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Toxicological Sciences 60, 385-396 (2001)
Copyright © 2001 by the Society of Toxicology


SYSTEMS TOXICOLOGY

Fumonisin B1 Is Hepatotoxic and Nephrotoxic in Milk-Fed Calves

Sheerin Mathur*, Peter D. Constable*,1, Robert M. Eppley{dagger}, Amy L. Waggoner{ddagger}, Mike E. Tumbleson§ and Wanda M. Haschek{ddagger}

* Departments of Veterinary Clinical Medicine, {ddagger} Veterinary Pathobiology, and § Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 61802; and {dagger} U.S. Food and Drug Administration, Washington, DC

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 B1 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 B1 at 1 mg/kg, iv, daily and controls (n = 5) 10 ml 0.9% NaCl, iv, daily until euthanized on day 7. Fumonisin B1-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 B1-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 B1-induced renal injury and organ sphingolipid alterations in cattle.

Key Words: fumonisin; sphingosine; sphinganine; sphingolipid; hepatotoxicity; cholesterol; nephrotoxicity; proximal renal tubules.


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S. Mathur, P. D. Constable, R. M. Eppley, M. E. Tumbleson, G. W. Smith, W. J. Tranquilli, D. E. Morin, and W. M. Haschek
Fumonisin B1 Increases Serum Sphinganine Concentration but Does Not Alter Serum Sphingosine Concentration or Induce Cardiovascular Changes in Milk-Fed Calves
Toxicol. Sci., April 1, 2001; 60(2): 379 - 384.
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