Our previous studies have indicated that tumour
necrosis factor alpha (
TNFalpha) is involved in
fumonisin B1 (FB1)-induced toxic responses. To investigate the role of
TNFalpha in FB1 toxicity further we employed male transgenic mice expressing human
TNFalpha 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
TNFalpha levels in plasma 1 day after the last injection. The
mRNA for
TNFalpha in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic
TNFalpha 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 NFkappaB in liver. The cytosolic NFkappaB was significantly higher in TG compared with WT. Induction of NFkappaB, caused by increased endogenous production of
TNFalpha, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NFkappaB in FB1-induced liver damage.