|Dragan, Y - CHRI, OSU, COLUMBUS, OH|
|Bidlack, W - AGR/CSPU, POMONA, CA|
|Cohen, S - PATH, MED/U NE, OMAHA, NE|
|Goldsworthy, T - ILS/HLTH SCI DIV, RTP, NC|
|Hard, G - AMER HLTH FOUND/VALHALLA|
|Howard, P - NCTR/FDA, JEFFERSON, AR|
Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 18, 2001
Publication Date: March 1, 2001
Interpretive Summary: Fumonisin B1 is a toxic chemical produced by a mold that is commonly found on corn. Recent studies have shown that fumonisin B1 can cause cancer in the liver and kidney of rodents. But how they cause cancer is not known. Many chemicals that cause cancer can interact directly with the chemicals in our genes (DNA) in a way that results in changes that are called mutations. Mutations in certain genes can lead to cancer. In the United States we call cancerous chemicals that react directly with DNA, genotoxic carcinogens. However, there is little or no evidence that fumonisin B1 reacts directly with DNA and therefore it is considered to be non-genotoxic non-genotoxic (not DNA reactive) carcinogen. This manuscript is a theoretical proposal for a non-genotoxic mechanism, which could explain how fumonisin B1 causes cancer in rodent liver and kidney. The hypothesized hypothesized mechanism was developed by a group of scientific experts experts convened by the International Life Sciences Institute (North American Branch). The group agreed that the most likely mechaanism in rat kidney involved a fumonisin-induced shift in the balance between the rates of cell death and cell birth. Evidence in support of this hypothesis was also evident in mouse liver, but to a lesser extent thatn rat kidney. The proposed biochemical mechanism involved fumonisin-induced alterations in critical fats that are known to regulate both the rates of cell death and cell births in tissues. The proposed mechanisms are important because they indicate that it is possible to predict a level of fumonisin B1 exposure that should result in very little risk of cancer.
Technical Abstract: 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 B6C3F mice, the mycotoxin fumonisin B, 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 B, 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.