Recent advances in genetic technology have spurred a mini-revolution in the study of toxicology. Toxicologic studies are a national imperative, and the importance of the application of transgenic mice and knock-out technologies to these studies is widely recognized. For example, the use of Tg.AC transgenic mice, carrying an inducible v-H-ras gene, and p53+/-mice speeds the outcomes of the traditional 2-year bioassay of chemicals nominated for study (1-8). Mechanistic studies have been greatly enhanced by Big Blue transgenic animals that allow "shuttle" mutagenesis studies (9-11).
These genetic approaches have enhanced our knowledge of mechanisms that are important to molecular toxicology as well. By knocking out gamma-glutamyl transpeptidase, the paradoxical reduction of intracellular glutathione was found to be associated with the accumulation of DNA damage (12). Mechanistic roles for repair enzyme genes in toxocologic damage have been revealed with this technology. For example, mouse models of xeroderma pigmentosa produced by creating null mutations of xpc gene prove the critical function nucleotide excision repair by the xpc system in ultraviolet radiation-induced damage leading to skin cancer (13). By combining mutations, the overlapping roles of p53 (Trp53) and xpc, as well as base excision repair and mismatch repair, were revealed (14).
Similarly, this approach established the role of [Beta]-pol in long patch repair and established that the failure of this repair system can lead to chromosomal breakage and apoptosis (15,16). [Beta]-pol null cells were used to show that removal of 5'-deoxyribose phosphate moiety from DNA is a key step in base excision repair (17). The promise now is that knock-out technology, particularly combined with widespread application of gene array studies, will enhance the Environmental Genome Project goal of establishing mechanisms of gene-environment interaction (18).
The application of these technologies through model systems (fruitfly and Caenorhabditis elegans) that establish "the usual suspect" genes by sequence similarities was recently boosted with the completion of both the Drosophila and C. elegans genome projects (19). These projects revealed a surprising level of sequence conservation to the human. In the case of Drosophila, sequence homology to humans is estimated to be approximately 50%, and [is greater than] 60% of a subset of human disease genes (68% of human cancer genes) had orthologs in the Drosophila annotated genome. We know this conservation extends to important aspects of complete pathways as well, such as the Sonic hedgehog-Patched-GLI pathway (20).
The ability to take information from the model system to functional gene study with gain of function (e.g., transgenic) and loss of function (e.g., knock-out) mutations in analogous experimental systems such as the mouse is extremely powerful because of the genetic information available in mouse strains. It is important to remember that complete exploitation of this approach requires careful phenotypic analysis, which is often not available or difficult to obtain in the mouse.
Much of these data are already available or easily obtainable in the rat, however. Using the rat, physiologic and pathophysiologic data for common diseases and metabolic pathways have been gathered for nearly a century from models of diseases that are important to the national public health. Often the rat model most closely resembles the human from among acceptable experimental systems. Important rat models of human diseases include those for cardiovascular diseases, neurodegenerative diseases, behavioral disorders, metabolic disorders, and carcinogenesis, all of which have important environmental overlays that are often poorly understood at the mechanistic level (21,22).
The genomic resources for using rat models of human disease conditions are robust and growing rapidly (23,24). Particularly important in this regard is the recent announcement that the rat genome will be sequenced. …