Carcinogenicity and mechanism of action of fumonisin B1: a mycotoxin produced by Fusarium moniliforme (= F. verticillioides).
Fumonisins are fungal metabolites and suspected human carcinogens. They inhibit ceramide synthase in vitro, enhance tumor necrosis factor alpha (TNFalpha) production, and cause apoptosis. Fumonisin B1 (FB1) was fed to rats and mice for 2 years or, in separate studies, given to rats or mice for up to 4 weeks. Kidney tubule adenomas and carcinomas were found in male rats fed > or = 50 ppm, whereas liver adenomas and carcinomas were found in female mice fed > or = 50 ppm for 2 years. In the short-term studies, increases in tissue concentration of the ceramide synthase substrate sphinganine (Sa) and the Sa to sphingosine (So) ratio were correlated with apoptosis. Further, hepatotoxicity was ameliorated in mice lacking either the TNFR1 or the TNFR2 TNFalpha receptors. Thus, FB1 was carcinogenic to rodents and thefindings support the hypothesis that disrupted sphingolipid metabolism and TNFalpha play important roles in its mode of action.
Voss
Kenneth A
KA
Toxicology and Mycotoxin Research Unit, Richard B. Russell Agricultural Research Center, US Department of Agriculture, Athens, GA 30604-5677, USA. kvoss@saa.ars.usda.gov
Howard
Paul C
PC
Riley
Ronald T
RT
Sharma
Raghubir P
RP
Bucci
Thomas J
TJ
Lorentzen
Ronald J
RJ
D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D037341:Fumonisins / Q000633:toxicity*; D005670:Fusarium / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009183:Mycotoxins / Q000633:toxicity*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism
D002274:Carcinogens, Environmental; D004791:Enzyme Inhibitors; D037341:Fumonisins; D009183:Mycotoxins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D013107:Sphingolipids; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013110:Sphingosine