The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--Pharmaceuticals: An Efficient and Humane Approach to Predictors of Potential Toxic Effects of Drugs

Transgenic Animals and Mechanistic Toxicology

Leslie Recio
CIIT Centers for Health Research

Transgenic animals are proving to be useful in mechanistically-based toxicology research. Transgenic animals have been used to define genes that have a central role in regulating responses to nongenotoxic and genotoxic carcinogens, determine genes that confer genetic susceptibility of humans to the toxic effects of xenobiotics, determine mechanisms of in vivo genetic alterations at critical target genes, and dissect genomic pathways of response to chemicals.

The inactivation of specific genes involved in receptor-mediated carcinogenesis has proven useful to understand the spectrum of responses mediated by a specific receptor. The PPAR-alpha receptor regulates many of the liver responses to peroxisome proliferators including, induction of lipid metabolizing enzymes, hepatocyte proliferation, and hepatocellular adenomas and carcinomas. Transgenic mice with inactivation of genes involved in the bioactivation/detoxification of specific xenobiotics can identify the role of specific CYP450 isozymes in the biotransformation of these compounds. Mice with inactivated CYP2E1 have been used to determine the role of this enzyme in mediating the in vivo toxicity for a number of compounds and assess its relevance as a marker of genetic susceptibility in humans.

Mice heterozygous for tumor suppressor genes proposed as short-term cancer models (e.g., p53+/- mice) can be used to examine mechanisms of genetic alterations affecting target genes known to be important in human cancer. Tumors arising in p53+/- mice can be examined for genetic alterations affecting the p53 gene and surrounding chromosomal DNA. The p53+/- mouse model with a lacI transgene insert can also be used to examine mutational mechanisms during tumor development in target tissues. These studies allow the determination of in vivo mutational mechanisms involved in tumor development.

Recent studies are integrating genomic studies with transgenic animal to identify pathways of genomic responses to toxic agents. These studies can identify genes associated with cellular toxicities, genes that respond to nongenotoxic and genotoxic stress, and genes that are predictive of biological outcomes.