title: Comparison of the toxicity of several fumonisin derivatives in a 28-day feeding study with female B6C3F(1) mice.
abstract: 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.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA. Phoward@nctr.fda.gov
authors.forename: Paul C
authors.initials: PC
authors.lastname: Howard
authors.forename: Letha H
authors.initials: LH
authors.lastname: Couch
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Patton
authors.forename: Robert M
authors.initials: RM
authors.lastname: Eppley
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Mona I
authors.initials: MI
authors.lastname: Churchwell
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
authors.forename: Carlin V
authors.initials: CV
authors.lastname: Okerberg
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000737:chemistry / Q000633:toxicity*; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D005260:Female; D037341:Fumonisins / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D002274:Carcinogens, Environmental; D002518:Ceramides; D037341:Fumonisins; C056934:fumonisin B2; C073063:fumonisin B3; C056933:fumonisin B1; D002784:Cholesterol; D000469:Alkaline Phosphatase; D013110:Sphingosine; C005682:safingol