liver. These nodules of various diameters were composed of solid sheets or nests of hepatocytes. There were no discernible central veins or portal triads, and the perilobular connective tissue and adjacent parenchyma were compressed. Three other gilts maintained on the same diet for 27-80 days developed severe hepatopathies, but not nodular hyperplasia, necessitating euthanasia prior to conclusion of the feeding trial. At necropsy, 1 of the 6 gilts had grossly apparent hyperplastic plaques within the distal esophageal mucosa. On histopathologic examination, 6 of 6 gilts had mild to severe hyperkeratosis, parakeratosis, and formation of papillary downgrowths of the stratum basale of the distal esophageal mucosa. The hyperplastic nodules in the liver and the changes in the distal esophageal mucosa illustrate the unique chronic toxicity of this mycotoxin in pigs.

Topics: Animal Feed; Animals; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Female; Food Contamination; Fumonisins; Hyperplasia; Liver Diseases; Mycotoxins; Swine; Swine Diseases; Weaning

A study to evaluate the effects of dietary fumonisin B1 was conducted using 6 ponies (4 test and 2 control). A ration naturally contaminated with fumonisin B1 was fed in 3 phases: 1) 44 ppm fumonisin B1, 2) less than 1 ppm fumonisin B1, and 3) 88 ppm fumonisin B1. All ponies were monitored daily, weighed weekly, and limit fed at a rate of 0.8% body weight plus hay. Feed intake was measured daily, and a serum chemistry panel was completed once or twice weekly. Four to 7 days after initiation of the trial (Phase 1), all 4 test ponies had decreased feed consumption, and selected serum chemistry parameters were markedly elevated. On day 9, 1 pony died acutely with mild encephalopathy and hepatic necrosis. Another pony, euthanized on day 45, also had mild encephalopathy and hepatic necrosis. The remaining 2 test ponies continued the 44 ppm fumonisin B1 diet for 98 days. Phase 2 consisted of a diet with < 1 ppm fumonisin B1 for 120 days. During this phase, the serum chemistry values of the 2 ponies returned to normal. Following Phase 2, the 2 ponies were fed a diet containing 88 ppm fumonisin B1. After 75 days, 1 animal died of equine leukoencephalomalacia with mild hepatic necrosis. On day 78, the remaining pony was euthanized after showing distress; it also had leukoencephalomalacia and hepatic lesions.

Topics: Animal Feed; Animals; Brain; Brain Diseases; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Encephalomalacia; Food Contamination; Fumonisins; Horses; Liver; Liver Diseases; Mycotoxins; Necrosis; Zea mays

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