fumonisin-b1 and Proteinuria

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

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

Male rats were gavaged with fumonisin B1 (FB1) once daily for 11 consecutive days at doses of 0, 1, 5, 15, 35, and 75 mg FB1/kg body weight. Urine osmolality (at 5-75 mg FB1/kg) and organic ion transport in kidney slices (at 5-75 mg FB1/kg) were reduced. Urinary excretion of protein (at 15-75 mg FB1/kg) and of the enzymes LDH (at 5-75 mg FB1/kg), NAG (at 5-75 mg FB1/kg) and GGT (at 15-75 mg FB1/kg) were increased. These findings were indicative of glomerular and tubular toxicity. Histopathologic changes in the kidney consisted of necrosis of tubular epithelia of variable extent accentuated in the inner cortex. These changes were present at 1 and 5 mg FB1/kg and were more pronounced at 15-75 mg FB1/kg. Serum enzymes indicative of hepatotoxicity (ALT, GGT) were elevated compared to controls at 75 mg FB1/kg only. There were noticeable increases in mitotic figures in hepatocytes at 35-75 mg FB1/kg, while single cell necroses were increasingly numerous from 15-75 mg FB1/kg. The kidneys were considered to be the primary target organs in this study.

Topics: Acetylglucosaminidase; Animals; Creatinine; Fumonisins; gamma-Glutamyltransferase; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Leukocyte Count; Liver; Male; Mycotoxins; Osmolar Concentration; Proteinuria; Rats; Rats, Sprague-Dawley; Transaminases; Urine; Weight Gain

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.

Topics: Animals; Biomarkers; Carcinogens, Environmental; Creatinine; Electrophoresis, Polyacrylamide Gel; Fluorometry; Fumonisins; gamma-Glutamyltransferase; Glucuronidase; Injections, Intraperitoneal; Ion Transport; Kidney Cortex; Kidney Glomerulus; Kidney Tubules; L-Lactate Dehydrogenase; Male; Molecular Weight; Mycotoxins; Osmolar Concentration; p-Aminohippuric Acid; Proteinuria; Rats; Rats, Sprague-Dawley; Teratogens; Tetraethylammonium; Tetraethylammonium Compounds