Fumonisin hepatotoxicity is reduced in mice carrying the human tumour necrosis factor α transgene

Our previous studies have indicated that tumour necrosis factor alpha (TNF alpha) is involved in fumonisin B-1 (FB1)-induced toxic responses. To investigate the role of TNF alpha in FB1 toxicity further we employed male transgenic mice expressing human TNF alpha gene (TG) and their wild-type equivalent C57BL/6 (WT). It was hypothesized that TG animals would have enhanced response to FB1. Repeated subcutaneous treatment of animals with 2.25 mg/kg per day of FB1 for 5 days caused minimal changes in body weight, organ weights, blood cell counts, and TNF alpha levels in plasma 1 day after the last injection. The mRNA for TNF alpha in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic TNF alpha expression. Liver and kidney lesions were found in TG after FB1 treatment however, liver lesions seen in FB1-treated TG were considerably less than those observed in WT. The decreased hepatotoxicity in TG after FB1 treatment correlated with plasma concentrations of alanine aminotransferase and aspartate aminotransferase. Free sphinganine levels increased significantly in both the liver and kidney of WT and TG mice treated with FB1. The increase of free sphinganine in the liver from TG mice was 40% less than in WT mice and paralleled the changes in serum liver enzymes. Regional brain neurotransmitters and their metabolites were increased to a similar extent by FB1 in both WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NF kappa B in liver. The cytosolic NF kappa B was significantly higher in TG compared with WT. Induction of NF kappa B, caused by increased endogenous production of TNF alpha, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NF kappa B in FB1-induced liver damage.