Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta™Mouse)

Hakura, Atsushi; Tsutsui, Yoshie; Sonoda, Jiro; Kai, Junko; Imade, Toshio; Shimada, Michiyo; Sugihara, Yoshiki; Mikami, Takashi

doi:10.1016/s0027-5107(97)00248-0

Cited by 85 publications

(52 citation statements)

References 12 publications

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“…These were pedunculated, exophytic masses each consisting of a fibrous tissue core covered by a thick, heavily keratinized layer of well-differentiated appearing stratified squamous epithelium that formed multiple, variably sized papillary projections ( Figure 1A). In this study, the forestomach was a key target for BP-induced papilloma formation as expected since we used the gavage route and is consistent with other reports (Hakura et al, 1998). Papillomagenesis occurs in ∼9% of untreated mice .…”

Section: Resultssupporting

confidence: 91%

Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

et al. 2004

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The use of a bitransgenic mouse model for cancer is an effective approach for studying the impact of specific carcinogens and the occurrence of tissue-specific lesions. We studied the novel p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) mouse model because these mice contain a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele, both of which occur frequently in human cancers. Our aim was to characterize the short-term control and chemically induced tumor spectrum in this novel model. Mice were placed on basal semipurified diet containing 20% soy protein for 2 weeks prior to random allocation to groups. Subsequently, 15 male and 15 female mice were administered corn oil vehicle alone or containing benzo(a)pyrene (20 mg/kg body weight) via oral gavage 2 times per week for 10 weeks with subsequent observation for 18 weeks. Mice exhibited lesions characteristic of FVB/N, p53 heterozygous and Tg.AC mouse models. However, an array of unique, novel lesions were observed including uterine leiomyosarcomas, mammary gland carcinomas, mammary squamous cell carcinomas, and parotid salivary gland carcinomas suggesting tissue-specific interactions of the 2 genotypes. Thus, this bitransgenic model may provide further insight into the mechanistic interaction of 2 genes commonly mutated in neoplasia.

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Section: Resultssupporting

confidence: 91%

Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

et al. 2004

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“…2 A). Therefore, similar to findings in previous studies of MMR (24) and chemical carcinogens (25,26), tissue-specific cancer susceptibilities in Pol and Pol ␦ proofreading-deficient mice do not correlate with transgene mutant frequencies in vivo.…”

Section: Resultssupporting

confidence: 86%

DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice

Albertson

Ogawa

Bugni

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

206

221

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Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading-and lagging-strand DNA polymerases (Pols and ␦, respectively) have intrinsic proofreading exonucleases that cooperate with each other and mismatch repair to limit spontaneous mutation to less than 1 per genome per cell division. The relationship of these pathways in mammals and their functions in vivo are unknown. Here we show that mouse Pol and ␦ proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol proofreading elevates basesubstitution mutations and accelerates a unique spectrum of spontaneous cancers; the types of tumors are entirely different from those triggered by loss of Pol ␦ proofreading. Intercrosses of Pol -, Pol ␦-, and mismatch repair-mutant mice show that Pol and ␦ proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol and ␦ functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.DNA replication ͉ genetic instability ͉ DNA polymerase fidelity ͉ mismatch repair

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“…The lacZ and lacI transgenic rodent systems have proved to be appropriate models for in vivo mutagenesis before tumors develop [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide

Guttenplan

Chen

Khmelnitsky

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Previously we showed that the organoselenium compound, 1,4-phenylenebis(methylene) selenocyanate (p-XSC)1 inhibits 4-nitroquinoline-N-oxide (4-NQO)-induced tongue tumorigenesis in Fisher rats. Here we investigate possible mechanisms of this inhibition by monitoring mutagenesis and p53 protein levels in lacI and conventional Fisher rats treated with: 1) a carcinogenic dose of 4-NQO for 10 weeks in drinking water, 2) 4-NQO + p-XSC (15 ppm as selenium), and 3) 4-NQO followed by p-XSC. For mutagenesis studies, rats were euthanized at 7, 12 or 23 wks after the start of 4-NQO. For studies on p53 levels, rats were euthanized at 11, 15 and 23 wks. Appropriate controls were also monitored. In the 4-NQO-alone groups, the mutant fraction (MF) in the cII gene in tongue increased at least 50 × background level. The MF (in units of mutants/10 5 plaque forming units) for the 7, 12 and 23 week 4-NQO groups were respectively, 184 ± 88, 237 ± 105, 329 ± 110. Thus, mutagenesis increased with length of exposure and post-treatment time. p-XSC modestly (ca. 15 -30%) inhibited mutagenesis under all conditions. The inhibition reached significance at the last time point. When p-XSC was administered after 4-NQO, the MF was also modestly reduced. In 4-NQOalone animals, levels of p53 in tongue (determined by Western blotting) were 1, 1.5 and 2.4 control levels at 10, 15 and 23 weeks respectively. In the p-XSC + 4-NQO group, the enhancement in p53 levels by 4-NQO treatment was decreased about 90% at 15 weeks and 45% (P < 0.05) at 23 weeks, and by slightly smaller percentages in corresponding post-treatment groups. p-XSC alone did not alter p53 levels. As p53 levels generally increase in response to DNA damage, these results suggest that p-XSC reduces 4-NQO-induced DNA damage, resulting in reduced 4-NQO-induced mutagenesis and carcinogenesis. However, the fact that p-XSC is also effective when administered after 4-NQO, suggests additional mechanisms of inhibition exist.

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Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta™Mouse)

Cited by 85 publications

References 12 publications

Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice

Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide

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