The Mycotoxin Fumonisin Induces Apoptosis in Cultured Human Cells and in Livers and Kidneys of Rats

Tolleson, William H.; Dooley, Kenneth L.; Sheldon, Winslow G.; Thurman, J D; Bucci, Thomas J.; Howard, Paul C.

doi:10.1007/978-1-4899-1379-1_21

Cited by 88 publications

(55 citation statements)

References 23 publications

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“…Hepatocellular injury and biliary epithelial hyperplasia have been noted in livers of cattle fed FB 1 , 14 but apoptosis of hepatocytes has been identified only in rats and rabbits. 2,23 The cause of the biliary and hepatocellular injury during fumonisin exposure is not known. Fumonisins inhibit ceramide synthase in the de novo synthesis of sphingosine, with increased sphinganine/sphingosine ratios in livers of intoxicated animals.…”

mentioning

confidence: 99%

Chronic Experimental Fumonisin Intoxication of Calves

Baker

Rottinghaus

1999

J VET Diagn Invest

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Fumonisins are structurally related mycotoxins produced by the mold Fusarium moniliforme, which is the most common fungal contaminant of com. Fumonisin (FB 1 ) is the most abundant of the fumonisins produced by F. moniliforme. The fumonisins cause encephalomalacia in horses 11 and pulmonary hypertension with pulmonary artery medial hypertrophy and right ventricular hypertrophy in swine, 4,21 are hepatotoxic in most animal species 3,[8][9][10]14,24 and carcinogenic in rats 6 and possibly people, 22 and are nephrotoxic in rats and rabbits. 8,24 Swine also exhibit altered myocardial function when exposed to fumonisins, and porcine cultured endothelium exhibits disruption of barrier function when FB 1 is present. 7,21 Previously, cattle fed fumonisins experimentally for short periods of time to determine the effects exhibited only minimal hepatic and immune function changes. 14,15 Cattle in feed lots are fed large quantities of corn for weight gain and occasionally develop pulmonary hypertension and congestive heart failure even at altitudes that are not usually considered a risk for pulmonary hypertension. This experiment was conducted to determine if cattle develop pulmonary hypertension in response to consumption of fumonisins for prolonged periods of time at altitudes that are not usually associated with pulmonary hypertension in cattle.Fusarium moniliforme was prepared as previously described. 26 The F. moniliforme culture material was ground to a fine powder and analyzed for FB 1 by high-performance liquid chromatography (HPLC) as previously described. 27 The culture material contained 5,500 mg FB 1 /kg. This F. moniliforme culture material was mixed with com lacking FB 1 , and the resulting mixture was reassayed. The average fumonisin B 1 , B 2 , and B 3 levels in the final corn mixture fed to cattle was 328 FB 1 , 89 ppm FB 2 , and 23 ppm FB 3 .Five Holstein steers weighing 86-127 kg were individually housed in pens enclosed in an unheated barn and fed either alfalfa/grass mixed hay and rolled corn (group A) or alfalfa/grass mixed hay and corn mixed with fumonisin culture material (group B). Cattle were purchased after being weaned, allowed to acclimate to the environment, and fed corn at an increasing amount over a period of 7 days to a final consumption level of 0.72% of body weight once daily in all calves. Following 1 week of dietary acclimation, group A cattle were fed rolled corn at the same rate as group B calves. Group B calves were acclimated to the fumonisincontaminated corn over a period of 7 days by blending on treated corn and fumonisin-contaminated corn until after 7 Received for publication February 10, 1998. days the diet was entirely fumonisin-contaminated corn fed at the rate of 0.72% of body weight. Cattle were weighed weekly throughout the experiment, and the amount of corn fed to each calf was adjusted accordingly. Because only minimal effects were evident in the fumonisin-fed cattle, the amount of corn fed group A and B calves was slowly increased over 7 days to 1.07% of body weight,...

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mentioning

confidence: 99%

Chronic Experimental Fumonisin Intoxication of Calves

Baker

Rottinghaus

1999

J VET Diagn Invest

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“…The doses used in this study were 0, 99, 163, 234, and 484 ppm FB 1 (26,28). Rats were fasted overnight and euthanized by asphyxiation with carbon dioxide and bled via the orbital sinus before necropsy.…”

Section: Methodsmentioning

confidence: 99%

“…This was first described as single-cell necrosis in livers of rats and mice treated with FB 1 (24,25) and later confirmed as apoptosis (26). FB 1 -induced hepatocellular and renal tubule apoptosis is reviewed elsewhere in this issue (27).…”

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confidence: 96%

Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat.

Howard

Warbritton

Voss

et al. 2001

Environ Health Perspect

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Fumonisin B1(FB1) is a fungal metabolite of Fusarium verticillioides (= F. moniliforme), a fungus that grows on many crops worldwide. Previous studies demonstrated that male BD IX rats consuming diets containing 50 ppm fumonisin B1 developed hepatocellular carcinomas. In our recent studies, diets containing FB1 at 50 ppm or higher concentrations induced renal tubule carcinomas in male F344/N/Nctr BR rats and hepatocellular carcinomas in female B6C3F1/Nctr BR mice. The carcinogenicity of FB1 in rats and mice is not due to DNA damage, as several laboratories have demonstrated that FB1 is not a genotoxin. FB1 induces apoptosis in cells in vitro. Including FB1 in the diets of rats results in increased hepatocellular and renal tubule epithelial cell apoptosis. In studies with F344/N/Nctr BR rats consuming diets containing up to 484 ppm FB1 for 28 days, female rats demonstrated more sensitivity than male rats in the induction of hepatocellular apoptosis and mitosis. Conversely, induction of renal tubule apoptosis and regeneration were more pronounced in male than in female rats. Induction of renal tubule apoptosis and hyperplasia correlated with the incidence of renal tubule carcinomas that developed in the 2-year feeding study with FB1 in the F344/N/Nctr BR rats. The data are consistent with the hypothesis that the induction of renal tubule carcinomas in male rats could be partly due to the continuous compensatory regeneration of renal tubule epithelial cells in response to the induction of apoptosis by fumonisin B1.

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“…None of these have reproduced the in vivo effects of toxic F. moniliforme isolates (30,(52)(53)(54). Conversely, the link between F. moniliforme and fumonisin has been independently established by several research groups; that is, the in vivo toxicities of corn (involved in ELEM outbreaks) naturally contaminated with F. moniliforme (9,55), culture materials of (toxic) F. moniliforme isolates, polar culture material extracts, and purified FB 1 are qualitatively the same (5,32,45,(56)(57)(58)(59)(60)(61). FB 2 , fumonisin B 3 (FB 3 ), and probably also hydrolyzed FB 1 (HFB 1 ) exert the same in vivo effects (62)(63)(64).…”

Section: Toxicology: Subchronic Effects Of Fumonisins In Ratsmentioning

confidence: 99%

“…Others have noted a transient increase in the 5-bromo-2´-deoxyuridine labeling index in esophageal epithelium 3 days following an iv injection of 1.25 mg/kg bw (82), which suggests that FB 1 may be mitogenic under some conditions. However, there is no evidence from subchronic (5,57,58,61) or chronic (32,73) feeding studies of purified FB 1 that the esophagus is a target organ. Furthermore, FB 1 (5 mg/kg bw/day for 5 weeks) had no effect on the number of esophageal papillomas produced in rats concurrently given the esophageal carcinogen N-methylbenzylnitrosamine (83).…”

Section: Other In Vivo Toxicologic Findings In Ratsmentioning

confidence: 99%

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

Voss

Riley

Norred

et al. 2001

Environ Health Perspect

122

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Fumonisins are produced by Fusarium moniliforme F. verticillioides) and other Fusarium that grow on corn worldwide. They cause fatal toxicoses of horses and swine. Their effects in humans are unclear, but epidemiologic evidence suggests that consumption of fumonisin-contaminated corn contributes to human esophageal cancer in southern Africa and China. Much has been learned from rodent studies about fumonisin B1(FB1), the most common homologue. FB1 is poorly absorbed and rapidly eliminated in feces. Minor amounts are retained in liver and kidneys. Unlike other mycotoxins, fumonisins cause the same liver cancer promotion and subchronic (studies (3/4) 90 days) liver and kidney effects as (italic)F. moniliforme. FB 1 induces apoptosis of hepatocytes and of proximal tubule epithelial cells. More advanced lesions in both organs are characterized by simultaneous cell loss (apoptosis and necrosis) and proliferation (mitosis). Microscopic and other findings suggest that an imbalance between cell loss and replacement develops, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide synthase, and disrupt sphingolipid metabolism and, theoretically, sphingolipid-mediated regulatory processes that influence apoptosis and mitosis. Liver sphingolipid effects and toxicity are correlated, and ceramide synthase inhibition occurs in liver and kidney at doses below their respective no-observed-effect levels. FB1 does not cross the placenta and is not teratogenic in vivoin rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses. These data have contributed to preliminary risk evaluation and to protocol development for carcinogenicity and chronic toxicity studies of FB1 in rats and mice.

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The Mycotoxin Fumonisin Induces Apoptosis in Cultured Human Cells and in Livers and Kidneys of Rats

Cited by 88 publications

References 23 publications

Chronic Experimental Fumonisin Intoxication of Calves

Chronic Experimental Fumonisin Intoxication of Calves

Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat.

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

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