Characterization of mutations induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the colon of gpt delta transgenic mouse: novel G:C deletions beside runs of identical bases

Masumura, Kenichi

doi:10.1093/carcin/21.11.2049

Cited by 47 publications

(45 citation statements)

References 37 publications

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“…S3 shows the mutation spectrum detected in the gpt gene, of which the following features are noteworthy. In both uninfected and infected mice, hotspots occurred at nucleotides C64, G110, G115, and G418; C64, G110, and G115 are CpG sites and are known hotspots in this assay (38,39). Hotspots occurring in infected mice were located at A8, G116, and G143; A8 and G116 were found predominantly in infected females at both 6 and 12 mo, whereas G143, located at a CpG site, was a hotspot in infected animals of both sexes.…”

Section: Resultsmentioning

confidence: 74%

Mutagenic potency ofHelicobacter pyloriin the gastric mucosa of mice is determined by sex and duration of infection

Sheh

Lee

Masumura

et al. 2010

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

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Helicobacter pylori is a human carcinogen, but the mechanisms evoked in carcinogenesis during this chronic inflammatory disease remain incompletely characterized. We determined whether chronic H. pylori infection induced mutations in the gastric mucosa of male and female gpt delta C57BL/6 mice infected for 6 or 12 mo. Point mutations were increased in females infected for 12 mo. The mutation frequency in this group was 1.6-fold higher than in uninfected mice of both sexes (P < 0.05). A:T-to-G:C transitions and G:C-to-T:A transversions were 3.8 and 2.0 times, respectively, more frequent in this group than in controls. Both mutations are consistent with DNA damage induced by oxidative stress. No increase in the frequency of deletions was observed. Females had more severe gastric lesions than males at 6 mo postinfection (MPI; P < 0.05), but this difference was absent at 12 MPI. In all mice, infection significantly increased expression of IFNγ, IL-17, TNFα, and iNOS at 6 and 12 mo, as well as H. pylori-specific IgG1 levels at 12 MPI (P < 0.05) and IgG2c levels at 6 and 12 MPI (P < 0.01 and P < 0.001). At 12 MPI, IgG2c levels in infected females were higher than at 6 MPI (P < 0.05) and also than those in infected males at 12 MPI (P < 0.05). Intensity of responses was mediated by sex and duration of infection. Lower H. pylori colonization indicated a more robust host response in females than in males. Earlier onset of severe gastric lesions and proinflammatory, Th1-biased responses in female C57BL/6 mice may have promoted mutagenesis by exposing the stomach to prolonged oxidative stress.gpt delta mouse | Helicobacter | inflammation | mutagenesis | sexual dimorphism

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Section: Resultsmentioning

confidence: 74%

Mutagenic potency ofHelicobacter pyloriin the gastric mucosa of mice is determined by sex and duration of infection

Sheh

Lee

Masumura

et al. 2010

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

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“…A similar trend was observed in the medial part of the small intestine. This type of mutation has been shown to be induced by reactive oxygen (32) and chemical carcinogens (33). Because the old mice we examined were not exposed to carcinogens, reactive oxygen could account for the mutation.…”

Section: Mutations In Digestive Tract Of Old Micementioning

confidence: 91%

Spontaneous Mutations in Digestive Tract of Old Mice Show Tissue-Specific Patterns of Genomic Instability

Ono¹,

Ikehata²,

Pithani³

et al. 2004

Cancer Research

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In an attempt to evaluate the possible role of mutations in the agedependent increase of tumor incidence, we studied the mutational burden that accumulates in the aging process in different parts of the digestive tract in mice. The mutations were monitored in lacZ genes integrated in the mouse genome. The digestive tract was divided into the esophagus, stomach, proximal, medial, and distal part of the small intestine, and the colon. Epithelial tissues were separated from these tissues with the exception of the esophagus, in which case the whole tissue was examined. At a young age, the mutant frequencies as well as the molecular nature of the mutations were similar among the tissues examined. In old age, on the other hand, mutant frequencies were elevated to different degrees among the tissues; they were high in the small intestine and colon, intermediate in the stomach, and low in the esophagus. The molecular characteristics of the mutations also revealed distinct tissue-specificity; there were elevated rates of a small deletion mutation in the esophagus, G:C to T:A transversion in the proximal small intestine, and multiple mutations in the distal small intestine and colon. The results indicate that different parts of the digestive tract suffer from different kinds of mutational stress in the aging process. The nature of the multiple mutations suggests the presence of a mutator phenotype based on an imbalance in deoxyribonucleotide pools.

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“…These middlesize deletions may be induced by clustered DNA damage, which is often induced by high-dose radiation. PhIP and APNH induce one bp deletions at repetitive G:C sequences or immediate ‰anking run sequences (75,79). These one bp deletions are probably induced by TLS across DNA lesions induced by PhIP and APNH.…”

Section: Establishment Of Gpt Delta Transgenic Mice For In Vivo Genotmentioning

confidence: 99%

Novel DNA Polymerases and Novel Genotoxicity Assays

Nohmi

2007

Genes and Environment

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Human genome is continuously exposed to exogenous and endogenous genotoxic agents. The most hazardous and ubiquitous exogenous mutagen may be cigarette smoke, which contains more than 4,000 chemicals including about 60 known carcinogens. About 1% of oxygen metabolism leads to production of reactive oxygen species, a major source of endogenous mutagens. These genotoxic agents induce a variety of lesions in DNA, which results in mutations and chromosome aberrations upon replication. If such genetic alterations occurred in the genes involved in cell proliferations and/or maintenance of genome stability, the cells would proceed in multi-steps of carcinogenesis. The goal of environmental mutagenesis and genetic toxicology is to elucidate the mechanistic links between exposure to genotoxic agents and the health consequences, and to prevent the health hazard associated with DNA damage. To this end, we have investigated the mechanisms of mutagenesis induced by environmental chemicals and contributed to establish the paradigm that Y-family DNA polymerases play central roles in mutagenesis via translesion DNA synthesis across damaged bases in DNA. We also developed genotoxicity assays with bacteria and mice to evaluate the potential risk of environmental chemicals. Here, I review the roles of Y-family DNA polymerases in mutagenesis and introduce features of the novel bacterial and rodent genotoxicity assays. Future directions of environmental mutagenesis and carcinogenesis are also discussed.

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Characterization of mutations induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the colon of gpt delta transgenic mouse: novel G:C deletions beside runs of identical bases

Cited by 47 publications

References 37 publications

Mutagenic potency ofHelicobacter pyloriin the gastric mucosa of mice is determined by sex and duration of infection

Mutagenic potency ofHelicobacter pyloriin the gastric mucosa of mice is determined by sex and duration of infection

Spontaneous Mutations in Digestive Tract of Old Mice Show Tissue-Specific Patterns of Genomic Instability

Novel DNA Polymerases and Novel Genotoxicity Assays

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