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Title: INCREASED EXPRESSION OF CD95-LIGAND AND OTHER APOPTOTIC SIGNALING FACTORS BY FUMONISIN B1, A HEPATOTOXIC MYCOTOXIN, IN LIVERS OF MICE LACKING TUMOR NECROSIS FACTOR ALPHA.

Author
item SHARMA, R - VET MED/U GEORGIA
item HE, Q - VET MED/U GEORGIA
item JOHNSON, V - VET MED/U GEORGIA
item Voss, Kenneth

Submitted to: Cytokine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/2/2003
Publication Date: 11/1/2003
Citation: Sharma, R.P., He, Q., Johnson, V.J., Voss, K.A. 2003. Increased expression of CD95-ligand and other apoptotic signaling factors by fumonisin B1, a hepatotoxic mycotoxin, in livers of mice lacking tumor necrosis factor alpha. Cytokines. 24:226-236.

Interpretive Summary: Fumonisins are mycotoxins made by Fusarium fungi. They occur in corn and corn-based products. The most common fumonisin, fumonisins B1 (FB1), is toxic to animals and causes liver cancer in rodents. FB1 is suspected as a cause of cancer in humans. To determine whether FB1 or other fumonisins are a human health concern, it is important to understand how they cause disease. This includes identification of cell signaling molecules and pathways involved in fumonisin related liver injury. Tumor necrosis factor alpha (TNF) is a signaling molecule involved in apoptosis, a type of cell death characteristic of liver injury caused by FB1 in mice. To determine what signaling molecules besides TNF are involved, we gave FB1 to genetically modified mice lacking TNF (called TNF knockouts) and to unmodified mice (called wild types) having TNF. The expression of genes needed for the production of signaling molecules that promote or inhibit apoptosis in the liver were then compared. FB1 increased expression of a molecule called CD95L, which promotes apoptosis, in the knockout mice. FB1 also increased the expression of other apoptosis signaling molecules called bcl-2, b-myc, bax, max, mad, and IL1 alpha in the knockout mice to a greater extent than in the wild types. Identifying the cell signaling molecules other than TNF that are involved in the liver injury caused by FB1 is important for understanding how fumonisins cause disease in animals, for evaluating the potential risk of fumonisin exposure to humans, and for determining if limits for fumonisins in corn or foods are needed to protect consumers.

Technical Abstract: Fumonisin B1 (FB1) is a common mycotoxin found in corn and corn-based foods. It is toxic to animals and causes apoptosis and liver cancer in rodents. The molecular signals involved in apoptosis in the liver of FB1-exposed mice are not fully understood although it has been shown that one important signaling molecule, tumor necrosis factor alpha (TNFa), is not required for induction of apoptosis. To determine the other pro-apoptotic signaling pathways involved in liver apoptosis, genetically modified mice lacking TNFa (TKO) and intact wild type (WT) mice were given daily subcutaneous injections of a mildly hepatotoxic dose of FB1, 2.25 mg/kg, for 5 days (control TKO and WT mice received saline only) and the expression of selected apoptotic signaling factors was determined. Expression of CD95-ligand (FasL) was more than doubled in TKO mice by FB1, but was unaffected in the WT group. FB1 did not alter CD95 (the receptor for CD95L)expression in either strain. Expression of TRAIL and down-stream signaling factors FADD, TRADD, and caspase 8 was higher in FB1-treated TKO than in FB1-treated WT mice and constitutive levels of pro-apoptotic factors, except CD95L, were higher in the TKO strain. Expression of bcl-2, b-myc, c-myc, bax, max, mad, IL1a was also higher in TKO than in WT mice after FB1 treatment. These results indicate that FB1-induced heptotoxicity in mice is mediated by CD95L-CD95 modulated signals and that the relatively higher constitutive expression of some pro-apoptotic genes in TKO mice explains their increased sensitivity to FB1 compared to WT animals. The results are important for explaining the sensitivity of TKO mice to FB1, understanding the hepatotoxic mode of action of FB1 in mice, and determining the potential health risks to humans consuming fumonisin-contaminated foods.