Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion.

Abstract

We review the hepatocarcinogenic effects of fungal cultures of Fusarium verticillioides(= Fusarium moniliforme) strain MRC 826 in male BD IX rats. Subsequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB1 provide information about dose-response effects, relevance of hepatotoxicity during FB1-induced carcinogenesis, and the existence of a no-effect threshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body weight (bw)/day over approximately 2 years produce liver cancer in male BD IX rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, although mild toxic and preneoplastic lesions are induced. The nutritional status of the diets used in the long-term experiments was marginally deficient in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a cancer 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 supported the findings of long-term investigations indicating that a cytotoxic/proliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed for cancer induction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion.

Sequential dietary exposure to aflatoxin B1 and fumonisin B1 in F344 rats increases liver preneoplastic changes indicative of a synergistic interaction

“…The balance between the levels of the sphingolipid molecules elevated and/or depleted in liver, kidney, blood, and other tissues will determine which sphingolipid-dependent signaling pathways are affected: increased cell death or survival (Torres et al, 2015). The potential mechanisms proposed for FB 1 cancer induction include “the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion” (Gelderblom et al, 2001a; Gelderblom and Marasas, 2012; Riedel et al, 2015). …”

“…AFB 1 induced liver cancer is characterized by a G to T mutation at codon 249 of the p53 gene (Aguilar et al, 1993) and possibly epigenetic effects involving DNA methylation (Wu et al, 2013). On the other hand, FB 1 induces cancer in rodents and trout through the disruption of sphingolipid metabolism via inhibition of ceramide synthase leading to alterations of key signaling pathways, induction of oxidative damage, and alterations in growth regulation (Bulder, 2012; Gelderblom et al, 2001a; IARC, 2002; Merrill et al, 2001; Riedel et al, 2015; Riley et al, 2001). Based on relatively scarce evidence of co-exposure in animal models as compared to single mycotoxin research, AFB 1 and FB 1 co-treatment demonstrates additive or synergistic effects in enhancing liver toxicity (Carlson et al, 2001; Casado et al, 2001; Gelderblom et al, 2002; McKean et al, 2006; Orsi et al, 2007; Theumer et al, 2008).…”

Calcium montmorillonite clay reduces AFB1 and FB1 biomarkers in rats exposed to single and co‐exposures of aflatoxin and fumonisin

“…It is not known whether the uptake of AFB 1 and FB 1 also co-interact via these mechanisms, although the current study implies that they countered each other's’ absorption from the gut. The modulating role of FB 1 on lipid metabolism with the disruption of sphingolipid, phospholipid, cholesterol, and fatty metabolism has been reported, resulting in toxic effects including an increase in oxidative damage to different cellular constituents including the cellular membrane (Abel and Gelderblom 1998; Gelderblom et al 2001; Riley et al 2001). These different adverse biological parameters are likely to disrupt membrane integrity, leading to intestinal toxicity (Bouhet and Oswald 2007) and potentially altered absorption.…”

Development of a liquid chromatography/tandem mass spectrometry method for the quantification of fumonisin B1, B2 and B3 in cornflakes

“…Their structural similarity with sphingoid bases led to the hypothesis that fumonisins may inhibit ceramide synthase, a key enzyme involved in the de novo sphingolipid biosynthesis and in the reacylation of free sphingoid bases derived from sphingolipid turnover 4. These mycotoxins are associated with equine leukoencephalomalacia (ELEM), porcine pulmonary edema,5 and a range of toxicological effects such as nephrotoxicity, hepatotoxicity, immunosuppression and carcinogenicity 6–8. A provisional maximum tolerable daily intake (PMTDI) for nephrotoxicity has been set by the 56th Joint FAO/WHO Expert Committee on Food Additives at 2 µg total fumonisin kg −1 body weight 6.…”