fumonisin-b1 and Chemical-and-Drug-Induced-Liver-Injury

Cancer induction by the non-genotoxic mycotoxin, fumonisin B1, has been investigated by studying the mechanisms involved during cancer initiation and promotion in rat liver. Cancer initiation is effected through a toxic-proliferative response while the inhibitory effect on hepatocyte cell proliferation appears to be a key aspect determining cancer promotion. Dose-response effects of the fumonisins on the induction of early neoplastic lesions in both long- and short-term animal experiments have been established. The biphasic response of FB1 on hepatocyte proliferation will be discussed in relation to the known mechanisms of cancer induction by the genotoxic hepatocarcinogens. Recent investigations regarding the effect of the fumonisins on lipid biosynthesis and its inhibitory effect on hepatocyte growth stimulatory responses in vitro will be highlighted. Integration of our current knowledge regarding the carcinogenic potential of the fumonisins in setting a realistic and applicable risk assessment model for this non-genotoxic carcinogen will finally be addressed.

Topics: Animals; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Fumonisins; Humans; Liver Neoplasms, Experimental; Mycotoxins; Rats; Risk Factors

In a 196-day feeding trial, 48 male crossbred rabbits (New Zealand × Chinchilla) were randomly assigned and fed varied dietary fumonisin levels of 0.13, 5.0, 7.5 and 10.0 mg fumonisin B(1)/kg diet constituting treatments 1 (control), 2, 3 and 4 respectively. Five animals were randomly selected, stunned and killed per treatment. Relative weight of various visceral organs examined except heart and adrenal gland were significantly (p < 0.05) influenced by the dietary treatments. Liver and spleen weights of rabbits fed 10.0 mg fumonisin per kg were significantly (p < 0.05) lower than those fed control diet and diet 2. Kidney and testes weights were significantly (p < 0.05) lower in rabbits fed control diet and increased with increase in the dietary fumonisin levels. Histological examination of the organs revealed that rabbits fed diets 2, 3 and 4 showed increased severe lesion of approximately 20%, 40% and 60%, respectively, of the total slides examined for each treatment. Forty per cent and 80% of the rabbits fed diets containing 7.5 and 10.0 mg/kg fumonisin, respectively, showed severe necrosis whereas 40%, 60% and 20% of the rabbits fed 5.0, 7.5 and 10.0 mg/kg, respectively, showed mild–moderate liver necrosis/lesions as compared with non-significant lesion observed in the controls. Testicles of rabbits fed diets 3 and 4 showed mild–moderate lesions and sertoli cell degeneration. Tunica mucosa erosion was observed and predominant in the stomach and small intestine of rabbits fed 7.5 and 10.0 mg fumonisin per kg diet. This suggested that fumonisin B(1) above 5.0 mg/kg in rabbit diet is toxic to body organs with potential to induce their hypofunction or total damage.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chemical and Drug Induced Liver Injury; Diet; Dose-Response Relationship, Drug; Enteritis; Fumonisins; Kidney Diseases; Male; Rabbits; Stomach Diseases; Testicular Diseases

Obesity, which is a worldwide public health issue, is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. We investigated whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. Thus, metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. Mice received a high-fat diet (HFD) or normal chow diet (CHOW) for 15 weeks. Then, during the last three weeks, mice were exposed to these diets in combination or not with FB1 (10 mg/kg body weight/day) through drinking water. As expected, HFD feeding induced significant body weight gain, increased fasting glycemia, and hepatic steatosis. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. These results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Dysbiosis; Fumonisins; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Obesity

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

Previous studies by us or others have shown that endoplasmic reticulum (ER) stress was activated by fumonisin 1 (FB1) exposure, which is considered to be a critical event in the FB1-induced toxic effect. However, the detailed mechanisms underlying FB1-induced ER stress-mediated liver toxicity remain elusive. The objectives of the present study were designed to address the following issues: (1) the contribution of each arm of the unfolded protein response (UPR); (2) the downstream targets of ER stress that mediated FB1-induced liver toxicity; and (3) the relationship between ER stress and oxidative stress triggered by FB1. We also investigated whether the inhibition of ER stress by its inhibitor could offer protection against FB1-induced hepatotoxicity in vivo, which has not been critically addressed previously. The results showed that the activation of the IRE1α axis, but not of the PERK axis, of UPR contributed to FB1-induced ER stress-mediated hepatocyte toxicity; the activation of the Bax/Bak-mediated mitochondrial pathway lay downstream of IRE1α to trigger mitochondrial-dependent apoptosis in response to FB1; FB1-induced oxidative stress and ER stress augmented each other through a positive feedback mechanism; tauroursodeoxycholic acid (TUDCA)-mediated ER stress inactivation is an effective approach to counteract FB1-induced hepatotoxicity in vivo. The data of the present study allow us to better understand the mechanisms of FB1-induced hepatotoxicity.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum Stress; Endoribonucleases; Fumonisins; Hepatocytes; Humans; Liver; Oxidative Stress; Protein Serine-Threonine Kinases; Unfolded Protein Response

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

The genus Fusarium, especially F. verticillioides and F. proliferatum, has been found in several agricultural products worldwide, especially in maize. Regardless the occurrence of symptoms, the presence of Fusarium in maize constitutes an imminent risk due to its ability to produce fumonisins, mycotoxins with proven carcinogenic effect on rats, swine, and equines and already classified as possible carcinogens to humans. The toxicity of incremental levels of fumonisin B1 (FB1), that is, 50, 100, and 200 mg FB1/kg diet, and the role of Lactobacillus delbrueckii subsp. lactis DSM 20076 (LL) and Pediococcus acidilactici NNRL B-5627 (PA) supplementation in counteracting the FB1 effects in intoxicated rats were monitored over a period of 4 weeks. Effects on the feed intake and body weight gain were noticed. A significant (p ≤ 0.05) increase in the level of liver and kidney functions markers and DNA fragmentation was also noticed in rat groups T100 and T200. The lactic acid bacteria (LAB) supplementation could bring back the normal serum biochemical parameters in rats fed on fumonisin B1-contaminated diets (T50 and T100) compared to FB1-treated groups. In rats of high-dosage dietary groups supplemented with LAB (T200-LL and T200-PA), the supplementation reduced the serum activity levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine by 11.3, 11.9, 32, and 20%, respectively. DNA fragmentations were observed in the rat group treated with 200 mg FB1 after 3 weeks, while fragmentation was noticed in treated groups with 100 and 200 mg FB1 after 4 weeks. No DNA fragmentation was apparent in FB1-treated rats co-administered the LL or PA strain. These results suggest that in male rats consuming diets containing FB1, there is a time- and dose-dependent increase in serum enzyme activities and DNA lesions. Moreover, Lb. delbrueckii subsp. lactis (LL) and P. acidilactici (PA) strains have a protective effect against antigenotoxicity and precancerous lesions.

Topics: Administration, Oral; Animals; Chemical and Drug Induced Liver Injury; DNA Damage; DNA Fragmentation; Food Contamination; Fumonisins; Lactobacillus; Male; Probiotics; Rats; Rats, Sprague-Dawley; Teratogens; Treatment Outcome

The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis.

Topics: Adenoma, Bile Duct; Adenoma, Liver Cell; Animals; Chemical and Drug Induced Liver Injury; Diet; Dose-Response Relationship, Drug; Drug Administration Schedule; Fumonisins; Heterozygote; Homozygote; Liver; Liver Neoplasms; Mice; Mice, Transgenic; Random Allocation; Tumor Suppressor Protein p53

It was hypothesized that a mycotoxin binder, Grainsure E, would inhibit adverse effects of a mixture of fumonisin B1, deoxynivalenol, and zearalenone in rats. For 14 and 28 days, 8-10 Sprague-Dawley rats were fed control diet, Grainsure E (0.5%), toxins (7 μg fumonisin B1/g, 8 μg of deoxynivalenol/g and 0.2 μg of zearalenone/g), toxins (12 μg of fumonisin B1/g, 9 μg of deoxynivalenol/g, and 0.2 μg of zearalenone/g + Grainsure E), or pair-fed to control for food intake of toxin-fed rats. After 28 days, decreased body weight gain was prevented by Grainsure E in toxin-fed female rats, indicating partial protection against deoxynivalenol and fumonisin B1. Two effects of fumonisin B1 were partly prevented by Grainsure E in toxin-fed rats, increased plasma alanine transaminase (ALT) and urinary sphinganine/sphingosine, but sphinganine/sphingosine increase was not prevented in females at the latter time point. Grainsure E prevented some effects of fumonisin B1 and deoxynivalenol in rats.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diet; Female; Fumonisins; Kidney Diseases; Liver Diseases; Male; Mycotoxins; Rats; Rats, Sprague-Dawley; Trichothecenes; Zearalenone

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

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

Fumonisins are causative agents of diseases in mice and rats, including liver and renal toxicities, as well as cancer, and are specific inhibitors of ceramide synthase in the metabolism of sphingolipid. The purpose of this study was to determine whether an elevated level of sphingoid base 1-phosphate was related to the expressions of metabolism enzymes in the liver of fumonisin B1 (FB1)-treated mice and acted as a contributing factor to hepatotoxicity. In our previous study, FB1 was confirmed to be toxic to both liver and kidneys, coupled with simultaneous elevation of sphinganine 1-phosphate. ICR mice were treated intraperitoneally with 10 mg/kg/day FB1 for 5 days, with the concentrations of sphingolipid metabolites in the serum and liver measured using HPLC following Bligh-Dyer extraction. The levels of sphingoid bases and their 1-phosphates in the serum and liver were markedly elevated in response to treatment with FB1. In the liver, FB1 increased the expression of sphingosine kinase and inhibited the expression of sphingosine 1-phosphate lyase. The cleaved form of caspase-3 was detected in the liver of FB1-treated mice, indicating the occurrence of apoptosis in the liver following exposure to FB1. The expressions of proapoptotic signaling molecules, such as phosphorylated forms of c-Jun N-terminus kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK), were increased in the liver of FB1-treated mice. In conclusion, these results suggest the elevation of sphingoid base 1-phosphate, as a result of the activation of sphingosine kinase and the inhibition of sphingosine 1-phosphate lyase, may be a major target for FB1-induced hepatotoxicity via the activation of an apoptotic signaling pathway.

Topics: Aldehyde-Lyases; Animals; Caspase 3; Chemical and Drug Induced Liver Injury; Fumonisins; Liver; Lysophospholipids; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Mycotoxins; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Fumonisin B1 is a mycotoxin produced by Fusarium verticillioides, frequently associated with corn. It produces species-specific and organ-specific toxicity, including equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in most animal species. Fumonisin B1 perturbs sphingolipid metabolism by inhibiting ceramide synthase. Our previous studies in male mice indicated that fumonisin B1-induced hepatotoxicity is modulated by the localized activation of cytokines in liver macrophages and other cell types. In the current study, male athymic nude mice and their wild type counterparts (WT), the latter with or without depletion of T cells, were treated subcutaneously with fumonisin B1 at 2.25 mg/kg/day for 5 days and sampled 24 h after the last injection. Depletion of T cells in WT was achieved by a single intravenous injection of 50 microg monoclonal antibody against Thy-1.2 surface antigen of mature peripheral T lymphocytes 24 h before the first fumonisin B1 treatment. The depletion of T cells nearly abolished fumonisin B1-mediated liver toxicity as indicated by the near normal concentrations of circulating liver enzymes and by enumeration of apoptotic hepatocytes. There was no difference in the fumonisin B1-induced elevation in circulating liver enzymes between WT and nude mice. Fumonisin B1-induced mRNA expression of tumor necrosis factor alpha and interleukin-1alpha was observed in nude and WT mice but not in T cell-depleted mice. Hepatotoxic response to fumonisin B1 was unaltered in mice lacking natural killer cells. This study suggested that T cells and corresponding proinflammatory cytokines have a vital role in mediating fumonisin B1-induced hepatic toxicity.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Chemical and Drug Induced Liver Injury; Cytokines; Fumonisins; Isoantibodies; Macrophages; Male; Mice; Mice, Nude; T-Lymphocytes

Sphingolipids are important components of cell structure and cell signaling. Both external and internal stimuli can alter levels of cellular sphingolipids by regulating enzyme activities associated with sphingolipid metabolism. Fumonisin B1, mycotoxin produced by Fusarium verticillioides, is a reportedly specific inhibitor of ceramide synthase. In order to test our hypothesis whether ceramide synthase inhibition by fumonisin B1 alters other sphingolipid-metabolizing enzymes, we investigated the changes in free sphingoid bases and sphingomyelin (SM) and activities of key enzymes for their metabolism, sphingomyelinase (SMase), serine palmitoyltransferase (SPT), and sphingosine kinase (SPHK) in mouse liver. The hepatic free sphingoid bases increased significantly following five daily treatments with fumonisin B1 in mice. The activity of acidic SMase was enhanced by fumonisin B1, accompanied with a decrease in liver SM content. The expression and activities of SPT and SPHK1 in liver increased significantly following fumonisin B1 treatment. Another hepatotoxicant acetaminophen caused liver regeneration similar to fumonisin B1 but did not produce similar effects on liver sphingolipid-metabolizing enzymes, suggesting that activation of sphingolipid metabolism was not a consequence of hepatocyte regeneration. Data suggest that ceramide synthase inhibition by fumonisin B1 treatment stimulates sphingolipid-metabolizing systems to maintain a balance of cellular sphingolipids.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fumonisins; Injections, Subcutaneous; Isoenzymes; Liver; Mice; Mice, Inbred C57BL; Mycotoxins; Oxidoreductases; Phosphotransferases (Alcohol Group Acceptor); Serine C-Palmitoyltransferase; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingomyelins

Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB1 are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor alpha (TNFalpha) is an important modulator of FB1 hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB1 hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB1 in saline for three successive days. Gadolinium significantly attenuated FB1-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB1-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB1 treatments individually increased the expression of selected cell signal factors; e.g., TNFalpha, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin beta, interferon gamma, and transforming growth factor beta1; gadolinium chloride did not alter FB1-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB1 hepatotoxicity. Decreased FB1-induced sphinganine accumulation and increased protective TNFalpha signaling by gadolinium chloride may in part account for its ameliorating effect on FB1 liver damage.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cytokines; Female; Fumonisins; Gadolinium; Gene Expression; Hepatitis, Animal; Hepatocytes; Immunohistochemistry; In Situ Nick-End Labeling; Injections, Intravenous; Injections, Subcutaneous; Kupffer Cells; Mice; Mice, Inbred BALB C; Receptors, Cytokine

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

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

Fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides present on corn and corn-based products, causes species- and organ-specific diseases. The hepatotoxic effects of FB(1) in mice have been closely correlated with the accumulation of free sphinganine, a marker for ceramide synthase inhibition, and reduced biosynthesis of more complex sphingolipids. It has been shown that FB(1) modulates expression of many cell signaling factors. In the current study we used myriocin, a specific inhibitor of serine palmitoyltransferase, to investigate the role of free sphinganine accumulation in FB(1)-induced hepatotoxicity and increased expression of selected signaling genes in BALB/c mice. The mice were pretreated daily with intraperitoneal injection of 1.0 mg/kg myriocin 30 min before subcutaneous injections of 2.25 mg/kg of FB(1) for 3 days. Results showed that myriocin alone was not hepatotoxic and the combination of myriocin plus FB(1) completely prevented the FB(1)-induced elevation of hepatic free sphinganine and prevented the FB(1)-induced induction of selected cell signaling genes, suggesting that accumulation of free sphinganine and/or its metabolites contribute to the FB(1)-modulation of the cell signaling factors. However, the combination of myriocin and FB(1) did not prevent FB(1)-increased concentration of plasma alanine aminotransferase and only slightly attenuated aspartate aminotransferase; it did not affect the FB(1)-induced hepatocyte apoptosis or increased cell proliferation. A longer combined treatment of myriocin and FB(1) was highly toxic. The hepatotoxic effects in mice seen in this study are most likely due to a combination of factors including accumulation of free sphinganine, depletion of more complex sphingolipids and sphingomyelin, or other unknown mechanisms.

Topics: Acyltransferases; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fumonisins; Mice; Mice, Inbred BALB C; Serine C-Palmitoyltransferase; Sphingolipids; Sphingosine

Fumonisin B1 (FB1), a mycotoxin from Fusarium verticillioides, disrupts sphingolipid metabolism by inhibiting ceramide synthase leading to modulation of cytokines including tumor necrosis factor (TNF) alpha. Current study investigated the effect of interrupting TNFalpha signaling, known to be involved in FB1 hepatotoxicity. Male C57BL/6N mice were injected intravenously once with anti-TNFalpha antibodies or treated with pentoxifylline at 150 mg/kg intraperitoneally twice a day for 5 days to inhibit TNFalpha production before and during subcutaneous injection of 2.25mg FB1/kg daily for 5 days; mice were sampled one day after the last treatment. Results showed that both anti-TNFalpha antibodies and pentoxifylline did not prevent FB1 hepatotoxicity; the latter was somewhat augmented, indicated by increases in circulating alanine aminotransferase and aspartate aminotransferase, and incidence of apoptotic hepatocytes. Anti-TNFalpha antibodies did not alter FB1-induced accumulation of free sphingoid bases or expression of TNFalpha in liver following the FB1 treatment. Pentoxifylline significantly reduced accumulation of free sphinganine and expression of TNFalpha. Neither anti-TNFalpha antibodies nor pentoxifylline altered FB1-induced expression of interleukin-12, interferongamma, lymphotoxinbeta, and c-myc. Expression of c-myc, an inducer of cell death, increased after interference with TNFalpha signaling. These findings suggest a dual role of TNFalpha signaling activation in FB1 hepatotoxicity.

Topics: Alanine Transaminase; Analysis of Variance; Animals; Antibodies; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; DNA Primers; Fumonisins; Gene Expression; Immunohistochemistry; In Situ Nick-End Labeling; Liver; Male; Mice; Mice, Inbred C57BL; Mycotoxins; Pentoxifylline; Polymerase Chain Reaction; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha

Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB1, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB1/kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB1 in CBL but not in NZBW. FB1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB1-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB1 was equal in both strains of mice. The NZBW strain lacked the FB1-induced increases in the expression of liver tumor necrosis factor alpha, interferon gamma, receptor interacting protein (RIP), and tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB1 hepatotoxicity.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Cytokines; Fumonisins; Hepatitis; Hepatitis, Animal; Immunity, Innate; Liver; Lupus Vulgaris; Male; Mice; Mice, Inbred Strains; Signal Transduction; Sphingosine

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides found on corn and corn-based foods. It causes equine leukoencephalomalacia, porcine pulmonary edema, and liver and kidney damage in most animal species. Fumonisin B(1) perturbs sphingolipid metabolism by inhibiting ceramide synthase activity, leading to the production of cell signaling factors including tumor necrosis factor alpha (TNF-alpha). The signal pathways of TNF-alpha are important factors in the pathogenesis of FB(1) hepatotoxicity. In the present study, female BALB/c mice were treated daily with 750 mg/kg silymarin by gavage and 2.25 mg/kg FB(1) subcutaneously for 3 days. Then, 1 day after the last FB(1) injection, the mice were euthanized and blood and tissues were sampled for analyses. Silymarin significantly diminished FB(1)-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase activities and the number of apoptotic hepatocytes, while it augmented hepatocyte proliferation indicated by an increase in proliferating cells. Silymarin dramatically potentiated FB(1)-induced accumulation of free sphinganine and sphingosine in both liver and kidney. Silymarin itself slightly increased expression of hepatic TNF-alpha; however, it prevented the FB(1)-induced increases in TNF-alpha, TNF receptor 1, TNF receptor-associated apoptosis-inducing ligand, lymphotoxin beta, and interferon gamma. The induction of transforming growth factor beta1 expression in liver following FB(1) treatment was not affected by silymarin. These findings suggest that silymarin protected against FB(1) liver damage by inhibiting biological functions of free sphingoid bases and increasing cellular regeneration.

Topics: Acyltransferases; Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Carcinogens, Environmental; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cytokines; Female; Fumonisins; Immunohistochemistry; In Situ Nick-End Labeling; Kidney; Liver; Mice; Mice, Inbred BALB C; Nuclease Protection Assays; Proliferating Cell Nuclear Antigen; Serine C-Palmitoyltransferase; Silymarin; Sphingosine

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

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

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

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

Fumonisins are a group of mycotoxins that alter sphingolipid biosynthesis and induce leukoencephalomalacia in horses and pulmonary edema in pigs. Experimental administration of fumonisin induces hepatotoxicity in all species, including cattle, as well as nephrotoxicity in rats, rabbits, and sheep. We investigated the hepatotoxicity and nephrotoxicity of fumonisin B(1) to calves. Ten milk-fed male Holstein calves aged 7 to 14 days were instrumented to obtain blood and urine. Treated calves (n = 5) were administered fumonisin B(1) at 1 mg/kg, iv, daily and controls (n = 5) 10 ml 0.9% NaCl, iv, daily until euthanized on day 7. Fumonisin B(1)-treated calves were lethargic and had decreased appetite from day 4 onward, serum biochemical evidence of severe liver and bile duct injury, and impaired hepatic function. Treated calves also had biochemical evidence of renal injury that functionally involved the proximal convoluted tubules. Sphinganine and sphingosine concentrations in liver, kidney, lung, heart, and skeletal muscle were increased in treated calves. Sphinganine, but not sphingosine, concentration was increased in brains of treated calves. In fumonisin B(1)-treated calves, hepatic lesions were characterized by disorganized hepatic cords, varying severity of hepatocyte apoptosis, hepatocyte proliferation, and proliferation of bile ductular cells. Renal lesions in treated calves consisted of vacuolar change, apoptosis, karyomegaly, and proliferation of proximal renal tubular cells, as well as dilation of proximal renal tubules, which contained cellular debris and protein. This is the first report of fumonisin B(1)-induced renal injury and organ sphingolipid alterations in cattle.

Topics: Animals; Animals, Suckling; Anorexia; Bile Ducts; Carboxylic Acids; Cattle; Chemical and Drug Induced Liver Injury; Fumonisins; Heart; Hemodynamics; Injections, Intravenous; Kidney; Kidney Function Tests; Kidney Tubules, Proximal; Liver; Liver Function Tests; Lung; Male; Muscle, Skeletal; Mycotoxins; Myocardium; Sleep Stages; Sphingosine; Tissue Distribution

Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides and related fungi infests corn and other cereals, and causes a variety of toxic effects in different mammalian species. Hepatotoxicity is a common toxic response in most species. The cellular responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a corresponding induction of tumor necrosis factor alpha (TNFalpha). We recently reported that FB1 hepatotoxicity was considerably reduced in a mouse strain lacking tumor necrosis factor receptor 2 (TNFR2 or TNFR1b). To further investigate the relative contribution of the two TNFalpha receptors (TNFR1 and TNFR2 or P55 and P75 receptors) we evaluated the hepatotoxicity of FB1 in male C57BL/6J mice (WT) and a corresponding TNFR1 knockout (TNFRKO) strain, genetically modified by a targeted deletion of this receptor. The hepatotoxic effects of five daily injections of 2.25 mg/kg per day of FB1 were observed in WT but were reduced in TNFRKO, evidenced by the microscopic evaluation of the liver and increased concentrations of circulating alanine aminotransferase and aspartate aminotransferase. FB1 induced the expression of TNFalpha, and similar increases in free sphinganine and sphingosine in livers of both WT and TNFRKO mice. Results indicated that both P55 and P75 receptors are required for FB1-induced hepatotoxicity and TNFalpha plays an important role in such response in mouse liver.

Topics: Animals; Antigens, CD; Carboxylic Acids; Chemical and Drug Induced Liver Injury; Fumonisins; Leukocyte Count; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mycotoxins; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Sphingolipids

Fumonisin B1 (FB1), a potent mycotoxin prevalent in corn, is a carcinogen and causative agent of various animal diseases. Species and sex variations to chronic FB1 toxicity have been reported. Free sphingoid bases and cytokine levels are the two major biochemical alterations of FB1 in vivo and may explain any sex differences in FB1 toxicity. Male and female BALB/c mice (5/group) were injected subcutaneously with either saline vehicle or 2.25 mg/kg/day of FB1 for 5 days. One day after the last injection females showed a greater increase in circulating alanine aminotransferase and greater number of apoptotic cells in liver after FB1 treatment than males, indicating greater hepatotoxicity. Peripheral leukocytic counts, including neutrophils, were increased in females only after FB1 treatment. The increased toxicity in females correlated with a greater increase of sphinganine and sphingosine levels in liver after FB1 treatment compared to males. No sex differences in kidney sphinganine or sphingosine levels were observed after FB1 treatment. Previously we have shown the induction of tumor necrosis factor alpha (TNFalpha) in FB1-induced hepatotoxicity. While in males FB1 treatment caused increased expression of TNFalpha, interleukin (IL)-12 p40, interferon gamma (IFNgamma), IL-1beta, IL-6 and IL-10, females showed an increased expression of IL-6 only, and a downward modulation of IFNgamma, indicating gender differences in cytokine pathways in liver activated by FB1. The basal expression of TNFalpha, IL-12 p40, IL-1beta and IFNgamma in liver of females was higher compared to males. Gender differences in alterations of free sphingoid bases and cytokine modulation after FB1 treatment suggest their possible involvement in sex-dependent differential hepatotoxicity in mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carboxylic Acids; Carcinogens, Environmental; Chemical and Drug Induced Liver Injury; Cytokines; Erythrocyte Count; Female; Fumonisins; In Vitro Techniques; Kidney; Leukocyte Count; Liver; Male; Mice; Mice, Inbred BALB C; Mycotoxins; Sex Factors; Sphingosine

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

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

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

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

Pregnant Charles River CD1 mice were treated with a semipurified extract of Fusarium moniliforme culture containing 0, 12.5, 25, 50 or 100 mg FB1/kg each day orally (diluted in distilled water) between gestational days (GD) 7 and 15 to evaluate the developmental toxicity of FB1. Following sacrifice of dams on GD 18, litters were examined for gross abnormalities and divided equally for skeletal or visceral examination by routine techniques. Significant maternal mortality was observed at doses of 50 and 100 mg FB1/kg. Dose-dependent decreases in maternal body weight gains, number of live offsprings per litter, and mean body weight of the offspring were produced at FB1 doses of 25 mg/kg or higher. The percentage of implants resorbed increased at all doses in a dose-dependant manner. A dose-dependant increase, except at the lowest dose tested, in the incidence of ossification deficits involving digits and sternum, short and wavy ribs, and hydrocephalus of lateral and third ventricles was also evident. Cleft palate was seen only at the highest FB1 dose. Maternal intoxication manifested as a dose-dependant increase in the severity of ascites associated mainly with increased histopathologic scores reflecting hepatocellular damage at day 18. Concommittant increases in serum alanine amino transferase (ALT) on GD 12, reflecting parenchymal liver cell damage, was also observed at all doses above 12.5 mg of FB1/kg. These results suggest that FB1-containing F. moniliforme culture extract is developmentally toxic in mice, and that this toxicity may be mediated by maternal hepatotoxicity.

Topics: Abnormalities, Drug-Induced; Animals; Chemical and Drug Induced Liver Injury; Cleft Palate; Dose-Response Relationship, Drug; Female; Fetal Resorption; Fumonisins; Fusarium; Hydrocephalus; Litter Size; Mice; Mycotoxins; Pregnancy; Pregnancy Complications

Fumonisins are potent inhibitors of sphingolipid biosynthesis produced by several Fusarium species. Consumption of corn or corn products infected with F. moniliforme, or high levels of fumonisins, is associated with several animal diseases. In a 4-wk feeding study, the concentration of fumonisin B1 that caused nephrotoxicity in Sprague-Dawley rats was much less than that required to cause hepatotoxicity. This retrospective study shows a close correlation between the extent and severity of ultrastructural lesions and the degree of disruption of sphingolipid metabolism. The kidney was more sensitive to fumonisin B1-induced disruption of sphingolipid metabolism than liver with significant elevation of free sphingosine, free sphinganine, and the free sphinganine:free sphingosine ratio in rats fed 15, 50 and 150 micrograms/g fumonisin B1. Accumulation of free sphinganine and elevation of the free sphinganine:free sphingosine ratio in urine closely reflected the changes that occurred in kidney. The accumulated sphinganine and elevation of the free sphinganine:free sphingosine ratio was associated with accumulation of cells in urine. Thus, urine rather than serum is the fluid of choice for detecting elevated free sphingoid bases generated as a consequence of fumonisin-induced kidney damage.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diet; Female; Fumonisins; Kidney; Kidney Diseases; Liver; Male; Microscopy, Electron; Mycotoxins; Rats; Rats, Sprague-Dawley; Sphingolipids; Sphingosine

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

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

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

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