fumonisin-b1 and Disease-Models--Animal

This review summarizes the information regarding the in vivo studies of Fusarium mycotoxins in the last decade. The most common studies are classified as subacute toxicity, subchronic toxicity, acute toxicity, toxicokinetic studies and teratogenicity in order of importance. The most used animals in in vivo studies are pigs, rats, chickens and mice. Fumonisin B1, deoxynivalenol, zearalenone, nivalenol and T-2 toxin are the most studied fusarotoxins. Studies with combinations of mycotoxins are also frequent, deoxynivalenol generally being one of them. The predominant route of administration is oral, administered mostly in the form of naturally contaminated feed. Other administration routes also used are intraperitoneal, intravenous and subcutaneous. In vivo research on Fusarium mycotoxins has increased since 2010 highlighting the need for such studies in the field of food and feed safety.

Topics: Animal Feed; Animals; Chickens; Consumer Product Safety; Disease Models, Animal; Food Contamination; Food Microbiology; Fumonisins; Fusarium; Mice; Mycotoxins; Rats; Swine; T-2 Toxin; Trichothecenes; Zearalenone

Ochratoxin A (OTA) is a nephrotoxic mycotoxin with carcinogenic properties. Its presence was detected in various foodstuffs all over the world but with significantly higher frequency and concentrations in areas with endemic nephropathy (EN). Even though food is often contaminated with more than one mycotoxin, earlier studies focused on the occurrence and toxicology of only OTA. Only a limited number of surveys showed that OTA co-occurs in food with mycotoxins (citrinin-CIT, penicilic acid, fumonisin B1-FB1, aflatoxins-AF) which exert nephrotoxic, carcinogenic or carcinogen-promoting activity. This review summarises the findings on OTA and its co-occurrence with the mentioned mycotoxins in food as well as experimental data on their combined toxicity. Most of the tested mycotoxin mixtures involving OTA produced additive or synergistic effects in experimental models suggesting that these combinations represent a significant health hazard. Special attention should be given to mixtures that include carcinogenic and cancer-promoting mycotoxins.

Topics: Aflatoxins; Animals; Carcinogens; Citrinin; Disease Models, Animal; DNA Damage; Food Contamination; Fumonisins; Humans; Ochratoxins; Toxicity Tests

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

Topics: Animals; Carcinogens; Cell Culture Techniques; Disease Models, Animal; Esophageal Neoplasms; Food Contamination; Food Microbiology; Fumonisins; Fusarium; Humans; Leukoencephalopathies; Liver Neoplasms; Neural Tube Defects; Neurotoxins; Neurotransmitter Agents; Pulmonary Edema; Zea mays

We review the hepatocarcinogenic effects of fungal cultures of Fusarium verticillioides(= Fusarium moniliforme) strain MRC 826 in male BD IX rats. Subsequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB1 provide information about dose-response effects, relevance of hepatotoxicity during FB1-induced carcinogenesis, and the existence of a no-effect threshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body weight (bw)/day over approximately 2 years produce liver cancer in male BD IX rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, although mild toxic and preneoplastic lesions are induced. The nutritional status of the diets used in the long-term experiments was marginally deficient in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a cancer initiation/promotion model in rat liver provided important information about the possible mechanisms involved during the initial stages of cancer development by this apparently nongenotoxic mycotoxin. These studies supported the findings of long-term investigations indicating that a cytotoxic/proliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed for cancer induction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion.

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Carboxylic Acids; Carcinogens, Environmental; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Fumonisins; Fusarium; Lipids; Liver Neoplasms, Experimental; Male; Mycotoxins; Phospholipids; Rats

Fumonisin B1 (FB1 ) is found in corn-based foods and is a possible risk factor for neural tube defects (NTDs). The mechanism(s) underlying NTD induction by FB1 in LM/Bc mice is not understood; however, evidence suggests disrupted folate transport is involved.. Female LM/Bc mice were fed folate-sufficient (control) or folate-deficient diet beginning 5 wk before mating, treated with 0 (vehicle), 2.5 or 10 mg/kg FB1 by intraperitoneal injection on embryonic days 7 (E7) and E8, and their fetuses examined on E16. Dose-dependent NTD induction was found in groups fed the control diet: 3 of 13 low-dose and 10 of 11 high-dose litters were affected. Among groups fed folate-deficient diet, NTDs were found only in 4 of 11 high-dose litters. In another trial, consumption of folate-deficient diet also resulted in fewer NTDs at a dose of 10 mg/kg FB1 and reduced maternal red blood cell folate levels by 80%. In utero death did not fully account for the differences in NTD rates.. Folate deficiency does not exacerbate NTD induction by FB1 in LM/Bc mice. Interactions between folate, other nutritional factors, and FB1 in this mouse model for NTDs are complex and require further investigation.

Topics: Animals; Diet; Disease Models, Animal; Erythrocytes; Female; Folic Acid; Folic Acid Deficiency; Fumonisins; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred Strains; Neural Tube Defects

Mycoplasma hyopneumoniae has a primary role in the porcine respiratory disease complex (PRDC). The objective of this study was to determine whether fumonisin mycotoxins influence the character and/or the severity of pathological processes induced in the lungs of pigs by Mycoplasma hyopneumoniae. Four groups of pigs (n = 7/group) were used, one fed 20 ppm fumonisin B1 (FB1) from 16 days of age (group F), one only infected with M. hyopneumoniae on study day 30 (group M), and a group fed FB1 and infected with M. hyopneumoniae (group MF), along with an untreated control group (group C). Computed tomography (CT) scans of infected pigs (M and MF) on study day 44 demonstrated lesions extending to the cranial and middle or in the cranial third of the caudal lobe of the lungs. The CT images obtained on study day 58 showed similar but milder lesions in 5 animals from group M, whereas lungs from 2 pigs in group MF appeared progressively worse. The evolution of average pulmonary density calculated from combined pixel frequency values, as measured by quantitative CT, was significantly influenced by the treatment and the age of the animals. The most characteristic histopathologic lesion in FB1-treated pigs was pulmonary edema, whereas the pathomorphological changes in Mycoplasma-infected pigs were consistent with catarrhal bronchointerstitial pneumonia. FB1 aggravated the progression of infection, as demonstrated by severe illness requiring euthanasia observed in 1 pig and evidence of progressive pathology in 2 pigs (group MF) between study days 44 and 58.

Topics: Animals; Disease Models, Animal; Fumonisins; Lung; Mycoplasma hyopneumoniae; Mycotoxins; Pneumonia of Swine, Mycoplasmal; Pulmonary Edema; Random Allocation; Swine; Swine Diseases; Tomography, X-Ray Computed

Ceramide has been suggested to play a role in apoptosis during gastric ulcerogenesis. The present study is designed to investigate whether accumulated ceramide could serve as the effector molecules of ulcer formation in a rat model of acetic acid-induced gastric ulcer.. The effect of fumonisin B1, an inhibitor of ceramide synthase, and of d,l,-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP) and N-butyldeoxynojirimycin (NB-DNJ), both inhibitors of glucosylceramide synthase, on the accumulation of ceramide and formation of gastric ulcer were examined in the rat model of acetic acid-induced gastric ulcer.. Fumonisin B1 attenuated acetic acid-induced gastric ulcer formation, associated with a decrease in the number of apoptotic cells. Our results showed that it is neither the C18- nor the C24-ceramide itself, but the respective metabolites that were ulcerogenic, because PPMP and NB-DNJ attenuated gastric mucosal apoptosis and the consequent mucosal damage in spite of their reducing the degradation of ceramide.. The ceramide pathway, in particular, the metabolites of ceramide, significantly contributes to acetic acid-induced gastric damage, possibly via enhancing apoptosis. On the other hand, PPMP and NB-DNJ treatment attenuated gastric mucosal apoptosis and ulcer formation despite increasing the ceramide accumulation, suggesting that it was not the ceramides themselves, but their metabolites that contributed to the ulcer formation in the acetic acid-induced gastric ulcer model.

Topics: 1-Deoxynojirimycin; Acetic Acid; Animals; Apoptosis; Disease Models, Animal; Enzyme Inhibitors; Fumonisins; G(M3) Ganglioside; Gastric Mucosa; Glucosylceramides; Glucosyltransferases; Humans; Male; Morpholines; Rats; Rats, Sprague-Dawley; Sphingolipids; Stomach Ulcer

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

The present study tested the hypotheses that 1) short-term dietary deficiency (MgD) of magnesium (21 days) would result in the upregulation of ceramide synthase (CS) in left ventricular (LV), right ventricular, atrial, and aortic smooth muscle, as well as induce a synthesis/release of select cytokines and chemokines into the LV and aortic smooth muscle and serum; 2) exposure of primary cultured vascular smooth muscle cells (VSMCs) to low extracellular Mg concentration would lead to the synthesis/release of select cytokines/chemokines, activation of N-SMase, and the de novo synthesis of ceramide; and 3) inhibition of CS by fumonisin B1 (FB1) or inhibition of neutral sphingomyelinase (N-SMase) by scyphostatin (SCY) in VSMCs exposed to low Mg would result in reductions in the levels of the cytokines/chemokines and lowered levels of ceramide concomitant with inhibition of NF-κB activation. The data indicated that short-term MgD (10% normal dietary intake) resulted in the upregulation of CS in ventricular, atrial, and aortic smooth muscles coupled to the synthesis/release of 12 different cytokines/chemokines, as well as activation of NF-κB in the LV and aortic smooth muscle and sera; even very low levels of water-borne Mg (e.g., 15 mg·l(-1)·day(-1)) either prevented or ameliorated the upregulation and synthesis of the cytokines/chemokines. Our experiments also showed that VSMCs exposed to low extracellular Mg resulted in the synthesis of 5 different cytokines and chemokines concomitant with synthesis/release of ceramide. However, inhibition of the synthesis and release of ceramide by either FB1 or SCY attenuated, markedly , the generation of ceramide, release of the cytokines/chemokines, and activation of NF-κB (as measured by activated p65 and cRel).

Topics: Amides; Animals; Aorta; Cells, Cultured; Ceramides; Cytokines; Diet; Disease Models, Animal; Drinking; Eating; Enzyme Inhibitors; Female; Fumonisins; Heart Atria; Heart Ventricles; Magnesium; Magnesium Deficiency; Male; Muscle, Smooth, Vascular; Myocytes, Cardiac; NF-kappa B; Oxidoreductases; Proto-Oncogene Proteins c-rel; Pyrones; Rats; Regression Analysis; Signal Transduction; Sphingomyelin Phosphodiesterase; Time Factors; Transcription Factor RelA; Up-Regulation

The aim of this study was to determine the clinical, pathological and mycotoxicological effects of oral administration of fumonisin B1 (FB1) in rabbits. Eighteen rabbits were randomly assigned to two experimental groups: control group, 0 mg FB1; fumonisin group, 31.5 mg FB1/kg body weight, corresponding to about 630 mg FB1/kg diet. Fumonisin administered as a single oral dose to rabbits resulted in acute toxicity, significantly interfering with body and liver weight. Serum biochemical analysis revealed a significant increase of total protein, alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), urea and creatinine in the group receiving FB1 compared to control animals, a finding characterizing hepatic and renal injury in this group. Urinary protein concentrations were markedly elevated at 12, 24, 48 and 72 h after dosing, although visible pathological abnormalities were not observed, probably because of rapid repair of the damage. FB1 was detected in feces, with a maximum concentration at 24 h after administration, indicating that the enterohepatic circulation is important in rabbits. FB1 concentrations found in urine were low, with peak elimination at 12 h after intoxication. The highest FB1 concentrations were observed in feces compared to urine and liver, demonstrating that feces are the main routes of excretion.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Anorexia; Aspartate Aminotransferases; Body Weight; Creatinine; Disease Models, Animal; Feces; Fumonisins; gamma-Glutamyltransferase; Lethargy; Male; Organ Size; Rabbits; Tissue Distribution; Toxicity Tests, Acute; Urea

Ceramide is a sphingolipid with potent proinflammatory and proapoptotic properties. This study sought to determine whether pharmacological inhibition of ceramide biosynthesis in the intestine attenuates pathophysiological sequelae of shock induced by splanchnic artery occlusion and reperfusion. Ischemia and reperfusion injury was induced in anesthetized rats by clamping both the superior mesenteric artery and the celiac artery for 45 min followed by reperfusion. Within 6 min after reperfusion, animals developed significant systemic hypotension with 100% of the animals dying during the 4-h period of reperfusion. In parallel experiments, animals were necropsied after 60 min of reperfusion, and the ileum was harvested for histological examination and assessment of biochemical changes. Administration of fumonisin B1 (FB1), a competitive and reversible inhibitor of ceramide synthase (3 mg/kg, 15 min before reperfusion), significantly reduced i) the increased ceramide expression as detected by immunohistochemistry; ii) peroxynitrite-mediated protein nitration; iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils following a decrease in intercellular adhesion molecule-1 expression; iv) production of the proinflammatory cytokine tumor necrosis factor-alpha; and v) apoptosis in the ileum. Overall, tissue-protective effects were clearly observed upon histological examination of the ileum. These beneficial events were ultimately linked to decreases in both the development of hypotension and overall mortality. These results implicate ceramide as a key signaling molecule in splanchnic arterial ischemia and reperfusion-induced shock. The broader implications of our results provide a pharmacological rationale for the development of inhibitors of ceramide biosynthesis as novel therapeutics for ischemia and reperfusion-induced shock of several etiologies.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Ceramides; Disease Models, Animal; Enzyme Inhibitors; Fas Ligand Protein; Fumonisins; In Situ Nick-End Labeling; Male; Mesenteric Vascular Occlusion; Oxidative Stress; Oxidoreductases; Peroxynitrous Acid; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Although mechanisms involved in the pathogenesis of asthma remain unclear, roles for oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation have been documented. Ceramide is a sphingolipid with potent proinflammatory and proapoptotic properties. This study aimed at determining whether increased formation of ceramide contributes to the development of airway inflammation and hyper-responsiveness, using a well characterized in vivo model of allergic asthmatic response and airway inflammation in ovalbumin-sensitized guinea pigs. Aerosol administration of ovalbumin increased ceramide levels and ceramide synthase activity in the airway epithelium associated with respiratory abnormalities, such as cough, dyspnea, and severe bronchoconstriction. These abnormalities correlated with nitrotyrosine formation in the airway epithelium and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation evident by the infiltration of neutrophils and eosinophils in lung tissues, mast cell degranulation, and release of prostaglandin D(2) and proinflammatory cytokines. Inhibition of de novo ceramide synthesis with the competitive and reversible inhibitor of ceramide synthase fumonisin B1 (0.25, 0.5 and 1 mg/kg b.wt.), given i.p. daily for 4 days before allergen challenge, attenuated nitrotyrosine formation and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation while improving the respiratory and histopathological abnormalities. These results implicate ceramide in the development of allergic asthmatic response and airway inflammation. Strategies aimed at reducing the levels of ceramide and downstream events should yield promising novel anti-asthmatic agents.

Topics: Allergens; Animals; Asthma; Bronchoconstriction; Disease Models, Animal; Fumonisins; Guinea Pigs; Inflammation; Male; Sphingosine N-Acyltransferase

The co-existence of the fumonisin and aflatoxin mycotoxins in corn merited studies to investigate their possible synergistic toxicological and carcinogenic effects. When utilising a short-term carcinogenesis model in rat liver, both the compounds exhibited slow cancer initiating potency as monitored by the induction of foci and nodules stained positively for the placental form of gluthatione-S-transferase (GSTP(+)). However, when rats were treated in a sequential manner with AFB(1) and FB(1) the number and size of GSTP(+) lesions significantly increased as compared to the separate treatments. Histopathological analyses indicated that the individual treatments showed far less toxic effects, including occasional hepatocytes with dysplastic nuclei, oval cell proliferation and, in the case of FB(1), a few apoptotic bodies in the central vein regions. The sequential treatment regimen induced numerous foci and dysplastic hepatocyte nodules, and with oval cells extending from the periportal regions into the centrilobular regions. This would imply that, in addition to the cancer promoting activity of FB(1) of AFB(1)-initiated hepatocytes, the AFB(1) pre-treatment enhanced the FB(1) initiating potency, presumably by rendering the liver more susceptible to the toxic effects of FB(1). The co-occurrence of AFB(1) and FB(1) in corn consumed as a staple diet could pose an increased risk and should be included in establishing risk assessment parameters in humans.

Topics: Aflatoxin B1; Algorithms; Animals; Body Weight; Carboxylic Acids; Carcinogens, Environmental; Cocarcinogenesis; Disease Models, Animal; Fumonisins; Glutathione S-Transferase pi; Glutathione Transferase; Immunohistochemistry; Isoenzymes; Liver; Organ Size; Rats; Staining and Labeling; Time Factors

We have used a murine model of subchronic mycotoxicoses produced by ingestion of mycotoxins. The five groups of animals studied were fed for 30, 60 and 90 days, respectively, with commercial diet (CD), experimental control diet (ECD), experimental with fumonisin B1 diet (EFD) and experimental with mixtures of mycotoxins diet (EMD). The animals fed EFD and EMD showed a significant increase in feed consumption/day with respect to the animals fed ECD (P < 0.005 for both groups). The biochemical measurements showed significant differences at 90 days in those animals fed EAD exhibiting a marked decrease in the values of alkaline phosphatase (ALP) and cholesterol (P < 0.05), along with a significant increase in calcium (P < 0.01). Differences in the decrease of the parameters studied were observed in mice fed EFD for triglycerides, cholesterol and calcium (P < 0.05 for all of them). The activity of aspartate transaminase (AST) increased significantly in animals fed EMD (P < 0.01). The tissue specimens at 60 days showed lesions in the livers of the animals fed EAD and EFD. At 90 days, and in those fed EAD, EFD and EMD, the lesions were intensified in the liver at 60 days in 80, 90 and 100% of the animals, respectively.

Topics: Aflatoxin B1; Alkaline Phosphatase; Animal Feed; Animals; Aspartate Aminotransferases; Body Weight; Calcium; Carboxylic Acids; Cholesterol; Disease Models, Animal; Eating; Food Contamination; Fumonisins; Intestine, Small; Liver; Male; Mice; Mycotoxicosis; Triglycerides

Fumonisin mycotoxins are common contaminants of maize and cause several fatal animal diseases. Liver is a target organ of fumonisins in intact animals, but liver slices and primary hepatocytes, which do not proliferate in culture, are resistant to fumonisin exposure. Hepatoma cell lines, on the other hand, undergo cell division in culture and are sensitive to the toxic effects of fumonisins. It was therefore hypothesized that fumonisin cytotoxicity is dependent on cell proliferation. To test this hypothesis, the partially hepatectomized rat was used as a model to determine whether fumonisin produced greater toxicity in rapidly proliferating liver in vivo. Rats were dosed intraperitoneally with fumonisin B1 (FB1) 24 h after sham operation or partial hepatectomy (PH) and were killed 24 h later. The dose-related increase in free sphingoid bases (a biomarker of fumonisin exposure) was enhanced in the PH-treated rats. Serum cholesterol and enzymes were higher in PH-treated rats dosed with FB1 than in those given PH without FB1 or in sham-operated, FB1-dosed rats. Multiple daily doses of FB1 after surgery elevated the number of apoptotic hepatocytes in both sham-operated and PH-treated rats to about the same degree, suggesting that apoptosis is not associated with the enhanced cytotoxicity of FB1 in regenerating liver. Proliferating cells appear to be more sensitive to the toxic effects of fumonisins. This enhanced cytotoxicity may be related to the increased ability of fumonisins to disrupt sphingolipid metabolism in hepatectomized rats, but this is yet to be determined.

Topics: Animals; Cell Division; Disease Models, Animal; Dose-Response Relationship, Drug; Fumonisins; Hepatocytes; Injections, Intraperitoneal; Liver; Male; Mycotoxins; Rats; Rats, Sprague-Dawley; Sphingosine; Time Factors