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Toxicological Sciences 57, 240-249 (2000)
Copyright © 2000 by the Society of Toxicology

Molecular and Genetic Toxicology

Altered Hepatic mRNA Expression of Apoptotic Genes during Dimethylnitrosamine Exposure

Thomas L. Horn*,1, Arindam Bhattacharjee2, Lawrence B. Schook* and Mark S. Rutherford*,3

Department of Veterinary PathoBiology, * Toxicology Graduate Program, University of Minnesota, St. Paul, Minnesota 55108

The role of TNF{alpha} in regulating apoptotic signaling was investigated during subacute, low-dose (5.0 mg/kg) dimethylnitrosamine (DMN)-induced hepatotoxicity. In TNF{alpha} receptor (TNFR) intact (wild-type, WT) mice following 4 and 7 DMN exposures, hepatic transcripts for TNF{alpha} and TNFR-1 were elevated as compared to vehicle controls. DMN hepatotoxicity in WT and TNFR-1/TNFR-2 double knockout (DKO) mice were then compared over a 7-d exposure period. Liver RNA was isolated to measure hepatic expression of TNF{alpha}/Fas-related genes and the Bcl-2 family of genes that impact apoptosis. Hepatic mRNA levels for Fas, the apoptosis-promoting gene Bax, and the anti-apoptotic gene, Bcl-XL, were up regulated following 4 and 7 DMN exposures in both WT and TNFR DKO mice as compared to vehicle controls. Notably, hepatic transcript levels for Bax were higher in TNFR DKO mice treated with DMN compared to identically treated WT mice. However, we detected approximately equal DMN-induced apoptotic degradation of liver DNA following 1, 4, and 7 exposures in WT and TNFR DKO mice. Taken together, these data show DMN-induced hepatic TNF{alpha} expression and suggest that TNFR-1 signaling may be up regulated following 4 and 7 daily DMN exposures. However, TNF{alpha} is not required for apoptotic signaling at the mRNA transcript level within the liver and instead may actually decrease Bax production.

Key Words: apoptosis; Bax; Bcl-XL; dimethylnitrosamine (DMN); Fas (CD95/APO-1); hepatotoxicity; TNF.


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