New insights into the organ-specific adverse effects of fumonisin B1: comparison between lung and liver.

Fumonisin B1 (FB1) is a well-known inhibitor of de novo sphingolipid biosynthesis, due to its ability to inhibit ceramide synthases (CerS) activity. In mammals, this toxin triggers broad clinical symptoms with multi-organ dysfunction such as hepatotoxicity or pulmonary edema. The molecular mechanism of CerS inhibition by FB1 remains unknown. Due to the existence of six mammalian CerS isoforms with a tissue-specific expression pattern, we postulated that the organ-specific adverse effects of FB1 might be due to different CerS isoforms. The sphingolipid contents of lung and liver were compared in normal and FB1-exposed piglets (gavage with 1.5 mg FB1/kg body weight daily for 9 days). The effect of the toxin on each CerS was deduced from the analysis of its effects on individual ceramide (Cer) and sphingomyelin (SM) species. As expected, the total Cer content decreased by half in the lungs of FB1-exposed piglets, while in contrast, total Cer increased 3.5-fold in the livers of FB1-exposed animals. Our data also indicated that FB1 is more prone to bind to CerS4 and CerS2 to deplete lung and to enrich liver in d18:1/C20:0 and d18:1/C22:0 ceramides. It also interact with CerS1 to enrich liver in d18:1/C18:0 ceramides. Cer levels were counterbalanced by those of SM. In conclusion, these results demonstrate that the specificity of the effects of FB1 on tissues and organs is due to the effects of the toxin on CerS4, CerS2, and CerS1.

Fumonisin B1 exposure and its selective effect on porcine jejunal segment: sphingolipids, glycolipids and trans-epithelial passage disturbance.

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides, the cause of Fusarium kernel rot in maize. FB(1) is toxic in domestic and laboratory animals, including pigs. This study investigated the effects of a seven-days-exposure of 1.5mg/kg b.w. FB(1) on the porcine intestinal epithelium. Statistically significant increases in the ratio of sphinganine to sphingosine, as well as alterations of the glycolipid distribution were observed in the jejunum. Using a porcine intestinal epithelial cell line (IPEC-1) derived from jejunum and ileum, we tested the effect of FB(1)in vitro in a time- and dose-dependent fashion. A significant increase in sphinganine concentration was observed after 2 days of FB(1) exposure at concentrations >100 microM, or from 6 days of FB(1) exposure at concentration >20 microM. We were also able to show that FB(1) exposure at 200 microM during 16 days increased the intestinal trans-epithelial flux of FB(1). These data indicate that, in pigs, this mycotoxin acts selectively on jejunum cells as follows: (i) FB(1) affects sphingolipid metabolism, as demonstrated by an increase of the amount of free sphingoid bases in a time- and dose-dependent manner, (ii) a depletion of the glycolipids in plasma membranes is observed, and (iii) an increase occurs in the trans-epithelial flux.