Tolerance to fumonisin toxicity in a mouse strain lacking the P75 tumor necrosis factor receptor.
Fumonisin B1 (FB1), a potent mycotoxin prevalent in corn and cereals, causes a variety of toxic effects in different mammalian species. The biochemical responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a possible involvement of tumor necrosis factor alpha (TNFalpha). To further characterize the role of TNFalpha, toxic response to FB1 was investigated in male C57BL/6J mice (WT) and a corresponding TNFalpha receptor knockout (TRK) strain, genetically modified to lack the TNFalpha1b receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg per day of FB1 were observed in WT but were reduced in TRK, evidenced by circulating alanine aminotransferase and aspartate aminotransferase levels and histopathological evaluation of the tissue. FB1 induced TNFalpha expression in the livers of both WT and TRK mice to a similar extent (3-4 fold over control); however, a corresponding increase of cellular NFkappaB, expected after the downstream cellular signaling of TNFalpha, was noted only in the WT. Accumulation of liver sphingosine after FB1 treatment was similar in both WT and TRK, but the FB1-induced increases in liver sphinganine and kidney sphingosine and sphinganine were lower in TRK than in WT. Results emphasized the role of TNFalpha in FB1-induced hepatotoxicity in mice and the possible relationship of sphingoid base accumulation and TNFalpha induction. Moreover, the presence of TNFalpha receptor 1b appears to be important in mediating the hepatotoxic responses of TNFalpha and FB1 in mice.
Sharma
R P
RP
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602-7389, USA. rpsharma@calc.vet.uga.edu
Bhandari
N
N
Riley
R T
RT
Voss
K A
KA
Meredith
F I
FI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002264:Carboxylic Acids / Q000633:toxicity*; D003600:Cytosol / Q000737:chemistry; D037341:Fumonisins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009183:Mycotoxins / Q000633:toxicity*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II; D013107:Sphingolipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D002264:Carboxylic Acids; D037341:Fumonisins; D009183:Mycotoxins; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha; C056933:fumonisin B1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020794:Receptor Protein-Tyrosine Kinases