|Corton, J. Christopher - CIIT CEN./RES.T.PARK, NC|
|Dunn, Corrie - CIIT CEN./RES.T.PARK, NC|
Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 16, 2006
Publication Date: February 28, 2006
Citation: Voss, K. A., Riley, R.T., Dunn, C., Corton, J. 2006. The role of tumor necrosis factor alpha and the peroxisome proliferator-activated receptor alpha in modulating the effects of fumonisin in mouse liver. Toxicology 222:165-174. Interpretive Summary: Fumonisins are mycotoxins that are made by Fusarium molds that grow on corn. Fumonisins are found in corn-based foods and are believed to increase the risk of cancer in humans. Fumonisins cause liver disease, including cancer, when fed to rodents. These effects are likely the result of changes in the balance between liver cell death (through a process called apoptosis) and cell division. Cytokines are molecules that affect cell death and cell division. Two of these, (a) tumor necrosis factor alpha (TNF) and (b) the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR) are known to modulate liver cell apoptosis and division and might therefore play roles in liver toxicity induced in rats and mice by fumonisins. We did a series of studies in which fumonisin-containing diets were fed to normal and genetically-modified mice lacking either TNF or PPAR. The livers were then examined for apoptosis, cell division and a specific metabolic change, increased cell sphinganine (a type of fat), that is also involved in fumonisin toxicity. We found that the severity of fumonisin's effects were significantly greater in the mice that lacked TNF than in the normal, genetically unmodified mice. In contrast, the absence of PPAR in the mice had little to no effect on apoptosis, cell division, or the sphinganine effects caused by fumonisins. These results indicate that TNF modifies the severity of fumonisin toxicity in mice exposed to fumonisins via the diet, whereas PPAR does not. Studies such as these, to determine the mechanisms by which fumonisins cause disease in laboratory animals, are important for determining the potential risk of these mycotoxins to human health.
Technical Abstract: Fumonisins are mycotoxins that are produced by Fusarium verticillioides. They are found in corn and corn-based foods and are suspected human esophageal carcinogens. Dietary exposure of rodents to F. verticillioides or fumonisin B1 causes hepatotoxicity and carcinogenicity, effects that likely result in part from alterations in the balance between cell proliferation and apoptosis. Because signaling pathways dependent on the cytokine tumor necrosis factor (TNF) and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) modulate hepatocyte proliferation and apoptosis, studies were done to test the hypothesis that fumonisin-induced hepatotoxicity in liver is modulated by these factors. Specifically, the effects of eight-day or five-week exposure to fumonisins, accomplished by adding F. verticillioides culture material (CM) to the diet, on hepatic apoptosis, mitosis and sphingoid base profiles in mice lacking TNF or PPAR were evaluated. Compared to wild-type mice, TNF-null mice exhibited increased hepatocyte proliferation and apoptosis as well as an enhanced fumonisin-induced increase in liver sphinganine. In contrast, the PPAR-null and wild-type mice exhibited similar patterns of hepatocyte apoptosis and proliferation, as well as similar sphingoid base profiles, when fed the CM. These findings therefore provide evidence that signaling pathways dependent on TNF, but not on PPAR, play a role in modulating fumonisin-induced hepatotoxicity in mice.