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Fumonisins (FNs) are ubiquitous contaminants of cereal grains. Fumonisin B(1) (FB(1)) was linked to several animal and human diseases. To validate FB(1) biomarkers for studying human disease risks, F344 rats were administered by gavage with either a single dose of 0, 10 or 25 mg FB(1)/kg body weight (BW) or repeated doses of 0, 1.0, or 2.5 mg FB(1)/kg BW/day for 5 weeks. FB(1) excretion and FB(1)-induced metabolic alterations of sphingolipids in rat urine, feces and serum were assessed. Dose-dependent urinary and fecal excretion of free FB(1) were found in both single-dose- and repeat-dose-treated rats. In the single-dose study, urinary sphinganine (Sa) to sphingosine (So) ratio (Sa/So) reached a maximum at day 7 for the high-dose group and at day 5 for the low-dose group, whereas serum Sa/So showed only marginal changes. In the repeat-dose study, urinary Sa/So was persistently elevated at 2 weeks, while serum Sa/So was unchanged. Time course changes of sphinganine 1-phosphate (SaP) and sphingosine 1-phosphate (SoP) were also examined. Although serum Sa/So and SaP/SoP ratios showed no signs of time- or dose-dependent changes, a 10-fold increase in urinary SaP/SoP was observed, suggesting that urinary SaP/SoP is a more sensitive biomarker for FB(1) exposure. The accumulation of SaP and SoP was evident in the time course of SaP/Sa and SoP/So, which may reflect activity changes of enzymes closely related to the metabolism and catabolism of SaP and SoP. These results provide concrete evidence towards the practical use of excreted FB(1), Sa/So and SaP/SoP as biomarkers of exposure to FNs.

Fumonisin B(1) (FB(1)) is a mycotoxin that commonly occurs in maize. FB(1) causes a variety of toxic effects in different animal species and has been implicated as a contributing factor of esophageal cancers in humans. In the present study, we examined the effect of dietary exposure to FB(1) on intestinal colonization by pathogenic Escherichia coli associated with extraintestinal infection. Three-week-old weaned pigs were given FB(1) by gavage as a crude extract or as a purified toxin at a dose of 0.5 mg/kg of body weight daily for 6 days. On the last day of the toxin treatment, the pigs were orally inoculated with an extraintestinal pathogenic E. coli strain. All animals were euthanized 24 h later, necropsies were performed, and tissues were taken for bacterial counts and light microscopic examination. Ingestion of FB(1) had only a minimal effect on animal weight gain, did not cause any macroscopic or microscopic lesions, and did not change the plasma biochemical profile. However, colonization of the small and large intestines by an extraintestinal pathogenic E. coli strain was significantly increased. Our results show that FB(1) is a predisposing factor to infectious disease and that the pig can be used as a model for the study of the consequences of ingesting mycotoxin-contaminated food.

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.

The carcinogenicity of fumonisin B1 (FB1), a worldwide contaminant of corn produced by Fusaria species of fungi, has been tested recently in 2-year feeding studies in Fischer F344 rats and B6C3F1 mice. Inclusion of FB1 at 50 and 80 ppm in the diet induced liver tumors in female mice, and at 50 and 150 ppm induced renal tumors in male rats (22). In the present study, the kidneys from the rat bioassay were examined to characterize the various histopathological changes associated with renal tumor induction. In all high-dose (150 ppm) and mid-dose (50 ppm) male rats, and to a lesser extent in high-dose (100 ppm) female rats, there was evidence of sustained nephrotoxicity manifested as basophilia, apoptosis, cell regeneration, and simple tubule hyperplasia, affecting proximal convoluted tubules in the deep cortex, extending into the outer region of the outer stripe of outer medulla. A further alteration consisted of sporadic areas of interstitial hyalinization in deep cortex, suggestive of expanded basement membrane, coupled with tubule atrophy. The continued presence of nephrotoxicity throughout chronic exposure to FB1 suggested that renal tumor development may have been an outcome of sustained cell loss and compensatory regeneration. In some cases, preneoplastic tubules or incipient renal tumors presented an immature or fetal form in association with interstitial hyalinization. The renal tubule tumors induced by FB1 were typified by a rare, highly malignant, anaplastic variant capable of growth by infiltration. Of the 10 renal tubule tumors diagnosed in the mid-dose males, and the 16 in the high-dose males, 8 and 10, respectively, were graded as carcinomas. Anaplastic variants represented 50% of the mid-dose carcinomas and 80% of the high-dose carcinomas. One of the anaplastic carcinomas in a mid-dose male was a true sarcomatoid phenotype not previously recorded in the rodent. Metastatic invasion of the lung occurred with 25% of the mid-dose carcinomas and 50% of the high-dose carcinomas. It was speculated that FB1 may have been influencing the growth characteristics of the induced renal tumors via its inhibitory action on the synthesis of sphingolipids, which in turn, participate in regulating cell contact, growth, and differentiation, or alternatively by affecting cell adhesion molecules.

Experts from the Nordic countries (Denmark, Norway, Sweden, Finland and Iceland) have carried out an evaluation of fumonisins. The working group members concluded that, at that time point, it was not possible to carry out a complete risk assessment. However, it was recommended that the human daily' intake of fumonisins should be less than 1 microg/kg bw/day. Subsequently, the presence of the Fusarium mycotoxins fumonisin B1 and B2 (FB1 and FB2) in corn-based food on the Danish retail market has been determined. A total of 70 samples were analysed and 37% contained FB1 and 21% contained FB2. No fumonisins were found in sweet corn (canned or frozen), corn-on-the-cob, corn starch or gruel powder for babies. FB1 was found in about half of the corn flakes, corn snack and popcorn (not popped) samples, whereas FB2 was seen to a lesser extent. Both FB1 and FB2 were found in 75% or more of the corn flour, tacos and polenta samples. In general, the content of FB1 was in the range of 1-1000 micro/kg and the content of FB2 was in the range of 4-250 microg/kg. Corn-based foods are consumed in rather low amounts and irregularly among the Danish population and therefore it is not meaningful to calculate an average daily funonisin intake. An estimate for an 'eater' shows that the intake of fumonisins will not exceed 0.4 microg/kg bw/day.

Fumonisin B1 (FB1) is an inhibitor of sphinganine N-acyltransferase and the increase in the sphinganine/ sphingosine (Sa/So) ratio in urine or serum has been proposed as a biomarker to evaluate exposure to fumonisins. The objectives of this study were to (1) develop a liquid chromatographic method sufficiently sensitive to determine the low concentration of free Sa in male human urine, and (2) analyse So and Sa in human urine and monitor the Sa/So ratio in urine of humans exposed to FB1 in corn diets over 1 month. The liquid chromatographic method involved isolation from human urine of exfoliated cells followed by an extraction of free sphingoid bases and their separation and quantification by high performance liquid chromatography. The detection limits for So and Sa were 0.15 ng/ml in female urine (2 ml used) and 0.005 ng/ ml in male urine (60 ml used). Twenty-eight healthy adult volunteers consumed for 1 month a normal diet containing their homegrown corn potentially contaminated with FB1. Immediately preceding the start of the test, morning urine samples for the determination of So and Sa were collected from each person, and the corn samples used in cooking were obtained from each family for the determination of FB1. At the end of the test period, morning-urine samples were collected from each person and analysed again. The daily FB1 intakes were estimated and used to assess the relationship between them and the urinary Sa/So ratios in humans exposed to dietary FB1 over 1 month. All the homegrown corn samples contained FB1 ranging from 0.08 to 41.1 mg/kg, and the estimated daily FB1 intakes ranged from 0.4 to 740 microg/kg b.w./day. The 1-month monitoring results suggest that sphingolipid metabolism of humans could be affected by FB1 intake, the urinary Sa/So ratio may be useful for evaluating FB1 exposure when the contamination of FB1 is high, and that males are more sensitive to FB1 disruption of sphingolipid metabolism than females.

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

Fumonisin B1 (FB1) is a carcinogenic mycotoxin produced by the fungus Fusarium moniliforme in corn. Feeding of FB1 to rats causes acute liver injury, chronic liver injury progressing to cirrhosis, and sometimes terminates in hepatocellular carcinoma or cholangiocarcinoma. This study describes the histolopathology and changes in gene expression in the rat liver during short-term feeding of FB1. Male Fischer rats were fed either FB1 250 mg/kg or control diet, and were killed weekly for 5 weeks. FB1 caused a predominantly zone 3 'toxic' liver injury, with hepatocyte death due to necrosis and apoptosis. Hepatocyte injury and death were mirrored by hepatic stellate cell proliferation and marked fibrosis, with progressive disturbance of architecture and formation of regenerative nodules. Despite ongoing hepatocyte mitotic activity, oval cell proliferation was noted from week 2, glutathione S-transferase pi-positive hepatic foci and nodules developed and, at later time points, oval cells were noted inside some of the 'atypical' nodules. Northern blot (mRNA) analysis of liver specimens from weeks 3 to 5 showed a progressive increase in gene expression for alpha-fetoprotein, hepatocyte growth factor, transforming growth factor alpha (TGF-alpha) and especially TGF-beta1 and c-myc. Immunostaining with LC(1-30) antibody demonstrated a progressive increase in expression of mature TGF-beta1 protein by hepatocytes over the 5 week feeding period. The overexpression of TGF-beta1 may be causally related to the prominent apoptosis and fibrosis seen with FB1-induced liver injury. Increased expression of c-myc may be involved in the cancer promoting effects of FB1.

Fumonisin B1 (FB1), a mycotoxin produced by a common corn contaminant Fusarium moniliforme and a hepatocarcinogen in rats, has been previously suggested to act as a poor initiator, but a better promoter of gamma-glutamyltranspeptidase (GGT)-positive rat liver preneoplastic lesions. Using glutathione S-transferase-placental form (GSTP) as a more sensitive marker of initiation, we have further evaluated the initiating capacity of various doses of purified FB1 administered (a) intraperitoneally (i.p.) to male Sprague-Dawley (SD) rats for 4 days and (b) orally (PO) to male and female SD rats for 11 days. Compared to their respective controls, significant increases in GSTP-positive hepatocytes were observed in male rats administered FB1 i.p. at 10 mg/kg body weight/day for 4 days, as well as in male and female rats treated with 35 and 75 mg/kg body weight/day FB1 p.o. for 11 days. The percentage section area of liver occupied by GSTP-positive mini-foci comprising of three to 12 cells was increased significantly in male rats given 10 mg/kg FB1 i.p., or in p.o.-treated males and females with 75 mg/kg FB1. Both i.p. and p.o. FB1 treatments resulted in dose-related enhanced hepatocyte proliferation as measured by proliferating cell nuclear antigen (PCNA) labeling with significant increases in the number of PCNA-positive nuclei at the same i.p. and p.o. dose levels where the number of GSTP-positive cells were elevated. In all studies, enhanced PCNA and GSTP expression occurred at FB1 doses which, based on serum biochemical and histopathological data previously reported from our laboratory, were shown to be hepatotoxic. Therefore, our data suggest that in a manner similar to known genotoxic carcinogens, FB1 has the capacity to initiate GSTP-positive hepatocytes with their subsequent development into GSTP mini-foci at exposure levels that induce enhanced hepatocyte proliferation in response to liver toxicity. In SD rats, this occurs as early as within 4 days of i.p. treatment or 11 days of p.o. treatment.

The capacity of fumonisin B1 (FB1) to induce morphological transformation of cultured mammalian cells was assessed using BALB/3T3 A31-1-1 mouse embryo cells. FB1 with 90% purity was prepared from Fusarium proliferatum grown on whole corn. Cell growth was not inhibited by 48 hr of exposure at concentrations up to 1000 micrograms/ml. Moderate inhibition was induced by 6 days of exposure. In transformation assays with a 48-hr exposure, increases in transformed foci were observed at some concentrations; however, the responses were not reproducible. Prolonged exposure for up to 4 wk at 10, 100 and 500 micrograms/ml failed to induce increases in transformed foci. Analysis of combined results showed that only the increase induced by a 48-hr exposure at 500 micrograms/ml was significant. A trend test indicated the lack of a dose response for concentrations of 10-1000 micrograms/ml. FB1 seems to lack in vitro transforming activity.

For 30 days, two groups of three steers each were fed a diet of herd-mix and alfalfa hay (control) or the diet with part of the herd-mix replaced by corn grits contaminated with 400 micrograms/g FB1 and 130 micrograms/g FB2. Premortem examination involved liver functionality tests; serum analyses for AST, GGT, LDH, cholesterol, and total bilirubin; urinalysis; and analyses of the blood, urine, and feces for the presence of fumonisins or their metabolites. Postmortem examination involved necropsy, histopathology, and analysis of tissue for fumonisins. Results of the liver functionality test indicated some hepatobiliary compromise in the test animals. Unmetabolized FB1 and FB2 were detected in the feces (> or = 80%), whereas trace amounts were detected in the urine. Postmortem analysis of the tissues showed 2070 ng/g FB1 in the liver (SD: 1870), 97.3 ng/g FB1 in the muscle (SD: 41), and 23.4 ng/g FB1 in the kidney (SD: 8.7).

In the rat, the target organs of fumonisin B1, a mycotoxin produced by Fusarium moniliforme, are the kidney and liver. Fumonisin B1 is also hepatocarcinogenic in the rat and is associated epidemiologically with esophageal cancer in humans. We investigated the effect of a single intravenous dose of fumonisin B1 on cell proliferation, lesion development, and glutathione status in the major target organs of the rat. Male Sprague-Dawley rats were injected intravenously with fumonisin B1 at 0 or 1.25 mg/kg and were euthanized at 12 hr or, 1,2,3, or 5 days. An intraperitoneal injection of 5-bromo-2'-deoxyuridine at 100 mg/kg was given 90 min prior to euthanasia. In fumonisin B1 treated rats, serum cholesterol and serum urea nitrogen were elevated; however, the activity of hepatic enzymes was unaffected. Hepatic and renal glutathione concentrations were depressed at 12 and 24 hr, respectively, with subsequent recovery. Histologic changes were most prominent in the outer medulla of the kidney, with cell proliferation and apoptosis followed by nephrosis. Cell proliferation also occurred in the liver and esophagus, but in the absence of tissue injury. The labeling index peaked on day 1 for the liver and on day 3 for the esophagus. These results confirm that the primary target organ of fumonisin B1 in the rat is the kidney and support the concept that fumonisin B1-induced mitogenesis may be the mechanism of carcinogenesis.

Fourteen 1-day-old male turkeys were randomly assigned to two adjacent floor pens and fed balanced rations containing 0 and 75 mg fumonisin B1 (FB1)/kg for 18 weeks. Inclusion of FB1 in the ration caused decreased body weight gain on weeks 4, 10, and 12 during the trial. Turkeys fed 75 mg FB1/kg had significantly heavier livers after treatment for 18 weeks. Chronic FB1 exposure resulted in an increased total white blood cell count, absolute heterophil count, absolute lymphocyte count, and heterophil-to-lymphocyte ratio. No mortality was noted in turkeys in either treatment group. Turkeys are relatively resistant to chronic FB1 exposure.

Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme, a fungus that infects corn and other grains in the U.S. Fumonisin ingestion causes a variety of effects including equine leukoencephalomalacia and porcine pulmonary edema, and has been associated epidemiologically with human esophageal cancer. Fumonisin B1 produces growth inhibition and increased apoptosis in primary human keratinocyte cultures and in HET-1A cells. In order to set the doses for a 2-year tumor bioassay, male and female F344 rats were fed fumonisin B1 (99, 163, 234, and 484 ppm) for 28 days and the organs examined histologically. There was a dose dependent decrease in liver and kidney weights in the rats. The liver weight loss was accompanied by the induction of apoptosis and hepatocellular and bile duct hyperplasia in both sexes, with the female rats being more responsive at lower doses. The induction of tubular epithelial cell apoptosis was the primary response of the kidneys to dietary fumonisin B1. Apoptosis was present at all doses in the kidneys of the male rats, and occurred in the females only at 163, 234, and 484 ppm fumonisin B1. These results demonstrate that fumonisin B1 treatment causes a similar increase in apoptosis both in vivo and in vitro.

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 values in barrows given the combination diet were significantly decreased from those in barrows given the single toxin diets. It was concluded that AF and FB1 (from culture material), singly or in combination, can adversely affect clinical performance, serum biochemical, hematologic, and immunologic values and induce lesions in growing barrows. For most of the variables we evaluated under our study conditions and dosages of toxins, measurements were affected more by the combination diet than by either single toxin diet, and the toxic responses could be described as additive or more than additive, particularly for induction of liver disease.

Fusarium moniliforme culture material containing fumonisin B1 (FB1) was fed to white Pekin ducklings from 1 to 21 days of age. Four dietary treatments were prepared with 0, 100, 200, and 400 mg FB1/kg ration. Ducklings fed rations containing FB1 had a dose-dependent decrease in feed intake and weight gain. Increasing levels of FB1 in the ration were associated with increasing absolute organ weights of liver, heart, kidney, pancreas, and proventriculus. Liver sphinganine to sphingosine ratios increased significantly in ducklings fed FB1. Two of eight ducklings fed a ration containing 400 mg FB1/kg died prior to the termination of the experiment. Mild to moderate hepatocellular hyperplasia was evident in all ducklings fed FB1. Mild to moderate biliary hyperplasia was also noted in the liver sections of ducklings fed 400 mg FB1/kg in the ration. Ducklings, like other poultry, are relatively resistant to the toxic effects of FB1.

The mycotoxin fumonisin B1 (FB1) produced by Fusarium moniliforme in corn causes pulmonary edema in finishing swine. Effects of lower nonlethal amounts and effects in lactating sows with suckling pigs are unknown. An initial study was conducted to determine a nonlethal concentration of FB1 for lactating sows; whether ingested FB1 could be detected in the milk; and whether toxicosis could be detected in the pigs, as determined by necropsy. Another study was conducted to determine toxicosis in the pigs by measuring liver sphinganine-to-sphingosine ratio, and whether ingested FB1 affected T-lymphocyte function in sows and their pigs. Furthermore, sows of this study were maintained in controlled hot (27 to 32 C, 50 to 70% relative humidity) and thermoneutral (21 C, 55% relative humidity) environments to determine whether high temperature exacerbated the effects of FB1. In the first study, 100 micrograms of FB1/g of corn soybean meal diet was found to be nonlethal when fed for 14 days. Fumonisin B1 was not detected in the milk at 30 ppb and lesions were not found in the necropsied pigs, including 1 from a sow that died of porcine pulmonary edema syndrome after ingesting FB1 at a concentration of 175 ppm. In the second study, differences in liver sphinganine-to-sphingosine ratio of pigs were not found. Expressions of cell surface antigens on blood lymphocytes and lymphocyte proliferation response to various mitogens were not affected by FB1 or high temperature in sows or their pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats were injected intraperitoneally with saline or fumonisin B1 (FB1) at doses of 7.5 and 10.0 mg FB1/kg for 4 days. For each day of dosing, 24-hr urine samples were collected and analyzed for creatinine and protein content and the enzymes gamma-glutamyl-transpeptidase, lactate dehydrogenase, and N-acetyl-beta-D-glucosaminidase. Twenty-four hours after the last dose, animals were killed and kidneys removed for ion transport measurement and histopathology. Significant increases in urine volume and decreases in urine osmolality were observed in both FB1 dose groups. Creatinine excretion was decreased only in the 10 mg FB1/kg group on the final day of the study. Urine protein excretion was elevated in both treated groups and found to be due primarily to high-molecular-weight proteins indicative of increased glomerular permeability. Enzymuria, a marker of tubular cell damage, was also observed with increases in the urinary excretion of all three enzymes measured. In renal cortical slices tubular transport of the anion p-aminohippuric acid was reduced by 75-80% and cationic transport of tetraethylammonium was reduced by 40% in the FB1-treated animals. While these results suggest significant alterations in renal function, only minor histopathologic changes were observed in the kidneys of both dose groups. Results of the present study indicate that urine volume, proteinuria, enzymuria, and ion transport are sensitive indicators of early FB1-induced nephrotoxicity.

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.

Fumonisin B2 (FB2), a secondary metabolite of the fungus Fusarium moniliforme, was administered at a dose of 7.5 mg/kg body weight to male BD IX rats by ip injection or by gavage. FB2 was rapidly absorbed from the peritoneum, its level in plasma reaching a maximum within 20 min after injection. It was rapidly eliminated from plasma with a half-life of 26 min. After 24 hr, FB2 could not be detected in plasma (< 20 ng/ml). Analysis of rat plasma for FB2 following a gavage dose failed to detect any toxin over a 6-hr period after dosing. The elimination of FB2 in the urine and faeces was determined over a 3-day period after dosing. After i.p. injection, the mean urinary excretion over this period was 1.2% and faecal elimination accounted for 84.1% of the dose. Similarly, after dosing by gavage, 0.2 and 82.0% of the dose was recovered in urine and faeces, respectively. FB2 appeared to be excreted unmetabolized.

Fumonisins are a class of mycotoxins produced by Fusarium moniliforme and other Fusarium spp. These compounds are widely distributed in corn. Equine leukoencephalomalacia, pulmonary oedema in swine, and nephrotoxicity, hepatotoxicity and liver cancer in male rats, all of which are caused by toxic F. moniliforme, have been experimentally reproduced using fumisin B1 (FB1) (ca 90-94% purity). To investigate the effect of purified (> or = 99% purity) FB1, to compare the effects of FB1 in males and females, and to obtain dose-response information for FB1, three rats per sex were fed diets containing 0, 15, 50 or 150 FB1 for 4 weeks. Serum chemical, organ weight and histopathological evidence showed that 150 mg/kg FB1 was hepatotoxic in both sexes. Nephrosis was found in males fed > or = 15 mg/kg and females fed > or = 50 mg/kg FB1. Altered sphingolipid profiles, specifically increased free sphinganine concentrations and increased sphinganine:sphinogosine ratios, were found in the liver, kidney, serum and urine of FB1-fed rats. These findings support the hypothesis that in vivo toxicity caused by fumonisins may result from altered sphingolipid metabolism.

The pharmacokinetic fate of the mycotoxin fumonisin B1 (FB1) was investigated using 4 Holstein cows. Two animals each were administered FB1 intravenously (0.05 or 0.20 mg kg-1) and by oral gavage (1.0 or 5.0 mg kg-1). Blood samples were collected at specific time intervals over 12 hr postdosing, then daily for 13 more days, and analyzed for FB1, the hydroxylated aminopental metabolite, and their conjugates. Following intravenous dosing, the plasma-concentration profile of FB1 underwent a very rapid biexponential decrease, with toxin concentrations falling below detectable levels by 120 min postdosing. No known metabolites were detected in plasma. The similarity in pharmacokinetic parameters between the low- and high-dose animals suggests that FB1 distribution and elimination from blood was not dose-dependent at these levels of toxin administration. Following oral administration of the toxin, no FB1 or known metabolites could be found in the plasma, indicating no or very limited bioavailability in ruminants. The effects of FB1 on plasma-free sphinganine (Sa) and free sphingosine (So) concentrations were also determined. Following oral gavage at either dose, no effects on plasma sphingolipid concentration or Sa/So ratio were noted beyond typical daily variations. At the low intravenous dose (0.05 mg kg-1), changes in Sa or So concentrations were also not apparent. However, following intravenous administration at the higher dose (0.20 mg kg-1), the plasma Sa/So ratio was increased marginally in the one dosed cow, due essentially to a transient increase in Sa concentrations, which rose by approximately 60-65% over average predose levels; So levels remained relatively constant.

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.

The mycotoxin fumonisin B1 (FB1) was dosed as 14C-labelled FB1, to male vervet monkeys (Cercopithecus aethiops) both by intravenous (i.v.) injection (2 monkeys, dose 1.72 mg [86 kBq]/kg body weight) and by gavage (2 monkeys, dose 6.42 mg [321 kBq]/kg body weight). Excreta were collected over a 24-hr period, whereafter the monkeys were sacrificed and selected organs and contents of the gut collected to determine the distribution of the 14C-label. The bulk of the radioactivity recovered from tissue was found in the liver (mean of 1.92% in i.v.-dosed monkeys; 0.64% in gavage-dosed monkeys). Of the other organs analysed, the following mean amounts of radioactivity were recovered in organs of i.v.- and gavage-dosed monkeys, respectively: muscle, 0.62% and 0.14%; kidney, 0.37% and 0.03%; brain, 0.08% and 0.02%; lung, 0.07% and 0.03%; heart, 0.04% and 0.01%; spleen, 0.02% and < 0.01%; plasma, 0.66% and 0.12%; red blood cells, 0.11% and 0.01%; while a further 68.1% and 64.0% were recovered in excreta, bile, and the gut contents. Analysis of faeces and gut contents showed that radioactivity was due to FB1, its partially hydrolysed metabolites, and trace amounts of the fully hydrolysed aminopentol moiety. Analysis of bile showed an absence of hydrolysis products, indicating that hydrolysis occurred only in the gut, resulting in the removal of the tricarballylic acid moiety at the C14-position. Determination of FB1, levels in plasma following a gavage dose indicated that only limited amounts of FB1 were absorbed, as plasma levels peaked after 1-2 hr with levels below 210 ng/ml.

Fumonisin B1 (FB1) and fumonisin B2 (FB2) were determined in milk by liquid chromatography (LC) following immunoaffinity column cleanup. Recoveries from milk spiked with 5-50 ng each fumonisin/ml averaged 79-109%. The aminopentol hydrolysis product of FB1 (AP1) was determined by LC after cleanup on a C18 solid phase phase extraction column; mean recoveries were 69-83% at spiking levels of 50-100 ng AP1/ml milk. Detection limits were of the order 3-7 ng/ml for FB1 and FB2, and 20-25 ng/ml for AP1. A stability study showed no losses of FB1 and FB2 in milk under conditions of freezing, refrigeration and boiling. A transmission study using four cows dosed with pure FB1 either orally (1.0 and 5.0 mg FB1/kg b.w.) or by i.v. injection (0.05 and 0.20 mg FB1/kg b.w.) showed no detectable residues of FB1 or AP1 in the milk, with or without hydrolytic treatment with beta-glucuronidase/sulfatase to liberate any conjugates.