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Transgenic Rat Models for Mutagenesis and Carcinogenesis


Transgenic Rat Models for Mutagenesis and Carcinogenesis

Takehiko Nohmi et al. Genes Environ.


Rats are a standard experimental animal for cancer bioassay and toxicological research for chemicals. Although the genetic analyses were behind mice, rats have been more frequently used for toxicological research than mice. This is partly because they live longer than mice and induce a wider variety of tumors, which are morphologically similar to those in humans. The body mass is larger than mice, which enables to take samples from organs for studies on pharmacokinetics or toxicokinetics. In addition, there are a number of chemicals that exhibit marked species differences in the carcinogenicity. These compounds are carcinogenic in rats but not in mice. Such examples are aflatoxin B1 and tamoxifen, both are carcinogenic to humans. Therefore, negative mutagenic/carcinogenic responses in mice do not guarantee that the chemical is not mutagenic/carcinogenic to rats or perhaps to humans. To facilitate research on in vivo mutagenesis and carcinogenesis, several transgenic rat models have been established. In general, the transgenic rats for mutagenesis are treated with chemicals longer than transgenic mice for more exact examination of the relationship between mutagenesis and carcinogenesis. Transgenic rat models for carcinogenesis are engineered mostly to understand mechanisms underlying chemical carcinogenesis. Here, we review papers dealing with the transgenic rat models for mutagenesis and carcinogenesis, and discuss the future perspective.

Keywords: Carcinogenicity; Chemoprevention; DNA damage; Genotoxic carcinogens; Genotoxicity; Non-genotoxic carcinogens; Organ specificity; Threshold; gpt delta; lacI.


Fig. 1
Fig. 1
Mutant selections for Big Blue rats. a lacI selection. When LacI, the repressor protein of the lac operon, is active, it represses the expression of beta-galactosidase, which leads to colorless plaques. When the lacI gene is inactivated by mutations, beta-galactosidase is expressed, which leads to blue plaques. b cII selection. The cII protein is the critical switch in the lytic/lysogenic cycles of lambda phage. It activates the expression of the lambda cI (repressor) and int (integrase) genes, which are required for the establishment of lysogeny. The cII protein is negatively regulated by host E. coli Hfl protease, which digests the cII protein. In the hfl - background, the cII level is high, and therefore the lambda becomes lysogen. Only cII mutants can enter a lytic cycle and make plaques at 24 °C. The cI - mutants can’t enter the lytic cycle at this temperature. Therefore, the cII selection for Big Blue rats is conducted at 24 °C
Fig. 2
Fig. 2
Mutant selection for gpt delta rats. a gpt selection. The E. coli gpt gene encodes guanine phosphoribosyl transferase, which attaches a phosphoribose to 6-TG. The phosphoribosylated 6-TG is further phosphorylated and finally incorporated into DNA. Incorporation of 6-TG is toxic to E. coli and cell death is induced. Therefore, only when the gpt gene is inactivated by mutations, E. coli can make colonies on a plate containing 6-TG. b Spi- selection. The wild-type lambda phages lyse E. coli, thereby making phage plaques. However, if the E. coli chromosome harbors P2 phage DNA, which is called P2 lysogen, the wild-type lambda phage can’t lyse P2 lysogen. Only the defective lambda phage whose red and gam genes are inactivated can lyse P2 lysogen. The resulting plaques are called P2 plaques. Because the red and gam genes are localized in lambda genome side by side, the inactivation of two genes are most likely induced by deletions in the region

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