TOXICITY OF FUMONISIN, A MAJOR FOOD CONTAMINANT: ROLE OF LIPID METABOLISM AND DETOX DIET STRATEGY – Fumolip

With more than 800 million tons per year, corn is one of the most important crop in the world. Unfortunately, this cereal is often contaminated with Fusarium verticillioides or F. proliferatum, two strains producing mycotoxins, especially fumonisin B1 (FB1). Of note, the climate conditions during the last years in France favored an increased level of mycotoxin contamination forcing the French authorities to request to the EU a temporary derogation for the maximum levels of mycotoxins in maize and maize products. FB1, is most prevalent and the occurring and the most toxic of a family of toxins consisting of more than 20 derivatives. FB1 contamination has been observed in more than 50% of food and feed at average doses of one to several thousand of µg/Kg. As other mycotoxins, FB1 is very resistant to most technological treatment. Thus strategies to reduce the level of this toxin remain limited and mainly concern agricultural practices (crop rotation, plowing…). Adsorbent such as clay or yeast cell walls have a limited efficacy and none of them have been
approved at the European level.

FB1 also causes severe mycotoxicosis in animals with a variety of clinical symptoms. This toxin elicits nephrotoxicity, hepatotoxicity and immunotoxicity. Other specific clinical symptoms have also been reported such as leukoencephalomalacia, pulmonary edema and cardiac dysfunction, neural tube defects in through changes in folate transport. FB1 is a contributing factor in human esophageal cancers; it demonstrates carcinogenic effects in rodents and has been classified by IARC in the Group 2B as a potential carcinogenic chemical to humans. At the cellular level, FB1 disrupts sphingolipid metabolism by blocking the de novo synthesis of ceramides through inhibition of ceramide synthases (CerS). The differential tissue distribution of the various CerS isoforms may explain the diverse clinical symptoms

Our proposal is based on recent findings of partners involved in this project. We have demonstrated that, in pig, ingestion of FB1 regulate a set of genes controlled by the Liver X Receptor (LXR), a nuclear receptor that plays a central role in the entero-hepatic cycle. Using LXR Knockout mice, we have shown that LXR activity can be regulated by a nutritional approach. In addition, as already demonstrated for Fumonisin, our data suggest that LXR is involved in the regulation of sphingolipid metabolism. Altogether, these data led us to speculate that LXR may contribute to the regulations of FB1 sensitive pathways, to the clearance of the mycotoxin and thereby influence its toxicity. In addition, since dietary lipids modulate LXR activity, we postulate that FB1 toxicity may be dependant of the fatty acid profile of the diet.

The objectives of the FUMOLIP project are
to further characterize the effects of FB1, with a focus on lipid metabolism using a model and a target species (mouse and rat)
to use a top-down systems biology approach using system-wide data originating from various untargeted omics technologies (metabolomics, transcriptomics and lipidomics) in combination with statistical modeling to unravel the endogenous metabolic pathways disrupted by FB1 in mice and pigs.
to better characterize the molecular interactions between FB1 and sphingolipid and lipid metabolisms
to assess the FB1 toxicity is dependant on the fatty acid profile of the diet
to determine whether a lipid-enriched diet can modulate FB1 toxicity in order to develop dietary strategies applicable to feeding livestock.

To achieve these aims, we have built a consortium of 3 research teams from INRA and INSERM, with complementary expertises on mycotoxins, lipids, metabolism and systems biology. Four technological platforms dedicated to lipidomics, metabolomics, transcriptomics, and animal research are also associated. Finally, the French technical institute for fats and oils, ITERG, and an agricultural cooperative ARTERRIS complete the consortium.