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Toxicological Sciences 61, 6-17 (2001)
Copyright © 2001 by the Society of Toxicology

FORUM

Implications of Apoptosis for Toxicity, Carcinogenicity, and Risk Assessment: Fumonisin B1 as an Example

Yvonne P. Dragan*, Wayne R. Bidlack{dagger}, Samuel M. Cohen{ddagger},1, Thomas L. Goldsworthy§, Gordon C. Hard, Paul C. Howard||, Ronald T. Riley||| and Kenneth A. Voss|||

* Ohio State University, James Cancer Center, 1148 James CHRI, 300 W. 10th Avenue, Columbus, Ohio 43210–1240; {dagger} California State Polytechnic University-Pomona, College of Agriculture, 3801 W. Temple Avenue, Pomona, California 91768; {ddagger} University of Nebraska Medical Center, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, Nebraska 68198–3135; § Integrated Laboratory Systems, Inc., Health Science Division, P.O. Box 13501, Research Triangle Park, North Carolina 27709; American Health Foundation, One Dana Road, Valhalla, New York 10595; || Division of Biochemical Toxicology, HFT-110, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Drive, Jefferson, Arkansas 72079–9502; and ||| USDA, Toxicology and Mycotoxin Research Unit, P.O. Box 5677, Athens, Georgia 30604–5677

The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F1 mice, the mycotoxin fumonisin B1 caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B1 caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B1 exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B1 administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B1. Fumonisin B1 is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B1 may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.

Key Words: apoptosis; fumonisin; mycotoxins; kidney cancer; liver cancer; regeneration; carcinogenesis.


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