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

摘要

References(41) Cited-By(1) 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.