NTP Historical Controls for Genetically Modified Models
NTP uses genetically modified models in specific instances to test substances for toxic and carcinogenic effect. Historical controls for the transgenic models TG.AC and p53 are described below. For additional information, see Historical Tumor Rates Controls.
This mouse model has an alteration of specific tumor suppressor genes that have been shown to be key genes associated with induced tumors in rodents and in human malignancies. The TG.AC transgenic line is produced in FVB/N mice by pronuclear injection. Pronuclear injection is the most widely used method for the creation of transgenic mice. The procedure involves injecting genetic material into an early stage embryo and implanting the modified embryo into a foster dam/mother for development to a live pup. Once born, the offspring may or may not have the transgene. The genetically modified mice are known as TG.AC Heterozygous mice with the v-Ha-ras transgene.
TG.AC mice behave like genetically initiated mice, rapidly developing epidermal papillomas, small wart-like growths on the skin, in response to topical tumor promoter or carcinogen treatment. In some experiments, the time to first tumor appearance has been as short as three weeks, but all substances tested that produced papillomas did so in less than 20 weeks. A dose-response relationship has been observed with promoters and carcinogens studied to date. In some studies, mice have developed numerous papillomas. In addition, TG.AC mice appear to respond to cancer-causing substances that are genotoxic (i.e., damaging to the cell’s genetic material) as well as nongenotoxic. While the response in treated mice is dramatic, it is important to note that untreated, singly-housed TG.AC mice usually develop few, if any, spontaneous tumors; generally, the histology, or microscopic structure of the skin, is normal.
With respect to mechanism of the v-Ha-ras transgene, it has been shown the transgene is not significantly expressed in non-tumor bearing TG.AC tissues. However, the transgene is over-expressed in the outgrowth of benign and malignant tumors. Thus, it appears that expression of the transgene drives proliferation and subsequent tumor development in carcinogen treated TG.AC skin.
This mouse model has an alteration of the p53 tumor suppressor gene, a gene critical to cell cycle control and DNA repair. This gene is often found to be mutated or lost in human and rodent tumors. Mice with a single copy of the wildtype p53 allele (p53+/- heterozygous) offer a single target for mutagens, a condition similar to humans with some heritable forms of cancer.
The heterozygous state of these mice—that is, those mice that carry one mutant allele for the same gene—should increase the probability for either:
- Loss of p53 tumor suppressor function
- Gain of transforming activity by requiring only a single mutation
P53 heterozygous mice are viable and show a low background tumor incidence up to almost 12 months of age. Nullizygous (p53-/-) mice, or mice that carry two mutant alleles for the same gene, have a higher rate of spontaneous tumors. The tumor sites are determined by the mouse strain's genetic background.