The B6C3F1 mouse strain, a cross between the hepatocarcinogen-resistant C57Bl/6J (B6) strain and the hepatocarcinogen-susceptible C3H/HeJ strain (C3H), is commonly used to assess human carcinogen risk. Recently mapped hepatocarcinogen sensitivity (hcs) loci probably influence the molecular mechanisms underlying hepatocarcinogen resistance and susceptibility. We propose that these loci affect the expression of genes whose products play important roles in DNA repair and hepatocyte growth control. Hepatic transcript profiles of B6 and C3H mice, obtained using the Clontech Atlas mouse 1.2-II array (covering a total of approximately 1,200 genes), showed twofold or greater differences in approximately 8% of the genes assayed. Approximately 88% of the altered genes showed increased expression in the C3H mice, whereas the other 12% were repressed. These genes are involved in a wide range of cellular activities, including the control of apoptosis and cellular proliferation. We are initiating transcript profile studies of chemically induced tumors to determine the role of these genes in hepatocarcinogenesis. Preliminary data from WY-14,643-induced tumors revealed significantly altered expression of peroxisome proliferator-activated receptor-γ and interferon-γ signaling pathway genes compared with surrounding (noncancerous) and control (untreated) tissue. Characterization of differences in gene expression in resistant versus susceptible mouse strains and of how these differences are manifested when cells are exposed to a chemical carcinogen will lead to a better understanding of the mechanisms of hepatocarcinogenesis in mice. This knowledge will help to determine the relevance of the mouse liver tumor response for human risk assessments.