These studies identify critical target genes and alterations in genes that may be important in chemical carcinogenesis. Genetic alterations in oncogenes (eg.-ras, beta-catenin) and tumor suppressor genes (eg. - p53 and p16) from rodent tumors induced by certain carcinogens and from human cancers of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis. We have identified beta-catenin mutations in mouse liver tumors induced by certain chemicals. These are the same mutations as those identified in human hepatocellular carcinomas and in childhood hepatoblastomas. In the mouse hepatoblastomas b-catenin protein accumulated in the cytoplasm and nucleus, while in hepatocellular neoplasms b-catenin accumulated only along the cell membranes. Identification of other proteins that interact with b-catenin in liver is now being studied. We have found that cyclin D1, a target for b-catenin/Wnt signalling is strongly upregulated in hepatoblastomas, while c-jun appears to be upregulated in hepatocellular neoplasms. We are now beginning some gene expression profiling and related studies to understand what leads to b-catenin mutation during liver carcinogenesis. We hypothesize that it is due to oxidative stress, and pilot experiments to measure isoprostane formation, a marker of oxidative damage, showed increased formation following exposure to oxazepam. We are also continuing our study to identify the Par2 mouse lung tumor susceptibility gene on chromosome 18 that may have a relevant human homolog. Due to the near completion of the human and mouse genome projects, we have narrowed the locus to a small region and are now identifying candidate genes in that region.