In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

Kanki, Keita; Nishikawa, Akiyoshi; Masumura, Ken-ichi; Umemura, Takashi; Imazawa, Takayoshi; Kitamura, Yasuki; Nohmi, Takehiko; Hirose, Masao

doi:10.1002/mc.20061

Cited by 51 publications

(55 citation statements)

References 41 publications

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“…These data provided support for the conclusion that hepatocarcinogenesis by IQ and NPYR depends on genotoxic processes and speciˆc DNA adduct formation while DEHP exerts its in‰uence via a non-genotoxic promotional pathway. Our data also indicate that analysis of speciˆc in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis (8). In fact, thymine adducts were detected at levels as much as guanine adducts in the liver of rats given NPYR (9).…”

Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 65%

“…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 order to cast light on carcinogen-speciˆc molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo genotoxicity and mutation spectra of known genotoxic rat hepatocarcinogens Nnitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the non-genotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the non-carcinogen acetaminophen (APAP) were investigated in gpt delta transgenic rats (8). After 13-week treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were signiˆcantly increased in NPYR-and IQ-treated rats.…”

Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 99%

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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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Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 65%

Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 99%

Section: Examples Of Simultaneous Evaluation Of Genotoxicity and Carcmentioning

confidence: 99%

See 1 more Smart Citation

In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

Nishikawa¹,

Umemura²,

Ishii³

et al. 2008

Genes and Environment

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“…On the other hand, reporter gene mutation assays for KBrO 3 demonstrated inconsistent outcomes in terms of MFs in gpt and red/gam genes. This result might reflect the smaller increase in MFs following KBrO 3 exposure (2-3 fold) as compared to those seen (10-30 fold) with more potent genotoxic carcinogens 50) . These results, together with findings from microbial and Hprt mutation assays in mammalian cells 39) , suggest that the potential of KBrO 3 to induce mutations may be very weak 49) .…”

Section: Modes Of Carcinogenic Actionmentioning

confidence: 81%

Possible Carcinogenic Mechanisms Underlying Renal Carcinogens in Food

Umemura

2014

Food Safety

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Some chemicals contained in foods originating from a variety of sources including natural plants, food additives, residual pesticides, mycotoxins and by-products created during food processing and/or cooking have previously been demonstrated to be carcinogenic at various sites in rodents. This review focuses on reported renal carcinogens in natural products such as d-limonene and aristolochic acid (AA), food additives such as potassium bromate (KBrO 3 ) and madder color (MC), as well as mycotoxins such as ochratoxin A (OTA) and citrinin (CTN) and discusses data from reporter gene mutation assays. In addition to in vivo genotoxicity, recent information on several factors related to chemical carcinogenesis, such as DNA modifications and cell proliferation, gave insight into possible modes of action that underlie renal carcinogenesis. Given that neither d-limonene nor CTN induced increases in mutant frequencies (MFs) in some reporter genes, cell proliferation at target sites arising from compensatory and/or direct mitogenic action may play a key role in the carcinogenic mechanism of these compounds. Clear positive results from reporter gene mutation assays for AA, MC and OTA strongly suggest that genotoxic mechanisms are involved in carcinogenesis induced by these agents. While KBrO 3 elevated MFs in the red/gam gene (Spi − ), it did so to a lower extent than did potent genotoxic carcinogens. Accordingly, the participation of genotoxic mechanisms in KBrO 3 -induced renal carcinogenesis may be limited.

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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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In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N‐nitrosopyrrolidine, 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, and di(2‐ethylhexyl)phthalate

Cited by 51 publications

References 41 publications

In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

Possible Carcinogenic Mechanisms Underlying Renal Carcinogens in Food

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

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