Fumonisin hepatotoxicity is reduced in mice carrying the human tumour necrosis factor alpha transgene.
Our previous studies have indicated that tumour necrosis factor alpha (TNFalpha) is involved in fumonisin B1 (FB1)-induced toxic responses. To investigate the role of TNFalpha in FB1 toxicity further we employed male transgenic mice expressing human TNFalpha gene (TG) and their wild-type equivalent C57BL/6 (WT). It was hypothesized that TG animals would have enhanced response to FB1. Repeated subcutaneous treatment of animals with 2.25 mg/kg per day of FB1 for 5 days caused minimal changes in body weight, organ weights, blood cell counts, and TNFalpha levels in plasma 1 day after the last injection. The mRNA for TNFalpha in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic TNFalpha expression. Liver and kidney lesions were found in TG after FB1 treatment; however, liver lesions seen in FB1-treated TG were considerably less than those observed in WT. The decreased hepatotoxicity in TG after FB1 treatment correlated with plasma concentrations of alanine aminotransferase and aspartate aminotransferase. Free sphinganine levels increased significantly in both the liver and kidney of WT and TG mice treated with FB1. The increase of free sphinganine in the liver from TG mice was 40% less than in WT mice and paralleled the changes in serum liver enzymes. Regional brain neurotransmitters and their metabolites were increased to a similar extent by FB1 in both WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NFkappaB in liver. The cytosolic NFkappaB was significantly higher in TG compared with WT. Induction of NFkappaB, caused by increased endogenous production of TNFalpha, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NFkappaB in FB1-induced liver damage.
Sharma
R P
RP
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602-7389, USA. rpsharma@calc.vet.uga.edu
Bhandari
N
N
Tsunoda
M
M
Riley
R T
RT
Voss
K A
KA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D037341:Fumonisins; D015870:Gene Expression; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009183:Mycotoxins / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D001679:Biogenic Amines; D002264:Carboxylic Acids; D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; D016328:NF-kappa B; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha; C056933:fumonisin B1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase