Marion Régnier1, Pascal Gourbeyre1, Philippe Pinton1, Scott Napper2,3, Joëlle Laffite1, Anne-Marie Cossalter1, Jean-Denis Bailly1, Yannick Lippi1, Justine Bertrand-Michel4, Ana Paula F R L Bracarense5, Hervé Guillou1, Nicolas Loiseau1, Isabelle P Oswald1. 1. Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France. 2. Vaccine and Infectious Disease Organization - International Vaccine Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 3. Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 4. MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases, Université Paul Sabatier-Toulouse III, Toulouse, France. 5. Universidade Estadual de Londrina, Laboratory of Animal Pathology, Campus Universitário, Londrina, Paraná, Brazil.
Abstract
SCOPE: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium species. In mammals, this toxin causes widespread organ-specific damage; it promotes hepatotoxicity, is immunotoxic, alters intestinal functions etc. Despite its inhibitory effect on de novo ceramide synthesis, its molecular mechanism of action and toxicity is not totally elucidated. METHODS AND RESULTS: To explore the mechanism of FB1 toxicity, we analyzed the transcriptome and the kinome of two organs targeted by FB1: the liver and the jejunum. Pigs were fed for 4 weeks a control diet or a FB1-contaminated diet (10 mg/kg). As expected, FB1-exposed pigs gained less weight and displayed a higher sphinganine/sphingosine ratio. Comparison of the transcriptomes and the kinomes of treated versus control pigs showed striking differences. Among the disrupted pathways in liver and jejunum, we highlight Protein Kinase B (AKT) / Phosphatase and tensin homolog (PTEN) at the intersection of the FB1-modulated pathways. CONCLUSION: Most of the effects of FB1 are mediated by the regulation of ceramide level, which influences protein phosphatase 2 (PP2A) and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. This pathway might be a new target to counteract toxic effect of Fumonisin B1, which is one of the most spread food contaminant in the world.
SCOPE: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium species. In mammals, this toxin causes widespread organ-specific damage; it promotes hepatotoxicity, is immunotoxic, alters intestinal functions etc. Despite its inhibitory effect on de novo ceramide synthesis, its molecular mechanism of action and toxicity is not totally elucidated. METHODS AND RESULTS: To explore the mechanism of FB1 toxicity, we analyzed the transcriptome and the kinome of two organs targeted by FB1: the liver and the jejunum. Pigs were fed for 4 weeks a control diet or a FB1-contaminated diet (10 mg/kg). As expected, FB1-exposed pigs gained less weight and displayed a higher sphinganine/sphingosine ratio. Comparison of the transcriptomes and the kinomes of treated versus control pigs showed striking differences. Among the disrupted pathways in liver and jejunum, we highlight Protein Kinase B (AKT) / Phosphatase and tensin homolog (PTEN) at the intersection of the FB1-modulated pathways. CONCLUSION: Most of the effects of FB1 are mediated by the regulation of ceramide level, which influences protein phosphatase 2 (PP2A) and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. This pathway might be a new target to counteract toxic effect of Fumonisin B1, which is one of the most spread food contaminant in the world.