Time-course Comparison of Gene Expression Profiles Induced by the Genotoxic Hepatocarcinogen, Chrysene, in the Mouse Liver

抄録

Changes in gene expression profile in rodent liver at the acute stage within 48 h after administration of a hepatocarcinogen have not been extensively reported. In the present study we examined changes in gene expression in mouse liver within 48 h induced by chrysene, a polycyclic aromatic hydrocarbon and genotoxic hepatocarcinogen, by quantitative real-time PCR (qPCR). We quantified 50 candidate genes which discriminated genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens as determined from our previous DNA microarray studies. Chrysene (100 mg/kg bw) was injected intraperitoneally into male 9-week-old B6C3F₁ mice, and at 4, 16, 20, 24 and 48 h after chrysene administration, livers were dissected and processed for gene expression. A total of 35 genes exhibited statistically significant increases at least once within 48 h after chrysene administration. Cyp1a1 and Cyp1a2 showed remarkably consistent increases in gene expression during 4 to 48 h. Fifteen genes (Bhlhe40, Btg2, Casp4, Ccng2, Cdkn1a, Crp, Cyp1a1, Cyp1a2, Fkbp5, Gadd45b, Gadd45g, Hmox1, Igfbp1, Lcn2 and Ly6a) at 4 h, 6 genes at 16 h, 7 genes at 20 h, 7 genes at 24 h, and 10 genes (Bhlhe40, Ccnf, Cyp1a1, Cyp1a2, Ephx1, Hhex, Hmox1, Rcan1, Tubb2a and Tubb4b) at 48 h exhibited statistically significant increases of more than two-fold. At 4 h, 10 of 15 expression-increased genes were associated with DNA damage, DNA repair, cell cycle, cell proliferation and apoptosis. The expression-increased genes at 16 to 48 h were associated with a variety of biological processes. In conclusion three time-dependent patterns in gene expression were observed within 48 h after chrysene administration in mouse liver: Cyp1a1 and Cyp1a2 exhibited consistent increases; the highest number of genes (15 genes) increased in expression at 4 h; and 6 different genes expressed at 4 h increased at 48 h.