TY - JOUR
T1 - Altered hepatic mRNA expression of apoptotic genes during dimethylnitrosamine exposure
AU - Horn, Thomas L.
AU - Bhattacharjee, Arindam
AU - Schook, Lawrence B.
AU - Rutherford, Mark S.
PY - 2000
Y1 - 2000
N2 - The role of TNFα in regulating apoptotic signaling was investigated during subacute, low-dose (5.0 mg/kg) dimethylnitrosamine (DMN)-induced hepatotoxicity. In TNFα receptor (TNFR) intact (wild-type, WT) mice following 4 and 7 DMN exposures, hepatic transcripts for TNFα 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 TNFα/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-X(L), 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 TNFα expression and suggest that TNFR-1 signaling may be up regulated following 4 and 7 daily DMN exposures. However, TNFα is not required for apoptotic signaling at the mRNA transcript level within the liver and instead may actually decrease Bax production.
AB - The role of TNFα in regulating apoptotic signaling was investigated during subacute, low-dose (5.0 mg/kg) dimethylnitrosamine (DMN)-induced hepatotoxicity. In TNFα receptor (TNFR) intact (wild-type, WT) mice following 4 and 7 DMN exposures, hepatic transcripts for TNFα 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 TNFα/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-X(L), 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 TNFα expression and suggest that TNFR-1 signaling may be up regulated following 4 and 7 daily DMN exposures. However, TNFα is not required for apoptotic signaling at the mRNA transcript level within the liver and instead may actually decrease Bax production.
KW - Apoptosis
KW - Bax
KW - Bcl-X(L)
KW - Dimethylnitrosamine (DMN)
KW - Fas (CD95/APO-1)
KW - Hepatotoxicity
KW - TNF
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U2 - 10.1093/toxsci/57.2.240
DO - 10.1093/toxsci/57.2.240
M3 - Article
C2 - 11006354
AN - SCOPUS:0033800178
SN - 1096-6080
VL - 57
SP - 240
EP - 249
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -