Low dose genotoxicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in gpt delta transgenic mice

Masumura, Ken-ichi; Horiguchi, Mieko; Nishikawa, Akiyoshi; Umemura, Takashi; Kanki, Keita; Kanke, Yusuke; Nohmi, Takehiko

doi:10.1016/s1383-5718(03)00186-4

Cited by 35 publications

(35 citation statements)

References 41 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: 77%

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: 77%

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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“…The gpt and Spi − assay systems have been validated primarily in mice with many chemical mutagens/carcinogens, UV and ionizing radiation, for which mutagenicity, organ specificity and mutation spectrum have been thoroughly characterized. 1,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Recently, the outbred gpt delta SD rat was backcrossed with Fisher 344 (F344) rat, to establish an inbred gpt delta rat (F344). In this review, we focus on the spontaneous mutations detected by the gpt and Spi − assays in gpt delta mice and rats and discuss possible mechanisms underlying these in vivo mutations.…”

Section: Overview Of Gpt Delta Transgenic Rodentsmentioning

confidence: 99%

Spontaneous Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

Masumura

Nohmi

2009

JOURNAL OF HEALTH SCIENCE

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Transgenic rodents are valuable models for investigation of genotoxicity of chemicals in vivo. We have developed gpt delta transgenic mice (C57BL/6J background) and rats (Sprague-Dawley, SD), which have the ability to identify both point mutations by the gpt assay [6-thioguanine (6-TG) selection] and certain types of deletions by the Spi − (Spi, sensitive to P2 interference) assay. Recently, the gpt delta SD rat was backcrossed with the Fisher 344 (F344) rat to establish an gpt delta F344 rat. The average spontaneous gpt mutation frequencies (MFs) are about 4.5 × 10 −6 in both SD and F344 gpt delta rats as well as in gpt delta mice. The G:C to A:T transitions at 5 -CpG-3 sites and G:C to T:A transversions are the predominant spontaneous gpt mutations in rats and mice. However, there is one false mutation (e.g. A:T to T:A at position 299) in the rats. The base substitution may have arisen when the lambda EG10 transgene was introduced into the genome of the SD rat during transgenesis. In the Spi − assay, 1-bp deletions in repetitive sequences are predominantly observed in both mice and rats. Possible mechanisms underlying the spontaneous mutations in gpt delta rodents are discussed.Key words --gpt delta transgenic rodent, spontaneous mutation, mutation spectrum, gpt assay, Spi − assay OVERVIEW OF gpt DELTA TRANSGENIC RODENTSGene mutations play an important role in the etiology of many human diseases including cancer. Since humans are exposed to a variety of endogenous and exogenous mutagens, there has been considerable interest in the relationship between exposure, genotoxic effects, and cancer incidence. To assess the risk of mutagens to the human genome, genotoxicity tests have been developed, including in vivo mutation assays using experimental animals, which play a crucial role in risk assessment. To investigate in vivo genotoxicity, a number of transgenic rodent mutation assays have been developed by introducing reporter transgenes into the chromosome of every cell of the animal. 1, 2) Using these systems, mutagenic events induced in a rodent can * To whom correspondence should be addressed: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. Tel.: +81-3-3700-1141 (Ext. 280); Fax: +81-3-3707-6950; E-mail: masumura@nihs.go.jp be detected by recovering the transgene and analyzing the phenotype of the reporter gene in a bacterial host. These models permit quantitation of mutations and identification at the sequence level in any tissue or organ in the body. lacZ, lacI or cII have been employed as reporter genes in transgenic rodents, such as the Muta TM mouse, and the Big Blue R mouse and rat. 3-7) Despite differences in size and sequence context, spontaneous mutation frequencies of these reporter genes are in the mid-10 −5 range and those are predominantly base substitutions in most tissues. This high background of base substitutions may make it difficult to detect rare mutations such as deletions induced by ionizing radiation. 8,9) To...

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“…Our studies of genotoxic carcinogens such as environmental pollutants, nitrosamines and heterocyclic amines in these transgenic rodents have revealed good correlations between genotoxicity and carcinogenicity in terms of mechanism of action (6,8,(10)(11)(12)(13)(14)(15)(16).…”

Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 99%

In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

Nishikawa¹,

Umemura²,

Ishii³

et al. 2008

Genes and Environment

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Genotoxic carcinogens are chemicals or factors which not only induce neoplastic lesions in animal bioassays but also test positive in genotoxicity assays in vitro or in vivo. However, it is actually di‹cult to discriminate genotoxic and non-genotoxic carcinogens because both assays are basically independent each other, which raises a simple query as to how much the detected genotoxic potential can consequently contribute to carcinogenicity. To clarify this critical issue, we have studied the mechanisms of action of carcinogens in transgenic rats or mice carrying reporter genes, which are expected as powerful tools for the simultaneous evaluation of both genotoxicity and carcinogenicity at the same organ level. A number of studies of genotoxic carcinogens using these transgenic rodents have revealed good correlations between genotoxicity and carcinogenicity in terms of mechanism of action. On the other hand, a known non-genotoxic carcinogen dicyclanil increased in vivo genotoxicity as well as oxidative DNA damage in female mice, consistently with the sex speciˆci-ty of its carcinogenicity, albeit without clear evidence of direct DNA reactivity. In contrast, a genotoxic chlorinated water by-product MX failed to exert in vivo genotoxicity and carcinogenicity in mice. We also conˆrmed that such reporter gene-carrying rodents are not susceptible or resistant to carcinogenicity as compared with intact counterparts. These results thus indicate that understanding of the detailed mechanism of carcinogenic action could be crucial for more precise risk assessment, and bioassay systems using transgenic rodents carrying reporter genes would be extremely useful for that purpose.

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Low dose genotoxicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in gpt delta transgenic mice

Cited by 35 publications

References 41 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 Mutagenesis in Rodents: Spontaneous Gene Mutations Identified by Neutral Reporter Genes in gpt Delta Transgenic Mice and Rats

In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

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