Journal Article

Implications of Apoptosis for Toxicity, Carcinogenicity, and Risk Assessment: Fumonisin B<sub>1</sub> as an Example

Yvonne P. Dragan, Wayne R. Bidlack, Samuel M. Cohen, Thomas L. Goldsworthy, Gordon C. Hard, Paul C. Howard, Ronald T. Riley and Kenneth A. Voss

in Toxicological Sciences

Volume 61, issue 1, pages 6-17
Published in print May 2001 | ISSN: 1096-6080
Published online May 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/61.1.6
Implications of Apoptosis for Toxicity, Carcinogenicity, and Risk Assessment: Fumonisin B1 as an Example

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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.

Keywords: apoptosis; fumonisin; mycotoxins; kidney cancer; liver cancer; regeneration; carcinogenesis

Journal Article.  10585 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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