fumonisin-b1 and Necrosis

Mycotoxin fumonisin B(1) (FB(1)) is hepatotoxic and carcinogenic in experimental animals. It is known that long-term exposure of experimental animals to FB(1) causes apoptosis and lipid peroxidation. In this study, male adult Wistar rats were treated with single FB(1) doses (5, 50, and 500 microg/kg b.w.) and sacrificed 4, 24, and 48 hours after treatment. Parameters of oxidative stress, histopathological changes, and DNA damage were monitored in the liver of treated and control animals. Parameters of oxidative stress were not affected by such treatment. A significant increase in apoptotic cells appeared in animals when 5 microg/kg b.w. dose was given and sacrificed after 24 hours with further increase at higher doses. In contrast to the number of mitotic figures and karyomegaly seen mostly at lower FB(1) doses, necrosis was the prominent feature at higher doses. Significant increase in liver cells DNA mobility was observed 48 hours following treatment with 50 and 500 microg/kg b.w. as compared to control (tail length 15.2 +/- 0.3, 16.4 +/- 0.5, and 13.5 +/- 0.1 mum, respectively). Tail intensity appeared to be more sensitive parameter for detecting DNA damage even at 5 microg/kg b.w. after 48 hours (1.69 +/- 0.27% DNA; control 0.59 +/- 0.11% DNA). This study proved that FB(1)-induced DNA damage is time- and dose-dependent, and that it could be caused in Wistar rats by a single dose.

Topics: Administration, Oral; Animals; Apoptosis; DNA Damage; Dose-Response Relationship, Drug; Fumonisins; Liver; Liver Regeneration; Male; Mitotic Index; Necrosis; Oxidative Stress; Rats; Rats, Wistar; Time Factors

Mycotoxins are secondary metabolites of fungi that grow on various food and feed. These compounds elicit a wide spectrum of toxicological effects, including the capacity to alter normal immune function. Feed commodities are usually contaminated with more than one mycotoxin; however, extensive information on the interaction between concomitantly occurring mycotoxins and the consequence for their toxicity is lacking. In the present study, we examined the effects in vitro of fumonisin B1 (FB1) and alpha-zearalenol (alpha-ZEA), alone or in combination, on the immune function in the human lymphoblastoid Jurkat T cell line. Treatment of cells with increasing concentrations of FB1 resulted in a dose-dependent induction of proliferation. In contrast, alpha-ZEA showed a marked inhibitory effect on cell proliferation, even at very low doses, essentially mediated by apoptosis. In stimulated cells pre-incubated with FB1, the levels of IL-2 and IFN gamma mRNAs were similar to control whereas a reduction of cytokine transcripts was reported following alpha-ZEA treatment. Interestingly, co-administration of mycotoxins resulted in further inhibition of both proliferation and IFN gamma mRNA expression when compared with alpha-ZEA alone. In conclusion, FB1 and alpha-ZEA showed different immunomodulation abilities when individually administered. Combination of mycotoxins resulted instead in interactive effects.

Topics: Apoptosis; Caspases; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Drug Synergism; Fumonisins; Humans; Indicators and Reagents; Jurkat Cells; L-Lactate Dehydrogenase; Mycotoxins; Necrosis; RNA, Messenger; Zeranol

The effects of fumonisin B-glucose reaction products in swine diets was examined. Pigs were fed diets containing 528 micromol of total fumonisin B/kg (FB), 528 micromol of total FB-glucose adducts/kg (FB-G, 122 micromol of unreacted FB/kg), or 0 micromol of total FB/kg for 15 days to test the efficacy of the FB-G reaction products in detoxifying FB. Weight gain in FB pigs was lower than in FB-G or controls, which was correlated with feed intake reduction in FB pigs. Serum aspartate aminotransferase, gamma-glutamyltransferase, and total bilirubin in FB pigs were higher than in FB-G or control pigs. Serum sphinganine/shingosine ratios in FB pigs were higher than in FB-G or control pigs. Microscopic examination of tissues from FB pigs showed generalized liver necrosis and apoptosis with marked cellular pleomorphism and disorganized hepatic cords. The liver and kidneys in the FB-G group appeared to be normal. Tissues of controls were free of lesions. Results suggest that dietary FB-G products are less toxic to swine and may provide an detoxification approach in instances of widespread FB grain contamination (p < 0.05).

Topics: Animal Feed; Animals; Apoptosis; Aspartate Aminotransferases; Bilirubin; Diet; Fumonisins; gamma-Glutamyltransferase; Glucose; Liver; Necrosis; Swine; Weight Gain

Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia, impairs myelination, and inhibits neuronal growth in vitro. Intact mice do not show brain damage after systemic administration of FB1. We recently reported that intracerebroventricular administration of FB1 in mice caused neurodegeneration in the cortex and activation of astrocytes in the hippocampal area; results suggested that the neuronal damage may be secondary to activation of immunocompetent non-neuronal cells. Current study investigated effects of FB1 upon murine microglial (BV-2) and neuroblastoma (N2A) cell lines, and primary astrocytes and cortical neurons. BV-2 and N2A cultures and cells prepared from neonatal and postnatal brains of BALB/c mice were exposed to various concentrations of FB1 for 4 (BV-2 and N2A) or 4 and 8 (astrocytes and cortical neurons) days. FB1 at 25 microM decreased viability in BV-2 cells, whereas at 50 microM caused necrotic but not apoptotic cell death in both BV-2 and primary astrocytes (at day 8 only), assessed by lactic dehydrogenase release, and pripidium iodide and annexin V staining. Thymidine incorporation indicated that 2.5 microM FB1 decreased proliferation in BV-2 cells. DNA analysis by flow cytometry showed that the inhibition was not caused by cell cycle arrest. The mitochondrial activity decreased dose-dependently in BV-2 cells and was significantly elevated at 25 microM FB1, but not at 50 microM at days 4 or 8 in astrocytes. In BV-2 cells and primary astrocytes, the expression of TNFalpha and IL-1beta analyzed by real-time polymerase chain reaction was downregulated at 6 or 24 h. In all cell types tested the FB1 treatment caused accumulation of free sphinganine and decrease in free sphingosine levels at selected time points. Results indicated that primary and established murine brain immunocompetent cells are vulnerable to the FB1-dependent cytotoxicity in vitro whereas neuronal cells are not. The toxic effects on the neuronal tissue may therefore be secondary to modulation of astrocyte or glial cell function.

Topics: Animals; Astrocytes; Cell Death; Cell Line; Cell Proliferation; Cytokines; Fumonisins; Gene Expression; Mice; Mice, Inbred BALB C; Microglia; Mitochondria; Necrosis; Neuroblastoma; Neurons; Sphingolipids

Fumonisin B1 (FB1) is the most abundant of a series of sphingosine analog mycotoxins produced by the fungus Fusarium moniliforme, a ubiquitous contaminant of stored corn (maize) worldwide. FB1 exhibits a variety of biological activities including phytotoxicity, which is of particular interest for its potential role as a virulence factor to facilitate invasion of plant tissues by the fungus. Droplets of FB1 solution applied to the leaf surface of jimsonweed, black nightshade, and susceptible tomatoes caused necrosis, growth inhibition, and death. With Arabidopsis thaliana grown on agar plates, an IC50 (concentration causing half maximal phytotoxicity) of less than 1 ppm was observed. [3H]FB1 was prepared by biosynthetic incorporation of commercially-available radiolabeled presumptive precursors into the toxin in rice medium solid cultures of F. moniliforme JW#1. The labeled toxin produced by incorporation of [9,10(-3)H]palmitate induced phytotoxic symptoms identical to unlabeled material, indicating it had full biological activity. The area of necrosis on treated leaves was similar in light and dark treated plants. Using liquid scintillation counting to quantify radioactivity in excised plant parts, over 95% of the [3H]FB1 radioactivity applied to leaves of light or dark-treated plants was recovered from the treated leaf. When [3H]FB1 was applied to a wound site on target plants, severe damage occurred at the site of FB1 application and in tissue above the site. These results indicate that FB1 applied to intact surfaces of target plants exhibits primarily contact activity. Translocation of FB1 is limited, occurring only when FB1 is applied to a wound site, and it results in damage to tissue above the point of application, indicating that FB1 is xylem mobile.

Topics: Carboxylic Acids; Enzyme Inhibitors; Fumonisins; Necrosis; Palmitates; Plants; Tritium

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

Fumonisin B1 (FB1) is the most abundant of a series of sphingosine analog mycotoxins produced by the fungus Fusarium moniliforme, a ubiquitous contaminant of stored corn (maize) worldwide. FB1 exhibits a variety of biological activities including phytotoxicity, which is of particular interest for its potential role as a virulence factor to facilitate invasion of plant tissues by the fungus. Droplets of FB1 solution applied to the leaf surface of jimsonweed, black nightshade, and susceptible tomatoes caused necrosis, growth inhibition, and death. With Arabidopsis thaliana grown on agar plates, an IC50 (concentration causing half maximal phytotoxicity) of less than 1 ppm was observed. [3H]FB1 was prepared by biosynthetic incorporation of commercially-available radiolabeled presumptive precursors into the toxin in rice medium solid cultures of F. moniliforme JW#1. The labeled toxin produced by incorporation of [9,10-3H]palmitate induced phytotoxic symptoms identical to unlabeled material, indicating it had full biological activity. The area of necrosis on treated leaves was similar in light and dark treated plants. Using liquid scintillation counting to quantify radioactivity in excised plant parts, over 95% of the [3H]FB1 radioactivity applied to leaves of light or dark-treated plants was recovered from the treated leaf. When [3H]FB1 was applied to a wound site on target plants, severe damage occurred at the site of FB1 application and in tissue above the site. These results indicate that FB1 applied to intact surfaces of target plants exhibits primarily contact activity. Translocation of FB1 is limited, occurring only when FB1 is applied to a wound site, and it results in damage to tissue above the point of application, indicating that FB1 is xylem mobile.

Topics: Carboxylic Acids; Datura stramonium; Enzyme Inhibitors; Fumonisins; Fusarium; Inhibitory Concentration 50; Necrosis; Plant Development; Plants; Plants, Medicinal; Plants, Toxic; Solanum lycopersicum

Fumonisin B1 is hepatotoxic in all species, but nephrotoxicity has only been reported in rats. It is a specific inhibitor of sphinganine N-acyltransferase. Our objective was to determine the target organs for fumonisin toxicosis in the rabbit. We administered fumonisin B1 ( > 95% pure) intravenously to adult rabbits and examined selected clinical, biochemical, and histological parameters for up to 5 days. In a pilot study, rabbits were given fumonisin B1 at 1, 0.5, 0.3, 0.15, or 0 mg/kg daily for 4 or 5 days and then euthanized. Additional rabbits were given a single dose of fumonisin B1 at 1 mg/kg and euthanized on day 2 or 4. In the formal time-course study, rabbits were given a single dose of fumonisin B1 at 0 or 1.25 mg/kg and euthanized on days 1, 3, or 5. Rabbits given multiple doses of fumonisin B1 were lethargic and anorectic, and had decreased urine production. Liver- and renal-associated clinical chemistry parameters were elevated. Renal lesions consisted of severe proximal tubular necrosis. Liver lesions were variable and consisted of mild necrosis, hepatocyte vacuolation, and bile stasis. The sphinganine-to-sphingosine ratio, in both target and nontarget tissues, was markedly elevated in treated rabbits. A single dose of fumonisin B1 induced renal but not hepatic injury. Therefore, the target organs for fumonisin B1 toxicity in rabbits are kidney and liver, with the kidney being more sensitive.

Topics: Animals; Bile Ducts; Biomarkers; Carcinogens, Environmental; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fumonisins; Injections, Intravenous; Kidney Tubules, Proximal; Liver; Male; Mycotoxins; Necrosis; Pilot Projects; Rabbits; Sphingosine

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

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

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