|Sharma, R - VET MED, UGA, ATHENS|
|Bhandari, N - VET MED, UGA, ATHENS|
|Tsunoda, M - VET MED, UGA, ATHENS|
Submitted to: Archives of Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 28, 2000
Publication Date: N/A
Interpretive Summary: Fumonisin B1 is a toxic chemical produced by a fungus that occurs on corn worldwide. Animals exposed to high levels of FB1 often develop damage to the liver and kidney. In animals exposed to toxic levels of FB1, the earliest change in liver and kidney is blockage of a step in a pathway responsible for making a unique type of fat called sphingolipids. When this step is blocked, a fat known as sphinganine accumulates. The pathway that is blocked by FB1 is known to play a role in other pathways that control the amount of a chemical (Tumor Necrosis Factor-alpha [TNF]) that is important in an animals's response to infectious agents. When TNF is present it can kill cells in tissues. When mice are exposed to FB1 the expression of the message to produce TNF increases in liver. We hypothesized that strains of mice that produced excess amounts of TNF would be very sensitive to the liver damage caused by FB1. Surprisingly, when treated with FB1, the levels of sphinganine and the damage to liver was less in the strain of mice that produced excess amounts of TNF. This result did not support our hypothesis. Further study revealed that mice that over expressed the TNF message, also over expressed another chemical that is known to protect tissues from cell death caused by over expression of TNF. This work further shows that there is a close correlation between the FB1 blockage of the pathway for making the unique fats, the tissue damage, TNF over expression, and production of protective factors in liver.
Technical Abstract: We investigated the role of TNF-alpha in FB1 toxicity employing male transgenic mice expressing human TNF gene (TG) and their wild-type equivalent (WT). It was hypothehsized that TG animals would have enhanced response to FB1. Animals treated with FB1 for 5 days showed minimal changes in body weight, organ weights, blood cell counts, and TNF levels in plasma or liver. The mRNA and TNF in liver increased in both TG and WT after FB1 treatment, providing further evidence that FB1 induces hepatic TNF expression. Liver and kidney lesions were found in TG after FB1 treatment; however, liver lesions in FB1-treated TB were considerably less than those observed in WT. The decreased hepatotoxicity in TB after FB1 treatment correlated with levels of serum liver enzymes. Free sphinganine levels increased significantly in both liver and kidney of WT and TG mice treated with FB1. The magnitude of the increase in 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 WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NFkB in liver. The cytosolic NFkB was significantly higher in TG compared to WT. Induction of NFkB, caused by increased endogenous produciton of TNF is a possible explanation of decreased FB1 hepatotoxicity in TG. The results provide additional support for a role of TNF in FB1-induced hepatoxicity and suggest protective role for NFkB in FB1-induced liver damage.