Fumonisin-induced hepatocarcinogenesis: Mechanisms related to cancer initiation and promotion

We review the hepatocarcinogenic effects of fungal cultures of Fusarium ver ticillioides(= Fusarium moniliforme) strain MRC 826 in male ED IX rats. Sub sequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB 1 provide information about dose-response effects, relevance of hepatotoxic ity during FB1-induced carcinogenesis, and the existence of a no-effect thr eshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body w eight (bw)/day over approximately 2 years produce liver cancer in male ED I X rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, al though mild toxic and preneoplastic lesions are induced. The nutritional st atus of the diets used in the long-term experiments was marginally deficien t in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a can cer initiation/promotion model in rat liver provided important information about the possible mechanisms involved during the initial stages of cancer development by this apparently nongenotoxic mycotoxin. These studies suppor ted the findings of long-term investigations indicating that a cytotoxic/pr oliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed far cancer i nduction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cell ular membranes, and altered growth-regulatory responses as important events during promotion.