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Publisher Summary The potential applications of predictive statistical models in toxicology based on gene expression measurements are numerous. For example, short-term studies measuring gene expression could be used to predict long-term toxicity studies like those still performed by the National Toxicology Program (NTP). Other short-term gene expression studies could be used to predict which chemicals would be teratogenic or cause more subtle developmental changes after human prenatal exposure. In either case, the application of microarray analysis and predictive statistical models has the potential to be extremely useful from both economic and human health perspectives. The application of predictive statistical models to chemically induced gene expression is the next logical step in the developing field of toxicogenomics. The development of these models may eventually open the door to a new era of toxicological testing where relatively short and inexpensive microarray studies may allow the assessment of the human health risks associated with a previously untested chemical. However, the accuracy and applicability of these models are highly dependent of the quality of the training sets used in their development. As the public gene expression database grows, more chemicals may be added to training the models and those models will become more predictive.

Publisher Summary This chapter focuses on the genetic regulation of liver cancer development in mice. Understanding the mechanism of the action of specific genes that control hepatocarcinogenesis in rodents provides insights into the underlying biology of carcinogenesis and paradigms for understanding the action of risk-modifier genes in humans. Genetic approaches to understand the nature and regulation of the event associated stages of carcinogenesis include the comparative studies of inbred animal strains, linkage analysis to identify cancer susceptibility genes, and the analysis of carcinogenesis in animals that carry specific mutations. The studies of both spontaneous and chemically induced tumors in mice and rats have demonstrated that there is considerable variation among inbred strains in their susceptibilities to carcinogenesis. The cancer susceptibility genes that determine the differences in susceptibility between inbred strains can be identified through a “reverse genetic” approach. A wide variety of agents, including microsomal enzyme inducers, hypolipidemic agents, and steroid hormones, act as the promoters of hepatocarcinogenesis in rats and mice. Chronic treatment with phenobarbital (PB), a strong promoter of hepatocarcinogenesis in rat, resulted in significant increases in the number of preneoplastic and neoplastic hepatic lesions in DEN-treated C3H/He and DBA/2, but not C57BL/6 mice. Recent studies have provided clues to the molecular basis for the high susceptibility of C3H hepatocytes to in vitro transformation. The karyotypic analysis of cell lines derived from C3H hepatocytes revealed that all of the lines contained the monosomy or partial deletion of chromosome 4. Based on the results, it is proposed that this region of chromosome 4 contained a suppressor gene, designated Lci (liver cell immortalization) for which the C57BL/6 allele was more active than the C3H allele.