|Corton, J. Christopher|
|Miller, J. David|
Submitted to: US-Japan Coop Pgm on Dev and Util of Natural Products Abstracts Proceedings
Publication Type: Abstract Only
Publication Acceptance Date: 10/15/2003
Publication Date: 1/30/2004
Citation: Voss, K.A., Riley, R.T., Sharma, R.P., Corton, J., Miller, J., Bacon, C.W. 2004. The use of genetically modified mice for studying the in vivo mode of action of fumonisins: studies on tumor necrosis factor alpha and the peroxixome proliferator-activated receptor alpha. Abstracts of Proceedings of US-Japan Cooperative Program on Devlopment and Utililization of Natural Products. November 9-14, 2003. Tokyo, Japan.
Interpretive Summary: Abstract - UJNR - no interpretive summary required.
Technical Abstract: Fumonisins are produced by Fusarium verticillioides and related fungi. They occur worldwide in corn and corn-based foods. Fumonisins are toxic to various animal species and fumonisin B1 (FB1), the most common fumonisin, is a rodent carcinogen. Mechanistically, fumonisins inhibit ceramide synthase, thereby disrupting sphingolipid metabolism and "triggering" cellular events leading to toxicity. However, the events linking ceramide synthase inhibition and its direct consequences (increased tissue sphinganine (Sa) and sphingosine (So) concentrations, depletion of tissue complex sphingolipids) to toxicity are not well defined and likely involve multiple factors. In vivo investigations using genetically altered mice provide a potentially useful strategy for elucidating fumonisins' mode of action. Two examples follow. Mice lacking either of the tumor necrosis factor alpha (TNFalpha) receptors, TNFR1 or TNFR2, were less sensitive to the hepatotoxic effects of FB1 than control mice when the mycotoxin was administered (2.25 mg/kg BW by subcutaneous injection) to the mice for five days. However, the hepatotoxic response (apoptosis, increased tissue Sa, increased serum enzymes indicative of liver injury) to FB1 treatment was unchanged in mice lacking both TNFR1 and TNFR2 and was increased in mice lacking TNFalpha (TKO) when compared to control mice. This suggests that TNFalpha modifies but is not required for inducing hepatotoxicity in mice. FB1 increased the expression of CD95-ligand (FASL) more than two fold in the TKO strain but did not change CD95-ligand expression in wild-type mice. Expression of other pro-apoptotic factors was also greater in FB1-treated TKO mice suggesting that enhanced expression of CD95-ligand and other pro-apoptotic factors likely explain the sensitivity of TKO mice to FB1-induced hepatotoxicity. Peroxisome proliferators are hepatic carcinogens in mice and their effects are mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha). Binding of sphingoid bases to mouse PPARalpha in vitro has been demonstrated suggesting that Sa and So might also act as ligands for the PPARalpha in vivo. To investigate if fumonisin-induced hepatotoxicity in mice is PPARalpha-dependent, PPARalpha-null mice and their corresponding wild type strain (WT) were fed control diets or diets containing 300 ppm FB1, culture material (CM) of F. verticillioides isolate MRC 826 providing 300 ppm FB1, or 500 ppm of the peroxisome proliferator WY-14,643 for one week. The WT mice but not PPARalpha-null mice responded to WY-14,643 and WT mice given WY-14,643 exhibited no overt changes in liver Sa concentrations. FB1 and CM were hepatotoxic in both mouse strains as shown by increased liver Sa and hepatocyte apoptosis. Acyl-CoA oxidase expression, a marker protein for peroxisome proliferation, was enhanced only in the WT mice after WY-14,643 exposure. These findings suggest that the hepatotoxicity in mice exposed to fumonisins does not require PPARalpha and occurs independently of peroxisome proliferation.