fumonisin-b1 and Body-Weight

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

Aflatoxins (AF) and fumonisins (FU) are a major problem faced by poultry farmers, leading to huge economic losses. This experiment was conducted to determine the effects of AF (1 mg/kg of feed) and FU (25 mg/kg of feed), singly or in combination, on the lipid metabolism in commercial layers and investigate the efficacy of a commercial binder (2 kg/t of feed) on reducing the toxic effects of these mycotoxins. A total of 168 Hisex Brown layer hens, 37 wk of age, were randomized into a 3 × 2 + 1 factorial arrangement (3 diets with no binder containing AF, FU, and AF+FU; 3 diets with binder containing AF, FU, and AF+FU; and a control diet with no mycotoxins and binders), totaling 7 treatments. The hens contaminated with AF showed the characteristic effects of aflatoxicosis, such as a yellow liver, resulting from the accumulation of liver fat, lower values of plasma very low-density lipoprotein and triglycerides, and higher relative weight of the kidneys and liver. Hepatotoxic and nephrotoxic effects of FU were not observed in this study. On the other hand, the FU caused a reduction in small intestine length and an increase in abdominal fat deposition. The glucan-based binder prevented some of the deleterious effects of these mycotoxins, particularly the effects of AF on hepatic lipid metabolism, kidney relative weight, and FU in the small intestine.

Topics: Aflatoxin B1; Aflatoxins; Animal Feed; Animals; Body Weight; Chickens; Diet; Eating; Female; Food Contamination; Fumonisins; Glucans; Lipid Metabolism; Oviposition

1. Our objective was to evaluate the toxic effects of aflatoxin B1 (AFB1) and fumonisin B1 (FB1), administered singly or in combination to broilers. 2. Feeds were prepared with concentrations equal to 0, 50 and 200 microg AFB1/kg, and/or 0, 50 and 200 mg FB1/kg, and offered to broiler chicks from 8 to 41 d of age. The experimental design was totally randomised, in a 3 x 3 factorial arrangement with 9 treatments and 12 birds per treatment. Animals were vaccinated against Newcastle disease on d 14 of life and killed at 41 d. 3. Compared with controls, all mycotoxin-treated groups at 41 d had lower body weight and weight gain, and higher relative heart weight. The relative weight of the liver increased only in birds fed diets containing 200 mg FB1, singly or in combination with AFB1. 4. At 35 d, all groups receiving mycotoxin-treated rations had reduced geometrical mean antibody titres, with birds from groups fed combinations of AFB1 and FB1/kg having even lower values, when compared to the other groups. 5. Histological changes were observed only in liver from birds fed mycotoxin-contaminated rations, and in kidneys of birds fed the diet containing 200 microg AFB1 and 200 mg FB1/kg. Main alterations included vacuolar degeneration and cell proliferation of bile ducts in the liver, and hydropic degeneration in renal tubules in the kidneys. 6. We concluded that AFB1 and FB1 in combination have primarily additive effects on body weight, liver structure and immunological response of broilers at the concentrations used.

Topics: Aflatoxin B1; Animal Feed; Animals; Antibodies, Viral; Body Weight; Chickens; Fumonisins; Kidney; Liver; Male; Mycotoxicosis; Newcastle Disease; Poultry Diseases; Random Allocation; Viral Vaccines

Fumonisin B1 (FB1) is a secondary metabolite produced mainly by. In the present study, the. Based on the above evidence, the Nb5 nanobody may be considered as an additional FB1 detoxifier, contributing to FB1 decontamination.

Topics: Animals; Body Weight; Chickens; Cost-Benefit Analysis; Escherichia coli; Fumonisins; Fusarium; Humans; Milk; Single-Domain Antibodies

Fumonisin B1 (FB1) is one of the most common mycotoxins contaminating feed and food. Although regulatory limits about fumonisins have been established in some countries, it is still very important to conduct research on lower doses of FB1 to determine the tolerance limits. The aim of this study was to investigate the effects of different concentrations of FB1, provide further evidence about the toxic doses- and exposure time-associated influence of FB1 on mice, especially low levels of FB1 for long-term exposure.. Female BALB/c mice were treated intragastrically (i.g.) with fumonisin B1 (FB1) solutions (0 mg/kg body weight (BW), 0.018 mg/kg BW, 0.054 mg/kg BW, 0.162 mg/kg BW, 0.486 mg/kg BW, 1.458 mg/kg BW and 4.374 mg/kg BW) once a day for 8 weeks to obtain dose- and time-dependent effects on body and organ weights, hematology, blood chemical parameters and liver and kidney histopathology.. After the long-term administration of FB1, the body weights of the mice tended to decrease. Over time, FB1 first increased the relative spleen weight, then increased the relative kidney weight, and finally increased the relative liver weight. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hemoglobin (HGB), white blood cells (WBC), platelets (PLT), and mean platelet volume (MPV) were significantly elevated after treatment with FB1 for 8 weeks. Moreover, exposure time-dependent responses were found for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) level, which were coupled with hepatic histopathological findings, necroinflammation and vacuolar degeneration and detrital necrosis. Linear dose response was also found for liver histopathology, in which, even the minimum dose of FB1 exposure also caused changes. Renal alterations were moderate compared to hepatic alterations.. In conclusion, we demonstrated the systemic toxic effects of different doses of FB1 in female BALB/c mice at different times. Our data indicated that the effects observed in this study at the lowest dose tested are discussed in relation to the currently established provisional maximum tolerable daily intake (PMTDI) for fumonisins. This study suggested that recommendations for the concentration of FB1 in animals and humans are not sufficiently protective and that regulatory doses should be modified to better protect animal and human health. The toxicity of FB1 needs more attention.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Female; Fumonisins; Kidney; Liver; Mice; Mice, Inbred BALB C; Mycotoxins; Organ Size

Adult male Wistar rats were enrolled in a study to test the acute hepatic effects of 50 mg/kg fumonisin B

Topics: Administration, Oral; Animals; Antioxidants; Body Weight; Chemical and Drug Induced Liver Injury; Fatty Acids; Fumonisins; Lipid Peroxidation; Liver; Male; Organ Size; Phospholipids; Rats

Weaned rabbits were fed diets contaminated with 2 mg/kg diet T-2 toxin alone, or 10 mg/kg diet fumonisin B1 (FB1) alone, and both toxins in combination (2+10 mg/kg, resp.), as compared to a toxin free control. Samplings were performed after 2 and 4 weeks. Bodyweight of the T-2 fed group was lower after 4 weeks; the liver weight increased dramatically. Red blood cell (RBC) Na(+)/K(+) ATPase activity decreased after 4 weeks in the T-2 group, it increased in the FB1 group and antagonism was found by the combined treatment. The RBC membrane fatty acid profile was modified by both toxins similarly during the entire feeding. After 4 weeks T-2 alone and in combination (with FB1) was found to increase mean cell volume (MCV). The time-dependent alterations in the T-2 group were significant for MCV (increase) and the mean cell haemoglobin (increase). The active monovalent cation transport was altered by both mycotoxins. Most probably FB1 exerts its sodium pump activity modification via an altered ceramide metabolism (behenic acid decrease in the RBC membrane), while for T-2 toxin a moderate membrane disruption and enzyme (protein) synthesis inhibition was supposed (ca. 75% decrease of the sodium pump activity).

Topics: Animal Feed; Animals; Body Weight; Cell Membrane; Erythrocytes; Fatty Acids; Fumonisins; Fusarium; Liver; Male; Organ Size; Rabbits; Sodium-Potassium-Exchanging ATPase; T-2 Toxin

The carry-over of fumonisin B1 from contaminated feed into dairy milk also suggests its carry-over from contaminated food into breast milk. This study assessed fumonisin B1 contamination in breast milk and associated exposures of infants under 6 months of age. Breast milk samples were collected from 131 lactating mothers and the weight of their infants was measured during the first month of lactation. Fumonisin B1 was extracted using methanol:acetone, cleaned up with Strong Anion Exchange columns and quantified by HPLC. Fumonisin B1 exposure in each child was estimated using deterministic approach. Out of the 131 samples, 58 (44.3%) contained fumonisin B1 at levels ranging from 6.57 to 471.05 ng/ml. Of the contaminated samples, 10.3% had fumonisin B1 levels above the EU limit of 200 ppb for fumonisins in infants' food. Exposure in the infants ranged from 0.78 to 64.93 µg/kg body weight (bw) per day (median, 3 µg/kg bw/day) and exceeded the provisional maximum tolerable limit of 2 µg/kg bw/day in 29% of the infants. In conclusion, breast milk from mothers in Northern Tanzania is contaminated with fumonisins at levels that lead to unacceptable exposures in infants. Strategies to prevent lactating mothers from fumonisin exposure are urgently needed to minimise fumonisin exposure in infants.

Topics: Body Weight; Breast Feeding; Child, Preschool; Chromatography, High Pressure Liquid; Environmental Exposure; Fumonisins; Humans; Infant; Milk, Human; Tanzania

Fumonisin B1 (FB1) is a mycotoxin found in maize and maize-based foods. It causes animal diseases and is a suspected risk factor for cancer and birth defects in humans. Extrusion cooking reduces FB1 concentrations in maize however toxicity caused by unknown degradation or FB1-matrix reaction products might persist.. To test the efficacy of extrusion to reduce FB1 toxicity, Fusarium verticillioides fermented corn (= maize) grits (Batch-1= 9.7 ppm FB1; Batch-2= 50 ppm FB1) were extruded without (Batch-1E; Batch-2E) or with 10% glucose supplementation (Batch-1EG; Batch-2EG). FB1 concentrations were reduced 64% (Batch-2E) to 94% (Batch-1EG) after cooking. When the uncooked and processed grits were fed (50% w/w in rodent chow) to rats for up to 8 weeks, FB1 intakes averaged 354, 103, and 25.1 çg/kg body weight/day for Batch-1, Batch-1E and Batch-1EG and 1804, 698, and 222 çg/kg body weight/day for the Batch-2, Batch-2E and Batch-2EG, respectively. Nephrotoxicity including apoptotic lesions and elevated sphingoid base concentrations decreased in a dose-dependent manner in groups fed Batch-1, Batch-1E, Batch-2, Batch-2E, or Batch-2EG and was absent in the Batch-1EG group.. Extrusion cooking, especially with glucose supplementation, is potentially useful to reduce FB1 concentrations and toxicity of FB1-contaminated maize.

Topics: Animals; Apoptosis; Body Weight; Cooking; Dietary Supplements; Dose-Response Relationship, Drug; Fermentation; Food Contamination; Fumonisins; Fusarium; Glucose; Kidney; Male; Mycotoxins; Organ Size; Rats; Rats, Sprague-Dawley; Sphingolipids; Zea mays

In this study, we investigate the long-term exposure (20 weeks) to fumonisin B(1) (FB(1)) in grower-finisher pigs by conducting a quantitative exposure assessment (QEA). Our analytical approach involved both deterministic and semi-stochastic modeling for dietary comparative analyses of FB(1) exposures originating from genetically engineered Bacillus thuringiensis (Bt)-corn, conventional non-Bt corn and distiller's dried grains with solubles (DDGS) derived from Bt and/or non-Bt corn. Results from both deterministic and semi-stochastic demonstrated a distinct difference of FB(1) toxicity in feed between Bt corn and non-Bt corn. Semi-stochastic results predicted the lowest FB(1) exposure for Bt grain with a mean of 1.5 mg FB(1)/kg diet and the highest FB(1) exposure for a diet consisting of non-Bt grain and non-Bt DDGS with a mean of 7.87 mg FB(1)/kg diet; the chronic toxicological incipient level of concern is 1.0 mg of FB(1)/kg of diet. Deterministic results closely mirrored but tended to slightly under predict the mean result for the semi-stochastic analysis. This novel comparative QEA model reveals that diet scenarios where the source of grain is derived from Bt corn presents less potential to induce FB(1) toxicity than diets containing non-Bt corn.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Bacillus thuringiensis; Bacterial Proteins; Body Composition; Body Weight; Diet; Environmental Exposure; Fumonisins; Models, Biological; Plants, Genetically Modified; Stochastic Processes; Sus scrofa; Zea mays

The influences of dietary fumonisin B(1) (FB(1)), a metabolite of Fusarium verticillioides, on the onset of puberty, semen quality, fertility rates and testicular morphology in male rabbits (bucks) were studied. Forty male rabbits were randomly assigned and fed four diets containing 0.13, 5.0, 7.5 and 10.0 mg FB(1)/kg, constituting diets 1 (control), 2, 3 and 4 respectively, for a period of 175 days in a completely randomized design. During the last week of the feeding trial, two untreated female rabbits were mated to each of the four treated bucks per treatment to assess the fertility rate of the treated bucks. Onset of puberty in animals fed diets 3 and 4 was significantly (P<0.05) delayed by some 9-12 days. The weight at puberty, sperm concentration and total sperm/ejaculate were not significantly influenced by the dietary FB(1). Sperm mass activities, motility and live spermatozoa of the rabbits' semen significantly (P<0.05) declined with an increase in the dietary FB(1). The highest sperm cell abnormalities were recorded in the animals fed 10.0 mg/kg FB(1), while the least was observed in the control animals. The conception rate, litter size and embryo survival rate were statistically the same among the dietary treatments. Embryo mortality was significantly (P<0.05) higher in rabbits fed diets 3 and 4 than in others. Testicular elements were significantly (P<0.05) impaired by the toxin in rabbits fed 7.5 and 10.0 mg FB(1)/kg. This suggests that LOAEL of 7.50 mg/kg FB(1) delayed puberty, impaired semen quality and spermatogenesis and induced embryo mortality without a statistically adverse effect on the fertility rates of male rabbits.

Topics: Animal Feed; Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Embryo Loss; Female; Fertility; Food Contamination; Fumonisins; Fusarium; Litter Size; Male; Pregnancy; Rabbits; Semen; Sexual Maturation; Sperm Count; Sperm Motility; Spermatozoa; Testis

The chemoprotective properties of unfermented and fermented rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal teas, and green and black teas (Camellia sinensis) were investigated against fumonisin B1 (FB1) promotion in rat liver utilizing diethylnitrosamine (DEN) as cancer initiator. The various teas differently affected the clinical chemical parameters associated with liver and kidney damage associated with FB1 suggesting specific FB1/iron/polyphenolic interactions. Green tea enhanced (P<0.05) the FB1-induced reduction of the oxygen radical absorbance capacity, while fermented herbal teas and unfermented honeybush significantly (P<0.05) decreased FB1-induced lipid peroxidation in the liver. The teas exhibited varying effects on FB1-induced changes in the activities of catalase, glutathione peroxidase (GPx) glutathione reductase (GR) as well as the glutathione (GSH) status. Unfermented rooibos and honeybush significantly (P<0.05) to marginally (P<0.1) reduced the total number of foci (>10microm), respectively, while all the teas reduced the relative amount of the larger foci. Fermentation seems to reduce the protective effect of the herbal teas. Differences in the major polyphenolic components and certain FB1/polyphenolic/tissue interactions may explain the varying effects of the different teas on the oxidative parameters, hepatotoxic effects and cancer promotion in rat liver.

Topics: Animals; Aspalathus; Beverages; Body Weight; Camellia sinensis; Cyclopia Plant; Fermentation; Flavones; Fumonisins; Glutathione; Lipid Peroxidation; Liver; Liver Neoplasms; Male; Oxidative Stress; Rats; Rats, Inbred F344

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

The nature of cancer initiation by fumonisin B(1) (FB(1)) was investigated in rat liver by monitoring the effect of phenobarbital (PB) as cancer promoter and evaluating the involvement of spontaneously initiated cells. A PB promoting regimen (0.05% in the diet) stimulated the outgrowth of FB(1)-induced placental glutathione S-transferase (GSTP) positive initiated hepatocytes. Reversion of the FB(1)-induced GSTP(+) foci was noticed in the absence of a promoting regimen. Younger rats were shown to be more sensitive to the induction of GSTP(+) foci by FB(1). Cancer initiation by FB(1) was associated with a hepatotoxic effect, which was less pronounced in older rats presumably due to a reduced intake. A specific role of spontaneously initiated cells and their promotion by FB(1) into the development of eosinophilic clear cell foci could not be established under the present experimental conditions. The ability of different stimuli to selectively promote the outgrowth of FB(1) initiated cells further verifies the cancer initiating potency of this apparent non-genotoxic mycotoxin. The underlying mechanism(s) involved in the genesis of the initiated hepatocytes is not known at present.

Topics: Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Diet; Enzyme Induction; Fumonisins; Glutathione S-Transferase pi; Glutathione Transferase; Hepatocytes; Liver Neoplasms, Experimental; Male; Phenobarbital; Rats; Rats, Inbred F344; Weight Gain

Twenty-four male Large White weaning pigs of 8-9 weeks of age averaging 6.94+/-0.26 kg were used to evaluate the effect of dietary fumonisin B(1) (FB(1)) on sperm reserves and production of pubertal boars. The animals were randomly assigned to 4 diets containing 0.2, 5.0, 10.0 and 15.0 mg FB(1)/kg constituting the control, diets 1, 2 and 3, respectively, in a 6-month feeding trial. Dietary FB(1) above 5mg/kg significantly (P<0.05) reduced testicular and epididymal sperm reserves as well as the daily sperm production (DSP) per boar. The total caudal sperm reserves of the animals on diets 2 and 3 were about 70% of those on the control diet. The DSP of the animals on the control diet and diet 1 were significantly (P<0.05) higher than those on diets 2 and 3. The study revealed that male weaning pigs for breeding should not be exposed to dietary FB(1) higher than 5mg/kg for no suppression in sperm production and reproductive performance.

Topics: Animal Feed; Animals; Body Weight; Epididymis; Fumonisins; Male; Organ Size; Random Allocation; Spermatogenesis; Swine; Testis

The effects of prolonged oral administration (21 days) of fumonisin B(1) (FB(1)) and aflatoxin B(1) (AFB(1)) were studied in male New Zealand rabbits by clinical, pathological, biochemical and sphingolipid analyses. Twenty-four animals were randomly divided into the following four experimental groups: (A) 0 mg FB(1)+0 microg AFB(1)/(kg body weight(bw)day) (control); (B) 0 mg FB(1)+30 microg AFB(1)/(kg bw day); (C) 1.5 mg FB(1)/(kg bw day)+30 microg AFB(1)/(kg bw day); (D) 1.5 mg FB(1)/(kg bw day)+0 microg AFB(1). Animals from group B and principally from group C presented clinical signs of intoxication. Rabbits from group C presented a lower body weight gain than controls. Differences were observed between intoxicated rabbits and controls with respect to absolute and relative liver and kidney weight, hepatic function, serum urea and creatinine levels and Sa/So ratio. The most frequent hepatic and renal injuries were vacuolar degeneration of the liver and kidney as shown by the histopathological and serum biochemical results. Combined administration of AFB(1) and FB(1) resulted in synergistic toxic effects both in the liver and in the kidney, but hepatic injuries were more marked.

Topics: Administration, Oral; Aflatoxin B1; Animals; Body Weight; Fumonisins; Male; Organ Size; Rabbits; Sphingolipids; Sphingosine

Partially purified fumonisin B1 (FB1) was orally administrated for 77 d to 5 groups of 8 mule ducks starting at 7 d of age; the concentrations corresponded to 5 diets containing 0, 2, 8, 32, and 128 mg of FB1/kg of feed. No mortality was observed, and no effects on feed consumption and body weight gain were observed at the end of the treatment period. But, surprisingly, FB1 ingested at 32 and 128 mg/kg led to decreased body weight from d 28 to 63 and from d 7 to 63, respectively. FB1 had no effect on the relative weight of heart and breast muscle, whereas a significant increases in the relative weights of gizzard, spleen, and liver were measured in ducks receiving 32 and 128 mg of FB1/kg of feed without evidence of detectable microscopic modification of these organs. FB1 had no significant effect of the serum aspartate aminotransferase and gamma-glutamyltransferase levels but increased serum total protein, cholesterol, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase levels when 128 mg of FB1/kg of feed was given. Serum, liver, and kidney sphinganine to sphingosine ratio was significantly increased in ducks fed 8 to 128 mg of FB1/kg of feed. The biggest increase was observed in kidneys, suggesting that this organ is the most sensitive to detect FB1-induced disruption of sphingolipid metabolism.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Blood Proteins; Body Weight; Cholesterol; Diet; Ducks; Fumonisins; Kidney; L-Lactate Dehydrogenase; Organ Size; Sphingosine

Fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia and hepatotoxicity. We studied the modulation of FB(1) toxicity in brain and liver of female BALB/c mice after endotoxin administration to compromise the blood-brain barrier (BBB) integrity. Mice were injected intraperitoneally with saline or 3 mg/kg of lipopolysaccharide (LPS) followed 2 h later by either a single or three daily subcutaneous doses of 2.25 mg/kg of FB(1). After 4h of a single FB(1) injection the inhibition of sphingolipid biosynthesis occurred in liver. Circulating alanine aminotransferase increased by LPS alone at this time. In brain LPS triggered inflammation increasing the expression of tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, interleukin (IL)-1beta, IL-6, and IL-12; no effect of FB(1) was observed. In liver LPS+FB(1) attenuated the expression TNFalpha and IFNgamma compared to LPS alone. One day after the 3-day FB(1) treatment the biosynthesis of sphingolipids was markedly reduced in brain and liver and it was further inhibited when LPS was given before FB(1). FB(1) induced hepatotoxicity, as measured by circulating liver enzymes, was reduced after the combined treatment with LPS+FB(1) compared to FB(1) alone. FB(1) decreased the LPS-induced brain expression of IFNgamma and IL-1beta, whereas the expression of IL-6 and IL-12 was augmented. In liver FB(1) also reduced the expression of IL-1beta and IFNgamma compared to LPS alone. Results indicated that endotoxemia concurrent with FB(1) intoxication facilitated the permeability of fumonisin in brain indicated by increased accumulation of sphinganine and endotoxin modified the effects of FB(1) in both brain and liver.

Topics: Animals; Blood-Brain Barrier; Body Weight; Brain; Cell Proliferation; Cytokines; DNA Primers; Dose-Response Relationship, Drug; Endotoxins; Female; Fumonisins; Gene Expression; Lipopolysaccharides; Liver; Mice; Mice, Inbred BALB C; Organ Size; RNA; Sphingolipids

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides and F. proliferatum that commonly occurs in maize. In swine, consumption of contaminated feed induces liver damage and pulmonary edema. Pasteurella multocida is a secondary pathogen, which can generate a respiratory disorder in predisposed pigs. In this study, we examined the effect of oral exposure to fumonisin-containing culture material on lung inflammation caused by P. multocida. Piglets received by gavage a crude extract of fumonisin, 0.5mg FB(1)/kg body weight/day, for 7 days. One day later, the animals were instilled intratracheally with a non toxin producing type A strain of P. multocida and followed up for 13 additional days. Pig weight and cough frequency were measured throughout the experiment. Lung lesions, bronchoalveolar lavage fluid (BALF) cell composition and the expression of inflammatory cytokines were evaluated at the autopsy. Ingestion of fumonisin culture material or infection with P. multocida did not affect weight gain, induced no clinical sign or lung lesion, and only had minimal effect on BALF cell composition. Ingestion of mycotoxin extract increased the expression of IL-8, IL-18 and IFN-gamma mRNA compared with P. multocida infection that increased the expression of TNF-alpha. The combined treatment with fumonisin culture material and P. multocida delayed growth, induced cough, and increased BALF total cells, macrophages and lymphocytes. Lung lesions were significantly enhanced in these animals and consisted of subacute interstitial pneumonia. TNF-alpha, IFN-gamma and IL-18 mRNA expression was also increased. Taken together, our data showed that fumonisin culture material is a predisposing factor to lung inflammation. These results may have implications for humans and animals consuming FB(1) contaminated food or feed.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cough; Cytokines; Fumonisins; Lung Diseases; Pasteurella Infections; Pasteurella multocida; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Swine; Swine Diseases

1. A 28-d experiment was conducted to evaluate the effects of fumonisin B1 (FB1) on egg production and egg quality of young laying Japanese quail fed on fumonisin-contaminated rations. 2. To this end, 128 7-week-old birds were randomly distributed into 4 experimental groups (32 birds per group) and given rations containing 0 (control), 10, 50 and 250mg FB1/kg feed. Each treatment consisted of 4 replicates of 8 quail. Egg production and egg weight were checked daily. Feed consumption and feed conversion were determined weekly. Eggs laid on the last day of each 7-d period were collected and subjected to individual analysis for specific gravity, Haugh units and percentage eggshell. 3. Compared with controls, quail given > or = 50 mg FB1/kg had reduced feed intake and lower body weight gain. Feed conversion was reduced only in birds given 250 mg FB1/kg. 4. Mean egg production and egg weight were lower in birds given 250mg FB1/kg. Eggshell weight was reduced in birds given > or =50mg FB1/kg. However, mean specific gravity, Haugh units and percentage eggshell were not affected by FB1. 5. No histopathological changes were observed in liver, kidney or heart samples from any treatment group. 6. The results indicated that exposure to FB1 at concentrations > or = 50 mg/kg could adversely affect quail performance, emphasising the importance of controlling fumonisin contamination of quail rations.

Topics: Animal Feed; Animals; Body Weight; Coturnix; Dose-Response Relationship, Drug; Eating; Eggs; Female; Food Contamination; Fumonisins; Oviposition; Ovum; Poultry Diseases

Maize co-contamination with aflatoxin B1 (AFB1) and fumonisin B1 (FB1) is frequently found in several countries. Although the alterations on nutritional and immunologic parameters induced by these mycotoxins, when administered individually, are partially characterised, little is known about the effects induced in animals by a subchronic administration of both toxins mixtures. We have studied the nutritional and immunological alterations induced in rats fed during 90 days with a diet without mycotoxins, containing 40 ppb AFB1, and with a diet containing a mixture of 40 ppb AFB1 and 100 ppm FB1. Animals fed with the mixture of toxins obtained lower body weight than the control ones. The mitogenic response of spleen mononuclear cells (SMC) in vivo was higher in animals fed with AFB1. In in vitro studies, lower proliferations of SMC pre-exposed to AFB1 and to the mixture of toxins were detected. The SMC of animals fed with AFB1 produced lower levels of IL-2, higher of IL-4 and equal levels of IL-10. The SMC of animals fed with both toxins produced higher levels of IL-4, lower of IL-10 and equal levels of IL-2. The SMC preincubated with an AFB1-FB1 mixture produced higher concentrations of IL-4, lower of IL-10 and equal levels of IL-2. The peritoneal macrophages of animals that consumed AFB1 released less H(2)O(2), while animals fed with the mixture of toxins produced higher levels. In in vitro studies, macrophages pre-exposed to the mixture of toxins released less H(2)O(2). These results show different immunobiological effects produced by a mixture of mycotoxins in comparison to the individual action of the same toxins.

Topics: Aflatoxin B1; Alkaline Phosphatase; Animals; Body Weight; Eating; Fumonisins; Hydrogen Peroxide; Interleukins; Male; Mycotoxicosis; Rats; Rats, Wistar; Spleen

Fumonisin B1 (FB1) is one of several mycotoxins produced by Fusarium moniliforme, a major fungal pathogen of corn and widely spread throughout the world. FB1 produces a wide range of biological effects, some of which are specific for particular organs or species and some are common to all investigated animals. In this study we have evaluated subchronic toxicosis features in young carp (Cyprinus carpio L.) exposed to 0.5 and 5.0 mg FB1 kg(-1) body weight for 42 days through nutritionally balanced diet. During the trial we observed loss of body weight in both treated groups, together with higher incidence of infective bacterial dermatological lesions erythrodermatitis cyprini (Aeromonas salmonicida subsp. nova) in the group treated with the higher FB1 dose. Several hematological parameters (erythrocyte count, platelet count) and serum chemical concentrations (creatinin, total bilirubin) and activities (aspartate aminotransferase, AST and alanine aminotransferase, ALT) were greater in the fumonisin treated groups than in the control group. Our results indicate that long-term dietary exposure to 0.5 and 5.0 mg FB1 kg(-1) body weight is not lethal to young carp, but can produce adverse physiological effects. These findings also suggest that primary target organs of FB1 in the carp are kidney and liver, as it has already been observed in other animal species tested. Specifically changed red blood cell- parameters reveal that FB1 probably causes erythrocyte membrane defect or interferes with carp's respiratory process.

Topics: Alanine Transaminase; Animal Feed; Animals; Aspartate Aminotransferases; Body Weight; Carcinogens, Environmental; Carps; Creatinine; Erythrocyte Count; Fish Diseases; Fumonisins; Hematocrit; Hemoglobins; Leukocyte Count; Platelet Count; Random Allocation; Statistics, Nonparametric; Toxicity Tests

The effects of chronic oral exposure (28 days) to aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)) were studied in weaned piglets. Six experimental groups, each comprising two neutered males and two females, were fed ad libitum with rations containing: (A) 0 mg of FB(1) and 0 mg of AFB(1)/kg of feed (control); (B) 10 mg of FB(1)/kg of feed; (C) 30 mg of FB(1)/kg of feed; (D) 50 microg of AFB(1)/kg of feed; (E) 10 mg of FB(1) plus 50 microg of AFB(1)/kg of feed; (F) 30 mg of FB(1) plus 50 microg of AFB(1)/kg of feed. The animals were inspected twice daily and their body weight and feed consumption were recorded weekly and daily, respectively. Samples of feces and urine were collected 24 h after the start of the experiment, to check for fumonisin residues by HPLC analysis. Blood samples were drawn at the start of the experiment and after 28 days for quantification of hematological and biochemical parameters. Necropsies were performed after 28 days; at necropsy, the organs were weighed, inspected macroscopically and processed for histopathological and toxicological analyses. All piglets from groups C and F presented typical signs of pulmonary edema, with reduced feed consumption and body weight gain as well as pathological alterations. FB(1) was detected in feces and urine at 24 h of intoxication and in liver after 28 days of intoxication. Increases were detected regarding the following hematological and biochemical parameters in animals from treatments C and F: erythrocyte number; hematocrit; total bilirubin; total protein; activity of serum alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Cholesterol levels were significantly aumented only in animals from groups C and F, whereas albumin concentrations increased in groups C, F, B and E. The average organ/body weight ratio of piglets (hearth, liver and lung) were significantly greater in groups C and F. The only joint effects of FB(1) and AFB(1) detected (group F) were a decrease in feed consumption during the last week of intoxication and in feed conversion throughout the 28 days of intoxication. Chronic intoxication of piglets with AFB(1) and FB(1) leads to important losses of productivity.

Topics: Aflatoxin B1; Animals; Body Weight; Carcinogens, Environmental; Diet; Dose-Response Relationship, Drug; Eating; Feces; Female; Fumonisins; Fusarium; Liver; Male; Swine

Fumonisinmycotoxins are produced by Fusaria fungi that grow worldwide primarily on corn. Fumonisin B(1), the most predominant form in corn samples, is a renal carcinogen in male F344/N rats and a hepatocarcinogen in female B6C3F(1) mice when fed at concentrations higher than 50 ppm (70 micromol/kg) in the diet for 2 years. We sought to determine the relative toxicities of several naturally occurring fumonisin derivatives when included in the diet of female B6C3F(1) mice. Mice were fed diets containing fumonisin B(1), fumonisin B(2), fumonisin B(3), fumonisin P1, hydrolyzed-fumonisin B(1), N-(acetyl)fumonisin B(1), or N-(carboxymethyl)fumonisin B(1) (approximately 0, 14, 70, and 140 micromol/kg diet) for 28 days. None of the doses used caused a decrease in body weight gain over the 28 days. Serum levels of total bile acids, cholesterol, and alkaline phosphatase were increased only in mice receiving 72 and 143 micromol/kg fumonisin B(1), suggesting that only fumonisin B(1) was hepatotoxic in the mice. Corroborating this observation, the liver weight, relative to body weight, was decreased only in the mice that consumed 143 micromol/kg fumonisin B(1). Consistent with fumonisin B(1) inhibition of ceramide synthase, the liver sphinganine-to-sphingosine ratio was increased and the liver ceramide levels were decreased only in the mice receiving 72 and 143 micromol/kg fumonisin B(1). Increased hepatocellular apoptosis, hepatocellular hypertrophy, Kupffer cell hyperplasia, and macrophage pigmentation were detected in the mice consuming 72 and 143 micromol/kg fumonisin B(1). The other fumonisin derivatives did not alter serum analytes, organ weights, or hepatic structure. These results suggest that, of the naturally occurring fumonisins, fumonisin B(1) is the principal hepatotoxic derivative in the B6C3F(1) mouse.

Topics: Alkaline Phosphatase; Animals; Bile Acids and Salts; Blood Chemical Analysis; Body Weight; Carcinogens, Environmental; Ceramides; Cholesterol; Chromatography, High Pressure Liquid; Diet; Female; Fumonisins; Mice; Mice, Inbred Strains; Organ Size; Proteinuria; Sphingosine

Fumonisin B1 (FB1), the principal secondary metabolite produced by the fungus Fusarium verticillioides (Gibberella fujikuroi mating population A), is a potent toxin that can be found in fungus-contaminated corn and corn-based food products. We have investigated the immunobiological effects of subchronic dietary exposure to FB1 in male Wistar rats. Animals were fed with diets containing 0 (control) or 100 ppm of FB1 for 12 weeks. The total FB1 intake on day 90 was 810 mg/kg of body weight. Food consumption, body weight, and body weight gain on day 90 were reduced in animals exposed to FB1. Histopathologic changes consisted of histiocytic perivascular infiltrate and an increased number of Kupffer cells in the liver, necrosis and apoptosis of tubular epithelial cells in the kidney, and increased mitotic figures and lymphocytic infiltrate in the small intestine. Serum enzyme alkaline phosphatase was significantly elevated in rats fed FB1, while triglyceride levels decreased compared to controls. Treatment with FB1 in vivo or in vitro did not have a significant effect on mitogen-induced proliferation of spleen mononuclear cells. However, increased levels of interleukin-4 (IL-4) and decreased levels of IL-10 were released by these cells in culture compared to controls. FB1 in vivo or in vitro decreased the hydrogen peroxide (H(2)O(2)) released by peritoneal macrophages, while no changes in levels of superoxide anion produced by total peritoneal cells were detected. The results from the present work demonstrate that subchronic FB1 intake could affect the small intestine and alter the interleukin profile and some main functions of macrophages in antitumor activity.

Topics: Animals; Body Weight; Carboxylic Acids; Cytokines; Eating; Fumonisins; Hydrogen Peroxide; Immunity; Kidney; Liver; Lymphocyte Activation; Male; Mycotoxins; Rats; Rats, Wistar; Superoxides

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

Floor pen studies were conducted with 270 broiler chicks and 144 turkey poults, all 1 wk old, to evaluate the chronic effects of fumonisin B1 (FB1). A completely randomized design was used in both studies with six pen replicates of 15 chicks or eight pen replicates of six poults assigned to each of three dietary treatments from Weeks 1 to 7 (broilers) or to Week 14 (turkeys). Fusarium moniliforme (M-1325) culture material was added to a typical corn-soybean basal diet to supply 0, 25, or 50 mg FB1/kg diet. Feed intake, body weight gain, and feed conversion of chicks were not affected (P > 0.05) by FB1. Turkeys fed 50 mg FB1/kg had significantly (P < 0.05) lower feed intake than the controls. Compared with controls, chicks and turkeys fed FB1 diets had significantly higher liver sphinganine to sphingosine ratios (P < 0.05). Relative organ weights of chicks were not affected (P > 0.05) by FB1, other than those chicks fed 25 mg FB1/kg, which had lower (P < 0.05) relative proventriculus weights than the chicks fed 0 or 50 mg FB1/kg. Broilers fed 50 mg FB1/kg had decreased serum calcium and increased serum chloride when compared to broilers fed 0 or 25 mg FB1/kg. Hematology was not affected (P > 0.05) by dietary FB1. No lesions were present in any organ examined microscopically. Results indicate that 50 mg FB1/kg diet is detrimental to turkeys but is not toxic to broilers fed to market age.

Topics: Animal Feed; Animals; Body Weight; Chickens; Dose-Response Relationship, Drug; Feeding Behavior; Fumonisins; Liver; Male; Organ Size; Random Allocation; Species Specificity; Teratogens; Turkeys

The toxicity of low dietary levels of fumonisin B(1) (FB(1)), i.e. 1, 10 and 25 mg FB(1)/kg diet, were monitored in rats over a period of 24 months. No effects on the body weight gain and feed intake profiles were noticed, while the relative liver weight was significantly (P<0.05) reduced in the FB(1)-treated rats. Mild toxic effects, including single cell necrosis (apoptosis), proliferation of bile duct epithelial cells (DEC), and early signs of fibrosis, bile duct hyperplasia and in one case, adenofibrosis, were noticed in the liver of the rats fed the highest (25 mg/FB(1)/kg diet) dietary level. A significant (P<0.05) increase in the level of oxidative damage was also noticed in the liver of the rats of high dosage dietary group. The toxic effects were less severe in the 10 mg FB(1)/kg dietary group, whilst only a few ground glass foci were observed in the 1 mg FB(1)/kg dietary group. Hepatocyte nodules, staining positively for glutathione-S-transferase (placental form, PGST), were observed macroscopically in the 25 mg FB(1)/kg treated group and to a lesser extent in the 10 mg FB(1)/kg treated rats. The most prominent toxic lesions by FB(1) (10 and 25 mg FB(1)/kg dietary groups) in the kidneys were restricted to the tubular epithelium manifesting as granular cast, necrosis, apoptosis, calcification and the presence of regenerative foci in the proximal convoluted tubules. The existence of a cytotoxic/proliferative threshold with respect to cancer induction by FB(1) in rat liver became apparent, with a dietary level of <10-mg FB(1)/kg diet as a no effect threshold for the induction of hepatocyte nodules.

Topics: Animals; Body Weight; Carboxylic Acids; Cholesterol; Diet; Dose-Response Relationship, Drug; Fumonisins; Kidney; Liver; Male; Organ Size; Rats; Teratogens; Thiobarbituric Acid Reactive Substances

Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.

Topics: Animals; Body Weight; Carboxylic Acids; Carcinogens, Environmental; Cell Death; Cell Division; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Female; Food Contamination; Fumonisins; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Models, Biological; Mycotoxins; Organ Size; Risk Assessment; Sex Factors; Sphingosine

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

We conducted a chronic feeding study in vervet monkeys (Cercopithecus aethiops) over 13.5 years. The experimental design consisted of two dietary treatment groups, each including males and females, fed varying levels of culture material of Fusarium verticillioides (Sacc.) Nirenberg (= F. moniliforme Sheldon) strain MRC 826 mixed into their daily food ration. Two females were included as treatment controls. We conducted blood chemical analyses bimonthly and recorded all clinical signs during the course of the experiment. We took liver biopsies at various stages during the initial phase of the experiment. Several monkeys were terminated in extremis during the experiment. Detailed feed intake profiles were determined 5 years after the experiment began, and the fumonisin B (FB) mycotoxin content of the feed was determined during the final stages of the experiment. The apparent FB consumption patterns were related to changes observed in the biochemical parameters in the blood and urine, including the liver function enzymes and creatinine clearance as well as differential blood counts and sphingolipid levels in the serum and urine. An apparent no-effect threshold for kidney and liver damage is estimated to be between 0.11 and 0.18 mg FB/kg body weight (bw)/day, which corresponds to a feed contamination level of between 8.21 and 13.25 mg FB/kg bw diet. Apart from the effects on the liver and kidney, a wide variety of parameters, including cholesterol and creatine kinase, were also adversely affected. Several blood parameters, including white and red blood cells, also significantly decreased in the treated animals. The serum sphinganine level and the sphingosine/sphinganine ratio, monitored toward the end of the experiment, significantly increased in both the low-dose and high-dose animals. The present study provides important information about the diversity of lesions induced by culture material of F. verticillioides in vervet monkeys and the dosage levels of fumonisins to be used in long-term studies in nonhuman primates.

Topics: Animal Feed; Animals; Body Weight; Carboxylic Acids; Cells, Cultured; Chlorocebus aethiops; Creatinine; Dose-Response Relationship, Drug; Female; Fumonisins; Fusarium; Kidney; Liver; Liver Function Tests; Male; Mycotoxins; Organ Size; Regression Analysis; Sex Factors; Sphingolipids

Fumonisin B1 (FB1) is a mycotoxin isolated from Fusarium fungi that contaminate crops worldwide. A previous study demonstrated that FB1 promoted preneoplastic foci in initiated rats and induced hepatocellular carcinomas in BD IX rats at 50 parts per million (ppm), but fundamental dose-response data were not available to assist in setting regulatory guidelines for this mycotoxin. To provide this information, female and male F344/N/Nctr BR rats and B6C3F1 Nctr BR mice were fed for two years a powdered NIH-31 diet containing the following concentrations of FB1: female rats, 0, 5, 15, 50, and 100 ppm; male rats, 0, 5, 15, 50, and 150 ppm; female mice, 0, 5, 15, 50, and 80 ppm; male mice, 0, 5, 15, 80, and 150 ppm. FB1 was not tumorigenic in female F344 rats with doses as high as 100 ppm. Including FB1 in the diets of male rats induced renal tubule adenomas and carcinomas in 0/48, 0/40, 9/48, and 15/48 rats at 0, 5, 15, 50, and 150 ppm, respectively. Including up to 150 ppm FB1 in the diet of male mice did not affect tumor incidence. Hepatocellular adenomas and carcinomas were induced by FB1 in the female mice, occurring in 5/47, 3/48, 1/48, 19/47, and 39/45 female mice that consumed diets containing 0, 5, 15, 50, and 80 ppm FB1, respectively. This study demonstrates that FB1 is a rodent carcinogen that induces renal tubule tumors in male F344 rats and hepatic tumors in female B6C3F1 mice.

Topics: Animal Feed; Animals; Biological Assay; Body Weight; Carboxylic Acids; Carcinogens, Environmental; Dose-Response Relationship, Drug; Female; Fumonisins; Fusarium; Kidney; Kidney Neoplasms; Kidney Tubules; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Mycotoxins; Rats; Rats, Inbred F344; Survival Analysis

Fumonisin B1 (FB1), a potent mycotoxin prevalent in corn and cereals, causes a variety of toxic effects in different mammalian species. The biochemical responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a possible involvement of tumor necrosis factor alpha (TNFalpha). To further characterize the role of TNFalpha, toxic response to FB1 was investigated in male C57BL/6J mice (WT) and a corresponding TNFalpha receptor knockout (TRK) strain, genetically modified to lack the TNFalpha1b receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg per day of FB1 were observed in WT but were reduced in TRK, evidenced by circulating alanine aminotransferase and aspartate aminotransferase levels and histopathological evaluation of the tissue. FB1 induced TNFalpha expression in the livers of both WT and TRK mice to a similar extent (3-4 fold over control); however, a corresponding increase of cellular NFkappaB, expected after the downstream cellular signaling of TNFalpha, was noted only in the WT. Accumulation of liver sphingosine after FB1 treatment was similar in both WT and TRK, but the FB1-induced increases in liver sphinganine and kidney sphingosine and sphinganine were lower in TRK than in WT. Results emphasized the role of TNFalpha in FB1-induced hepatotoxicity in mice and the possible relationship of sphingoid base accumulation and TNFalpha induction. Moreover, the presence of TNFalpha receptor 1b appears to be important in mediating the hepatotoxic responses of TNFalpha and FB1 in mice.

Topics: Alanine Transaminase; Animals; Antigens, CD; Aspartate Aminotransferases; Body Weight; Carboxylic Acids; Cytosol; Fumonisins; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycotoxins; NF-kappa B; Organ Size; Receptor Protein-Tyrosine Kinases; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Sphingolipids; Tumor Necrosis Factor-alpha

In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Eucalyptus plants were screened. Consequently, the phlorogrucinol-monoterpene derivative, euglobal-G1 (EG-1), was obtained from the leaves of Eucalyptus grandis as an active constituent. EG-1 exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumors induced by 7, 12-dimethylbenz[a]anthracene (DMBA) as an initiator and fumonisin-B1, which has been known as one of mycotoxins produced by Fusarium monifliforme, as a promoter. Further, EG-1 exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse pulmonary tumor using 4-nitroquinoline-N-oxide (4-NQO) as an initiator and glycerol as a promoter.

Topics: 4-Nitroquinoline-1-oxide; 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antiviral Agents; Body Weight; Carboxylic Acids; Carcinogens; Carcinogens, Environmental; Eucalyptus; Female; Fumonisins; Glycerol; Lung Neoplasms; Mice; Mice, Inbred SENCAR; Neoplasms, Experimental; Phloroglucinol; Phytotherapy; Plants, Medicinal; Skin Neoplasms; Terpenes; Time Factors

Fumonisins B1 and B2 (FB1 and FB2) are fungal secondary metabolites produced by members of the genus Fusarium. Although FB1 is usually detected in greater quantities, FB2 frequently co-occurs in contaminated feeds and foods and contributes to the total toxin load. In the present study, the comparative toxicity of FB1 and FB2 was examined in male Sprague-Dawley rats administered toxin (0.75 mg/kg body weight) or vehicle control intraperitoneally (ip) for 2, 4 or 6 consecutive days. Clinical changes, including elevated serum cholesterol, alanine aminotransferase (ALT), creatinine and protein, were slightly more pronounced in FB1-treated rats. The most consistent hematological change was an increase in vacuolated bone marrow cells, which was more pronounced in FB1-treated rats. Histopathological changes were similar in FB1- and FB2-treated rats and included single cell necrosis in kidneys and liver, cytoplasmic vacuolation in adrenal cortex and lymphocytolysis in thymus. In the liver mRNA expression for the cyclin kinase inhibitor p21 gene was significantly increased in FB1- and FB2-treated rats, compared to controls. Expression of mRNA for the cyclin D1 gene was significantly depressed in FB2-treated rats. Hepatic cyclin E mRNA was elevated in response to FB1 and FB2 compared to controls. In FB2-treated animals this corresponded with decreased liver p27 mRNA expression. Hepatic proliferating cell nuclear antigen (PCNA) transcription was elevated in FB1- but not FB2- treated rats. Changes in liver microsomal protein levels of p27, cyclin E and PCNA were similar to changes in gene expression. In contrast, cyclin D1 protein levels were elevated in rats treated with FB1 and, to a lesser extent, FB2. The data indicate that FB1 and FB2 can alter the expression of genes associated with the cell cycle, and indicate a need for a further understanding of the mechanistic basis of FB1 and FB2 toxicity.

Topics: Animals; Body Weight; Carboxylic Acids; Cell Cycle; Cell Cycle Proteins; Eating; Fumonisins; Injections, Intraperitoneal; Kidney; Liver; Male; Mycotoxins; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger

An investigation of the toxicity of fumonisin B1 (FB1), a toxic metabolite of Fusarium moniliforme, in broiler chicks was conducted. Purified FB1 (98.1% pure) was incorporated into the diets of broiler chicks at 0, 20, 40, and 80 mg/kg, and fed to chicks from 0 to 21 d of age. Dietary FB1, at concentrations of 80 mg/kg or less, did not adversely affect body weight, feed efficiency, or water consumption of broiler chicks. The relative weights of the liver, spleen, kidney, proventriculus, and bursa of Fabricius were also unaffected (P < 0.05) by any dietary concentration of FB1 compared with the control (0 mg/kg) group. Total liver lipids of chicks fed 40 or 80 mg FB1/kg were significantly lower than those of the chicks fed either 0 or 20 mg FB1/kg of feed. Liver sphinganine concentration and the sphinganine:sphingosine ratio were increased significantly in all treated groups. Chicks fed dietary FB1 at 80 mg/kg had significantly higher serum glutamate oxaloacetate aminotransaminase:aspartate aminotransferase ratios and levels of free sphinganine in the serum. The results of this investigation agree with the results previously described, in which FB1 was supplied to diets from the use of F. moniliforme-contaminated grain; therefore, the use of such material as the source of the mycotoxin in animal feeding studies is appropriate.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Brain; Carboxylic Acids; Chickens; Diet; Drinking; Eating; Fumonisins; Hyperplasia; Kidney; Lipids; Liver; Male; Mycotoxins; Necrosis; Organ Size; Sphingosine; Spleen

Fumonisins and fusaric acid (FA) are mycotoxins produced by Fusarium moniliforme and other Fusarium which grow on corn. Fumonisins cause animal toxicities associated with F. moniliforme and, like F. monliforme, they are suspected human oesophageal carcinogens. Toxic synergism was obtained by simultaneous administration of FA and fumonisin B1 to chicks in ovo. To determine the effect of FA on in vivo toxicity of F. moniliforme culture material (CM), male rats (12 groups, n = 5/ group) were fed diets containing 0.025, 0.10 or 2.5% CM (providing dietary levels of 3.4, 18.4 or 437 ppm fumonisins, respectively) to which, at each CM level, 0, 20, 100 or 400 ppm FA were added. Additionally, an FA control group was fed 400 ppm FA only and an untreated control group was given neither FA nor culture material. Apoptosis and other effects consistent with those caused by fumonisins were present in the kidneys of animals fed 0.025% or more CM and in the livers of animals fed 2.5% CM. FA was without effect. No differences between the untreated and FA control groups were noted and no differences among the four groups (0-400 ppm FA) fed 0.025% CM, the four groups fed 0.10% CM or the four groups fed 2.5% CM were apparent. Thus, FA exerted no synergistic, additive or antagonistic effects on the subchronic in vivo toxicity of fumonisin-producing F. moniliforme.

Topics: Administration, Oral; Animals; Body Weight; Brain; Carboxylic Acids; Cholesterol; Diet; Dose-Response Relationship, Drug; Eating; Enzymes; Fumonisins; Fusaric Acid; Fusarium; Heart; Kidney; Liver; Male; Mycotoxins; Organ Size; Rats; Rats, Sprague-Dawley; Sphingolipids; Triglycerides

Beginning at 24 wk of age, control diets or diets containing 50 or 100 mg/kg moniliformin (M), 100 or 200 mg/kg fumonisin B1 (FB1), or a combination of 50 mg M and 100 mg FB1/kg of diet were fed to White Leghorn laying hens for 420 d. The hens were then fed the control diet for an additional 60 d. At the beginning of the experiment, each treatment consisted of four replicates of six hens. Egg production was reduced by approximately 50% by the end of the second 28-d laying period and remained at approximately this level for the 420 d in only the hens fed the diet containing 100 mg M/kg feed. Production returned to control levels or above within 60 d after hens were fed the control diet. Egg weights were reduced by the 100-mg M diet during the first three 28-d laying periods before returning to weights comparable with controls. The hens in this group also had significantly lower body weights than the other treatments. Mortality was minimal except in hens fed the 100 mg M/kg diet and the 100 mg FB1/kg diet, on which approximately 20% of the hens died. The hens were artificially inseminated with semen from males fed control diets, and fertility was not affected by the dietary treatments. Importantly, toxic synergy between M and FB1 was not observed for any of the parameters measured. Results indicate that laying hens may be able to tolerate relatively high concentrations of M and FB1 for long periods of time without adversely affecting health and performance. Interestingly, hens fed the 100-mg M/kg diet were able to recover when returned to control diets. The likelihood of encountering M or FB1 at these concentrations in finished feed is small.

Topics: Animal Feed; Animals; Body Weight; Carboxylic Acids; Chickens; Culture Media, Conditioned; Cyclobutanes; Diet; Drug Synergism; Female; Fertility; Food Contamination; Fumonisins; Fusarium; Mycotoxins; Oviposition

The fungal toxin fumonisin B1 (FB1) is a contaminant of corn-based foods and feeds produced by members of the genus Fusarium. Fumonisin B1 toxicity was examined using gavage administration of purified toxin to female Sprague-Dawley rats. For 11 consecutive days each rat received a single dose of FB1 at the following concentrations: control (saline), 1, 5, 15, 35, or 75 mg FB1/kg body weight/d. Significantly depressed body weight and food consumption occurred at 35 and 75 mg FB1/kg/d. By the end of the dosing period there were no significant changes in food consumption. Kidneys and bone marrow were most sensitive to FB1 exposure. Changes in renal morphology were observed from 5 to 75 mg FB1/kg/d, accompanied by transient changes in urine osmolality and urine enzyme levels. Increased cellular vacuolation was the primary change associated with bone-marrow toxicity, starting at doses of 5 mg FB1/kg/d. Hepatotoxicity was indicated by reduced liver weight, elevated serum alanine amonitransferase (ALT), and mild histopathological changes occurring at doses of 15 mg FB1/kg/d and higher. Increased cytoplasmic vacuolation of adrenal cortex cells occurred in rats treated with 15 mg FB1/kg/d and higher, indicating that the adrenals are also potential targets of FB1. Elevated serum cholesterol, which is a consistent response to FB1 was observed at 5 mg FB1/kg/d and higher. Based on responses in this study, gavage is an appropriate substitute for longer feeding studies. Compared to previous work with male rats, gender-related difference in FB1 responses lacked consistency but indicated that males may be marginally more sensitive than female Sprague-Dawley rats.

Topics: Administration, Oral; Adrenal Glands; Animals; Body Weight; Bone Marrow; Carboxylic Acids; Carcinogens, Environmental; Female; Fumonisins; Intubation, Gastrointestinal; Kidney; Liver; Male; No-Observed-Adverse-Effect Level; Organ Size; Rats; Rats, Sprague-Dawley; Sex Characteristics; Thymus Gland; Urinalysis

Fumonisin B1 (FB1), the major mycotoxin from Fusarium moniliforme, has been implicated as a causative agent in several animal and human diseases. Despite animal toxicity studies and human epidemiological studies of FB1, knowledge of its reproductive effects is scarce. In this study, one of a series of proposed studies that will allow extrapolation to humans, pregnant rats were given oral doses of 0, 1.875, 3.75, 7.5 or 15 mg FB1/kg on gestation days 3 16. Caesarean sections were performed on day 17 or 20, and maternal condition, implantation efficiency, foetal viability and foetal development were measured. Dose-related decreases in overall feed consumption and body weight gain were seen, but only the feed consumption decrease at 15 mg/kg, and the decreased body weight gain at 15 mg/kg on days 0-17 were statistically significant. Foetal body weights at day 17 were similar in control and treated groups; but in day-20 foetuses, female weight and crown-rump length were significantly decreased at 15 mg/kg. FB1 was not teratogenic at the doses tested, and no dose-related effects were seen in either skeletal or soft-tissue development. In day-17 animals, maternal and foetal brain, liver and kidney tissues, and maternal serum were preserved to study the levels of sphinganine (Sa), sphingosine (So), and the Sa/So ratios. Dose-related increases were seen in Sa/So ratios in maternal livers, kidneys and serum. Sa/So ratios of maternal brains were not affected, nor were those of foetal kidneys, livers or brains.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Brain; Carboxylic Acids; Drinking; Eating; Embryonic and Fetal Development; Female; Fumonisins; Kidney; Liver; Male; Organ Size; Pregnancy; Rats; Reproduction; Sphingosine; Teratogens

The individual and combined effects of feeding diets containing 300 mg fumonisin B1 (FB1), and 4 mg diacetoxyscirpenol (DAS) or 3 mg ochratoxin A (OA) were evaluated in two experiments using female turkey poults (Nicholas Large Whites) from day of hatch to 3 wk of age. When compared with controls, body weight gains were reduced 30% (Study 1) and 24% (Study 2) by FB1, 30% by DAS, 8% by OA, 46% by the FB1 and DAS combination, and 37% by the FB1 and OA combination. The efficiency of feed utilization was adversely affected by all treatments except FB1 in Experiment 2. Relative weights of the liver were significantly increased by all treatments except the DAS treatment. Serum concentrations of cholesterol were decreased and activities of aspartate aminotransferase and lactate dehydrogenase were increased and several hematological values were altered in poults fed FB1 alone and in combination with either DAS or OA. Results indicate additive or less than additive toxicity, but not toxic synergy, when poults are fed diets containing 300 mg FB1, and 4 mg DAS or 3 mg OA/kg of diet. The likelihood of encountering FB1, DAS, or OA at these concentrations in finished feed is small. However, under field conditions, other stress factors could alter the impact of these mycotoxins on the health and performance of poultry.

Topics: Animal Feed; Animals; Aspartate Aminotransferases; Body Weight; Carboxylic Acids; Cholesterol; Drug Interactions; Energy Metabolism; Erythrocyte Count; Female; Fumonisins; Fusarium; Hematocrit; L-Lactate Dehydrogenase; Liver; Mycotoxins; Ochratoxins; Organ Size; Trichothecenes; Triglycerides; Turkeys; Weight Gain

The individual and combined effects of feeding diets containing 300 mg fumonisin B1 (FB1), and 5 mg T-2 toxin (T-2)/kg of diet, or 15 mg/kg deoxynivalenol (DON, vomitoxin) from naturally contaminated wheat were evaluated in two studies in male broiler chicks from day of hatch to 19 or 21 d of age in Experiments 1 and 2, respectively. When compared with controls, body weight gains were reduced 18 to 20% by FB1, 18% by T-2, 2% by DON, 32% by the FB1 and T-2 combination, and 19% by the FB1 and DON combination. The efficiency of feed utilization was adversely affected by FB1 with or without T-2 or DON. Mortality ranged from none for the controls to 15% for the FB1 and T-2 combination. Relative weights of the liver and kidney were significantly increased by FB1 with or without T-2 or DON. Serum concentrations of cholesterol were increased in chicks fed FB1 with or without T-2 or DON. Activities of aspartate aminotransferase, lactate dehydrogenase, and gamma glutamyltransferase were increased in chicks fed FB1 at 300 mg/kg alone and in combination with T-2 or DON, indicating possible tissue damage and leakage of the enzymes into the blood. Results indicate additive toxicity when chicks were fed diets containing 300 mg FB1 and 5 mg T-2/kg of diet and less than additive toxicity when chicks were fed 300 mg FB1 and 15 mg DON/kg of diet. Of importance to the poultry industry is the fact that toxic synergy was not observed for either of these toxin combinations and the likelihood of encountering FB1 at this concentration in finished feed is small. However, under field conditions with additional stress factors, the toxicity of these mycotoxins could be altered to adversely affect the health and performance of poultry.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Calcium; Carboxylic Acids; Carcinogens, Environmental; Chickens; Cholesterol; Diet; Drug Combinations; Fumonisins; Fusarium; gamma-Glutamyltransferase; Gizzard, Avian; Kidney; L-Lactate Dehydrogenase; Liver; Male; Organ Size; Serum Albumin; T-2 Toxin; Trichothecenes; Triticum; Weight Gain

Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.

Topics: Acyltransferases; Animals; Body Weight; Carboxylic Acids; Chromatography, High Pressure Liquid; Embryo, Mammalian; Female; Fumonisins; Male; Maternal-Fetal Exchange; Neural Tube Defects; Organ Size; Pregnancy; Rabbits; Sphingolipids; Sphingosine N-Acyltransferase; Teratogens

The effects of repeated exposure to fumonisin B1 (FB1) on hepatic and renal mixed function oxidase activities and peroxisomal proliferation has been examined in rats following intraperitoneal administration at three dose levels (0.125, 0.25, and 2.5 mg/kg) once a day for 6 days. At the two highest doses, FB1 increased the renal and hepatic N-demethylation of erythromycin (CYP3A1) and the hepatic O-deethylation of ethoxyresorufin (CYP1A1). FB1, at the highest dose of 2.5 mg/kg, also increased the renal O-deethylation of ethoxyresorufin. The liver, but not the kidney, was also susceptible to FB1-dependent induction of the 12- and 11-hydroxylation of lauric acid, suggesting induction of the CYP4A subfamily. Immunoblot studies employing solubilized microsomes from FB1-treated rats revealed that FB1, at the two highest doses, increased the apoprotein levels of CYP1A1 and CYP4A1. The same treatment with FB1 increased the beta-oxidation of palmitoyl-coenzyme A (CoA) in liver homogenates, and immunoblot analysis showed an increase in the apoprotein levels of the trans-2-enoyl-CoA hydratase trifunctional protein. The possible implications of these findings to the hepatocarcinogenicity of this mycotoxin are discussed.

Topics: Animals; Body Weight; Carcinogens, Environmental; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Enzyme Induction; Fumonisins; Injections, Intraperitoneal; Kidney; Liver; Male; Microbodies; Mixed Function Oxygenases; Mycotoxins; Organ Size; Rats; Rats, Wistar

To examine the toxic effects of fumonisin B1 (FB1)-containing culture material and deoxynivalenol (DON)-contaminated wheat diets on barrows.. 24, 7-week-old crossbred barrows allotted to 4 equal groups of 3 replicates of 2 barrows/replicate.. Barrows were fed diets for 28 days that were formulated as follows: no additional FCM or DON/kg of feed (control); 100 mg FB1/kg of feed; 5 mg DON/kg of feed; or 100 mg FB1 plus 5 mg DON/kg of feed. Body weight and feed consumption were monitored weekly. On day 28, blood samples were obtained for serum biochemical, hematologic, and immunologic measurements. On day 29, barrows were euthanatized and necropsies were performed.. Analyzed mycotoxin content of diets were: none detected (control); 47 mg of FB1/kg of feed (FB1 diet); 4.5 mg of DON/kg of feed (DON diet); and 56 mg of FB1 and 3.7 mg of DON/kg of feed (FB1 plus DON diet). Differences were detected among groups of barrows for clinical performance, serum biochemical analytes, immunologic response, and histopathologic lesions.. Combining FB1-containing material and DON-contaminated wheat in the diets of growing barrows induces a more toxic response than that induced by either toxin singly. For many variables, the response could be described as additive; however, for some variables, responses were interactive in a greater-than-additive manner.. Caution should be exercised when formulating swine diets that could contain FB1 and DON, because the condition induced by their combination is more severe than that predicted for each mycotoxin's toxicity.

Topics: Animal Feed; Animals; Body Weight; Carboxylic Acids; Diet; Food Contamination; Fumonisins; Liver; Lung; Male; Mycotoxins; Orchiectomy; Organ Size; Swine; Triticum; Weight Gain

Developmental and toxic effects of aqueous extracts of F. moniliforme culture material containing known levels of fumonisin B1 were recently reported in mice and included maternal hepatotoxicity and lethality, maternal body weight gain reduction, increased embryonic resorptions, reduced offspring body weights, and fetal malformations including cleft palate, hydrocephalus, malformed ribs and incomplete digital and sternal ossification. These studies also suggested that the effects of the fungal extract on the mouse offspring may be mediated via maternal effects. The contribution of fumonisin B1 (FB1), a major toxic metabolite of F. moniliforme, in the induction of these effects was evaluated in this study by administering 0 to 100 mg pure FB1/kg of body weight on gestational days (GD) 7 through 15 to pregnant Charles River CD1 mice and assessing maternal health and fetal development till the end of gestation. Doses of 25 mg/kg or higher of pure FB1 induced maternal liver lesions (mostly necrotic changes), associated with ascites and increased hepatocytic nuclear diameter. Fumonisin doses of 50 mg/kg or higher also resulted in significantly increased maternal ALT on GD12, and reduced offspring bodyweights on GD18. Increased resorptions and decreased numbers of live offspring were only evident at 100 mg FB1/kg body weight. Offspring exhibited dose-dependent increase in the incidence and severity of hydrocephalus of both the lateral and third ventricles at doses of 25 mg/kg or higher. Doses of 25 mg/kg or higher also increased the sphinganine/sphingosine (Sa/So) ratios in maternal but not fetal livers. These results suggest that FB1 may be a developmental toxicant accounting for most but not all earlier reported effects of F. moniliforme culture extract. Association of FB1 effects on the offspring with maternal hepatoxicity and with alteration of Sa/So ratio in maternal but not fetal liver supported the earlier claim that FB1 effects on the mouse offspring are mediated by maternal hepatotoxicity.

Topics: Alanine Transaminase; Animals; Body Weight; Embryonic and Fetal Development; Female; Fetal Resorption; Fumonisins; Hydrocephalus; Litter Size; Liver; Mice; Mycotoxins; Pregnancy; Sphingosine

Diets containing 200 mg fumonisin B1/kg of feed and .75 mg aflatoxin/kg of feed singly or in combination were fed to female turkey poults (Nicholas Large White) from day of hatch to 21 d of age. When compared with controls, 21-d body weight gains were reduced 10% by fumonisin B1, 39% by aflatoxins, and 47% by the combination. Relative weights (grams/100 g body weight) of the kidney and pancreas increased in poults fed the diet containing aflatoxins alone, whereas the relative weight of the liver decreased. Relative weights of the liver and pancreas increased in the poults fed the fumonisin diet. Relative weights of the kidney, pancreas, and gizzard increased in the poults fed the combination diet, whereas the relative weight of the liver decreased. Most serum constituents, hematology values, and activities of enzymes measured were altered in poults receiving the diets containing aflatoxins with or without fumonisin B1. No major histological lesions were observed in tissues from control poults or poults fed the diet containing fumonisin alone. Lesions associated with aflatoxins were only observed in the liver and occasionally in the kidney of poults fed the diets containing aflatoxins with or without fumonisin B1. The primary hepatic change was bile duct hyperplasia with some hepatocellular degeneration and necrosis and megalocytosis. Occasional necrotic and degenerating tubular epithelial cells were observed in the kidneys. The increased toxicity in poults fed the combination diet for most variables can best be described as additive, although some variables showed less than additive toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aflatoxins; Animal Feed; Animals; Body Weight; Drug Interactions; Energy Metabolism; Female; Fumonisins; Fusarium; Longevity; Mycotoxins; Turkeys

Toxic effects of fumonisin B1 (FB1) were observed with cultured chondrocytes isolated from epiphyseal growth plates and with growing broiler chicks. Viability of chondrocytes was reduced after 48 h exposure to FB1, and half lethal concentration of FB1 was estimated to be greater than 250 microM. Increase in cell size was inhibited by as low as 25 microM FB1. Dietary inclusion of fumonisins (55 and 110 ppm) caused a reduction in body weight, increase in liver weight, and decrease in feed efficiency (P < .05). However, diarrhea and bone malformation were not observed. It is concluded that fumonisin by itself is not sufficient to cause skeletal problems in poultry.

Topics: Animals; Body Weight; Bone Development; Chickens; Fumonisins; Growth Plate; Mycotoxins

The toxicity of purified fumonisin B1 (FB1) administered ip was examined in male Sprague-Dawley rats. FB1 was injected at 7.5 or 10 mg/kg body weight/day for 4 consecutive days. This resulted in significant reductions in body weight, food consumption and faeces production. Polyuria without a compensatory increase in water consumption was observed in treated rats. Erythrocytosis, elevated haematocrits and haemoglobin levels were attributed to dehydration. Nephrotoxicity in treated rats was evident by clinical changes including elevated blood urea nitrogen and by subtle changes in kidney morphology. Histopathology and serum biochemistry also indicated that the liver was an important target organ in FB1-treated rats. A small increase in liver glutathione concentration was also evident in rats receiving 10 mg FB1/kg body weight. Effects on the immune system included reduced thymus weight, disseminated thymic necrosis and consistently elevated serum immunoglobulin M levels. Circulating phagocytic cell numbers were elevated in treated rats, probably owning to tissue damage associated with ip dosing. The liver and kidneys appear to be target organs of FB1 in Sprague-Dawley rats.

Topics: Animals; Body Weight; Bone Marrow; Carcinogens, Environmental; Energy Intake; Feces; Fumonisins; Glutathione; Hematocrit; Immunoglobulins; Injections, Intraperitoneal; Kidney; Liver; Male; Mycotoxins; Organ Size; Rats; Rats, Sprague-Dawley

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

White Leghorn Cornell K-strain chicks (3 replicates of 16 per pen) were started at Day 7 on feed amended with Fusarium proliferatum culture material containing fumonisin B1, fumonisin B2, and moniliformin at 61, 10.5, and 42.7 ppm, respectively. Observed effects on performance of treated birds included reduced feed conversion at 2 wk, and reduced body weight of males and females up to 6 wk (P < or = .05). Splenic, thymic, and liver weights, normalized for body weight, were reduced (P < or = .05) with no change in bursa of Fabricius. No significant changes were observed histologically in the spleen, bursa, kidney, heart, liver, cecal tonsils, colon, or tibia. Significant suppression in total Ig and IgG levels occurred. Macrophages from treated chicks exhibited a 34% reduction in phagocytic activity. Natural killer cell activity was not affected. These findings, which showed that Fusarium toxins alter performance and immune end points in chickens, imply that chickens exposed to mycotoxins may be more susceptible to infectious diseases.

Topics: Animals; Antibody Formation; Body Weight; Chickens; Cyclobutanes; Female; Fumonisins; Fusarium; Immunity; Macrophages; Male; Mycotoxins; Organ Size; Sheep

Aflatoxin (AF)-contaminated and fumonisin B1 (FB1)-contaminated (culture material from Fusarium moniliforme) diets were fed singly and in combination to growing cross-bred barrows. Six barrows (3 replicates of 2 each; mean body weight, 17.5 kg) per group were fed: 0 mg of AF and 0 mg of FB1/kg of feed (control); 2.5 mg of AF/kg of feed; 100 mg of FB1/kg of feed; or 2.5 mg of AF plus 100 mg of FB1/kg of feed for 35 days. The effects on production performance, serum biochemical, hematologic, immunologic, and pathologic measurements were evaluated. Body weight, gain, and feed consumption were significantly (P < 0.05) decreased by AF and AF plus FB1 diets. The FB1 diet decreased feed consumption, and although body weight was numerically decreased, it was not statistically significant. Aflatoxin increased serum gamma-glutamyltransferase (GGT) activity and total iron concentration and decreased urea nitrogen concentration and unsaturated iron-binding capacity. The FB1-alone diet increased serum GGT activity, whereas the AF plus FB1 diet increased serum aspartate transaminase, cholinesterase, alkaline phosphatase, and GGT activities, increased RBC count, triglycerides, and total iron concentrations, and decreased unsaturated iron-binding capacity and urea nitrogen concentration. For the most part, the effects of the AF plus FB1 diet on body weight and hematologic measurements could be considered additive. However, the effect of the AF plus FB1 diet on cholinesterase and alkaline phosphatase activities was greater than additive and was a synergistic response. One pig in the FB1-diet group and 2 pigs in the combination-diet group died. Postmortem lesions in pigs of the FB1-diet group consisted of ascites and increased liver weight. Observations at necropsy for pigs of the AF plus FB1-diet group consisted of hydrothorax, ascites, pulmonary edema, gastric erosions and ulceration, and increased liver and spleen weights. The AF diet increased relative liver weight and resulted in liver that was pale, rubbery, and resistant to cutting. Histologic lesions consisted of hepatic necrosis or degeneration, or both, with variable degrees of bile duct proliferation in barrows of the AF-diet groups. Renal tubular nephrosis was observed in barrows of the FB1-diet group, but this was not consistent in the AF plus FB1-diet group. Cell-mediated immunity, as measured by mitogen-induced lymphoblastogenic stimulation index, was decreased in barrows of the AF and FB1-diet groups, and v

Topics: Aflatoxins; Alkaline Phosphatase; Animal Feed; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Body Weight; Carcinogens; Carcinogens, Environmental; Cholinesterases; Chromatography, High Pressure Liquid; Erythrocyte Count; Fumonisins; Fusarium; gamma-Glutamyltransferase; Iron; Liver; Lung; Male; Mycotoxins; Organ Size; Random Allocation; Spleen; Swine; Weight Gain

The pharmacokinetics of the mycotoxin fumonisn B1 (FB1) were investigated in pigs. Animals were administered 14C-FB1 intravenously (IV; 0.25 microCi, 0.40 mg/kg) or intragastrically (IG; 0.35 microCi, 0.50 mg/kg); separate groups of pigs underwent bile cannulation prior to dosing (groups IV/B and IG/B, respectively). Blood, urine, faeces, (and bile), were collected at specific time intervals over 72 hr, and assayed for specific activity. Following IV dosing, plasma concentration-time profiles were triexponential, with the following mean values: t1/2 alpha, 2.2 min; t1/2 beta, 10.5 min; t1/2 gamma, 182 min; apparent volume distribution (Vd gamma), 2.4 l kg-1; plasma clearance, 9.1 ml min-1 kg-1. After 3 days, clearance of FB1-derived radioactivity from the body had slowed to trace levels; total recoveries in urine and faeces were 21.2% and 58.3%, respectively. In bile-interrupted pigs (IV/B) the absence of the slow terminal elimination phase (gamma) suggested FB1 underwent enterohepatic circulation. Biliary recovery was 70.8% of the IV-dose. Radioactivity remaining in tissues after 72 hr amounted to 19.8% and 11.9% of the dose given to IV and IV/B pigs, respectively; highest activities were measured in liver and kidney equivalent to 1,076 and 486 ng FB1 and/or metabolites per g tissue, respectively. Based on plasma and excretion data, systemic bioavailability following IG dosing was estimated to be a very limited 3-6%. Tissue residue levels following IG dosing were 10-20-fold less than IV dosing.

Topics: Administration, Oral; Animals; Body Weight; Carcinogens, Environmental; Fumonisins; Injections, Intravenous; Male; Mycotoxins; Swine; Tissue Distribution

Fumonisin B1, a toxin produced by Fusarium moniliforme, has been associated with a neurotoxic syndrome in horses known as equine leukoencephlomalacia. Previous investigations showed that F. moniliforme cultured on corn and incorporated into rat chow increased brain 5-hydroxyindoleacetic acid (5HIAA) and 5HIAA: serotonin (5HT) ratios in these animals. Therefore, this study was undertaken to determine whether fumonisin B1 would produce related neurochemical effects in the brain and pineal gland of male and female rats. Rats were fed fumonisin B1 at 15, 50, and 150 ppm for 4 weeks. No differences occurred in brain concentrations of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, 5HT, 5HIAA, and the 5HIAA to 5HT ratios in either male or female rats, nor where there differences between the sexes. When compared across sexes, the norepinephrine to dopamine ratios were decreased (P < 0.05) in the 150-ppm-treated animals. This may suggest a fumonisin B1-induced imbalance in brain norepinephrine and/or dopamine. No differences were observed in pineal norepinephrine, 5HT, 5HIAA, and the 5HIAA to 5HT ratios. Since fumonisin B1 failed to duplicate the effects of the F. moniliforme-induced imbalances in 5HT and 5HIAA metabolism in the brains of rats, other mycotoxins from F. moniliforme may be responsible for these effects.

Topics: Animals; Body Weight; Brain; Dopamine; Dose-Response Relationship, Drug; Female; Fumonisins; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Mycotoxins; Neurotransmitter Agents; Norepinephrine; Organ Size; Pineal Gland; Rats; Rats, Sprague-Dawley; Sex Characteristics

The effects of feeding Fusarium moniliforme culture material, containing known concentrations of fumonisin B1 (FB1), were studied in broiler chicks. Day-old chicks were allotted randomly to dietary treatments containing 0, 1.02, 2.04, 3.06, 4.08, 5.10, 6.12, and 7.14% fumonisin culture material (FCM). These levels of FCM supplied 0, 75, 150, 225, 300, 375, 450, and 525 mg of FB1/kg of feed. Each dietary treatment was fed to four pen replicates of six birds each for 21 days. Chicks fed FCM that supplied 450 and 525 mg FB1/kg diet had lower (P < .05) feed intakes and BW gains; increased (P < .05) liver and kidney weights; and increased (P < .05) mean cell hemoglobin, and mean cell hemoglobin concentrations. Compared with controls, chicks fed FCM had increased (P < .05) free sphinganine levels and sphinganine:sphingosine ratios. Treatment-associated histological lesions were only observed in the liver of chicks fed diets containing FCM that supplied 225 mg FB1/kg or higher. Diets containing FCM that supplied levels as low as 75 mg FB1/kg affected the physiology of chicks by increasing free sphinganine levels and sphinganine:sphingosine ratios. Because inhibition of sphingolipid biosynthesis has been hypothesized as the mechanism of action of FB1, this suggests that diets containing 75 mg FB1/kg FCM may be toxic to young broiler chicks.

Topics: Animal Feed; Animals; Blood Glucose; Blood Proteins; Body Weight; Carcinogens, Environmental; Chickens; Feeding Behavior; Female; Fumonisins; Fusarium; Hematocrit; Hemoglobins; Hyperplasia; Leukocyte Count; Liver; Mycotoxins; Necrosis; Organ Size

The effects of dietary fumonisin B1 were evaluated in young turkey poults. The experimental design consisted of 3 treatments, with 24 female turkey poults allotted randomly per treatment. Day-old poults were fed diets containing 0 mg (feed control), 100 mg, and 200 mg fumonisin B1/kg feed for 21 days. Body weight gains and efficiency of feed conversion decreased linearly with increasing dietary fumonisin. Liver, kidney, and pancreas weights increased linearly with increasing dietary fumonisin, and spleen and heart weights decreased. Serum aspartate aminotransferase levels increased with increasing dietary fumonisin, and serum cholesterol; alkaline phosphatase, mean cell volume, and mean cell hemoglobin all decreased. Biliary hyperplasia, hypertrophy of Kupffer's cells, thymic cortical atrophy, and moderate widening of the proliferating and degenerating hypertrophied zones of tibial physes were present in poults fed diets containing fumonisin B1. Results indicate that fumonisin B1, from Fusarium moniliforme culture material, is toxic in young poults, and the poult appears to be more sensitive to fumonisin than the broiler chick.

Topics: Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Atrophy; Body Weight; Carcinogens, Environmental; Cholesterol; Female; Fumonisins; Heart; Kidney; Liver; Mycotoxins; Myocardium; Organ Size; Pancreas; Spleen; Thymus Gland; Turkeys; Weight Gain

The fungus Fusarium moniliforme is ubiquitous on corn throughout the world and is a likely co-contaminant on corn infested with aflatoxin-producing Aspergillus flavus. Ammoniation has been used to detoxify aflatoxin-contaminated commodities. To determine the effect of ammoniation on the toxic potential of Fusarium moniliforme, male Sprague-Dawley rats were fed either diets containing 10% sound corn, ammoniated corn, corn culture material of hepatotoxic F. moniliforme strain MRC 826 (CM), or ammoniated CM for four weeks. They were observed for signs of toxicity and hematological, serum chemical and histopathological evaluations were made. Groups of male Balb/c mice were fed diets fortifies with 10% sound corn or CM for four weeks and evaluated by serum chemical and histopathological means to determine the suitability of mice as a model species for investigation of F. moniliforme-induced hepatotoxicity. Ammoniation was ineffective for detoxification of the CM. Hepatotoxicity and renal toxicity of CM and ammoniated CM were qualitatively similar, although renal tubular lesions appeared more advanced in rats fed ammoniated CM. Adrenal cortical cellular vacuolation was also found in CM and ammoniated CM-fed rats, while focal seminiferous tubular degeneration and aspermia were found only in the testes of ammoniated CM-fed rats. Fumonisin B1 concentrations of the CM and ammoniated CM diets averaged 99 and 75 ppm, respectively. CM containing 99 ppm fumonisin B1 also produced hepatotoxicity in mice similar to that found in CM-fed rats. Thus, mice may be useful for investigations of F. moniliforme-induced hepatotoxicity.

Topics: Ammonia; Animal Feed; Animals; Blood Cells; Body Weight; Eating; Food Microbiology; Fumonisins; Fusarium; Kidney; Liver; Male; Mice; Mice, Inbred BALB C; Mycotoxins; Random Allocation; Rats; Rats, Inbred Strains; Zea mays

The effects of dietary fumonisin B1 were evaluated in young broiler chicks. The experimental design consisted of 5 treatments each with 9 randomly allotted male broiler chicks. Day-old chicks were fed diets containing 0 (feed control), 100, 200, 300, or 400 mg fumonisin B1/kg feed for 21 days. Response variables measured were chick performance, organ weights, serum biochemistry, and histologic parameters. Body weights and average daily gain dramatically decreased with increasing dietary fumonisin B1, and liver, proventriculus, and gizzard weights increased. Diarrhea, thymic cortical atrophy, multifocal hepatic necrosis, biliary hyperplasia, and rickets were present in chicks fed diets containing fumonisin B1. Serum calcium, cholesterol, and aspartate aminotransferase levels all increased at higher fumonisin dietary levels. Results indicate that fumonisin, from Fusarium moniliforme culture material, is toxic in young chicks.

Topics: Animal Feed; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Calcium; Chickens; Cholesterol; Food Microbiology; Foodborne Diseases; Fumonisins; Gizzard, Avian; Liver; Male; Mycotoxins; Organ Size; Poultry Diseases; Proventriculus; Random Allocation; Serum Albumin

Fusarium moniliforme (FM) is associated with equine leukoencephalomalacia (ELEM) and hepatotoxicities in horses and rats. The neurochemical effects of ELEM-associated corn naturally infected with FM and FM strain MRC 826 were studied in rats. Increases in brain 5-hydroxyindoleacetic acid (5-HIAA, major metabolite of serotonin, 5-HT) and 5-HIAA/5-HT ratios were observed in rats fed the ELEM-FM corn. These rats had reduced body weights (17%, P less than 0.01) and increased brain weight/body weight ratios (14%, P less than 0.01) as compared with controls that were fed commercial corn. Rats fed a rodent chow supplemented (16%, w/w) with corn cultures of FM (MRC 826) had brain 5-HT and 5-HIAA increased (11% and 60%, P less than 0.01, respectively). At 20% FM (MRC 826)-chow diet, the 5-HIAA levels were increased (18%, P less than 0.01). In both the 16% and 20% diets, brain 5-HIAA/5-HT ratios were increased (45%, P less than 0.01 and 10%, P less than 0.05), body weights reduced (30% and 18%, P less than 0.01) and brain weight/body weight ratios increased (40% and 16%, P less than 0.01), respectively. The incidences of microscopic liver lesions (particularly bile duct proliferations, hepatocellular hyperplasia, and focal necrosis) were consistent with rats fed the FM contaminated and FM-fortified diets. These results suggest a possible FM (ELEM-associated)-induced dysfunction in either 5-HT metabolism or 5-HIAA elimination in rat brains.

Topics: Animal Feed; Animals; Body Weight; Brain Chemistry; Encephalomalacia; Food Microbiology; Fumonisins; Fusarium; Horse Diseases; Horses; Male; Mycotoxins; Neurotransmitter Agents; Rats; Zea mays

Fusarium moniliforme has been associated with several diseases including equine leukoencephalomalacia, human esophageal cancer and hepatotoxicity/hepatocarcinogenicity in laboratory animals. The potential health risks to animals and humans posed by F. moniliforme contaminated grains cannot be assessed until the toxins are identified and toxicologically evaluated. As part of a systematic approach to identifying the hepatotoxins produced by F. moniliforme, diets containing aqueous and chloroform/methanol (1:1) extracts of F. moniliforme strain MRC 826 culture material (CM) and/or the extracted CM residues were fed to male Sprague-Dawley rats for four weeks. Serum alanine aminotransferase, aspartate amino-transferase and alkaline phosphatase activities were increased after two and four weeks and microscopic liver lesions were found in those animals fed aqueous CM extract and the CM residue after chloroform/methanol extraction. Fumonisins B1 and B2 were extracted from the CM by water, but not chloroform/methanol, and were present in the toxic diets at concentrations of 93-139 and 82-147 ppm, respectively. Nontoxic diets contained less than or equal to 22 ppm fumonisin B1 and less than or equal to 65 ppm fumonisin B2.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Body Weight; Carcinogens, Environmental; Chloroform; Eating; Fumonisins; Fusarium; Liver; Male; Methanol; Mycotoxins; Random Allocation; Rats; Rats, Inbred Strains; Water

Cultures on corn of Fusarium moniliforme MRC 826 are known to cause leukoencephalomalacia in horses and to be toxic and hepatocarcinogenic in rats. Culture material of this F. moniliforme isolate has also been shown to exhibit cancer-promoting activity in a short-term cancer initiation-promotion bioassay with diethylnitrosamine-initiated rats and the induction of gamma-glutamyl-transpeptidase-positive (GGT+) foci as an endpoint after 4 weeks of promotion. This bioassay was used as a monitoring system to isolate cancer-promoting compounds from cultures of F. moniliforme MRC 826. Culture material was successively extracted with ethyl acetate and CH3OH-H2O (3:1). Most of the cancer-promoting activity was recovered in the CH3OH-H2O extract and remained in the aqueous phase following partitioning of this extract between CH3OH-H2O (1:3) and CHCl3. The CH3OH-H2O fraction was chromatographed on an Amberlite XAD-2 column, and the active fraction was eluted with CH3OH. This fraction was chromatographed on a silica gel column with CHCl3-CH3OH-CH3COOH (6:3:1) as eluent and further purified on a C18 reverse-phase column. Two pure compounds were isolated, and these have been chemically characterized and given the trivial names fumonisin B1 and B2. At least 2 g of the major compound fumonisin B1 was purified from 1 kg of culture material. Fumonisin B1 in the diet (0.1%) significantly (P less than 0.001) induced the formation of GGT+ foci in the livers of initiated as well as noninitiated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Carcinogens, Environmental; Chromatography; Diethylnitrosamine; Fumonisins; Fusarium; gamma-Glutamyltransferase; Liver Neoplasms, Experimental; Male; Mutagenicity Tests; Mycotoxins; Rats; Rats, Inbred Strains