Target organ and time-course in the mutagenicity of five carcinogens in Muta™Mouse: a summary report of the second collaborative study of the transgenic mouse mutation assay by JEMS/MMS

Suzuki, Takayoshi; Itoh, Satoru; Nakajima, Masahiro; Hachiya, Noriyuki; Hara, Takumi

doi:10.1016/s1383-5718(99)00104-7

Cited by 44 publications

(24 citation statements)

References 25 publications

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“…Similar results were previously observed in the lacZ gene of lacZ mice [38,39]. As mutagenesis generally requires an expression period during which DNA damage is converted to mutations [40], the 7 week treatment period presumably encompasses sufficient time for 4-NQO-induced damage to be converted to mutations. Twelve weeks after the start of 4-NQO exposure (including two weeks post-exposure) the mutant fraction further increased.…”

Section: Discussionsupporting

confidence: 86%

“…It has been reported that 4-NQO treatment leads to enhanced rates of cell proliferation in rat tongue relative to controls, and that co-and posttreatment with p-XSC reduces this effect [19]. It should also be noted that the treatment with 4-NQO continued for 10 weeks and typically four weeks post-treatment are needed for the fixation of most mutants [40] (although this is organ and mutagen specific). It is then possible that all of the mutations were fixed by 14 weeks and at that point mutagenesis was complete.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

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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“…As controls, three mice were treated with 50 lL PBS containing 0.05% Tween 80 and 1% DMSO. Mice were sacrificed 14 days after DEP or DEP extract treatment [Suzuki et al, 1999] and their lungs were removed, frozen in liquid nitrogen, and stored at À808C.…”

Section: Treatment Of Micementioning

confidence: 99%

Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust

Hashimoto

Amanuma

Hiyoshi

et al. 2007

Environ and Mol Mutagen

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Diesel exhaust (DE) is a major airborne pollutant of urban areas. It contains various polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs. In this study, gpt delta mice were treated with inhalation of 1 or 3 mg m(-3) DE, or a single intratracheal instillation of diesel exhaust particles (DEP) or DEP extract. In the lungs of mice treated with inhalation of 3 mg m(-3) DE for 12 weeks, the mutant frequency (MF) was 3.2-fold higher than that of the control group (1.90 x 10(-5) and 0.59 x 10(-5), respectively). An instillation of DEP and DEP extract resulted in a significant dose-dependent linear increase in MF. In mice treated with 0.5 mg DEP and 0.2 mg DEP extract, the MFs were 3.0- and 2.7-fold higher than that of the control group, respectively. The mutagenic potency (MF mg(-1)) of DEP extract (5.6 x 10(-5)) was double that of DEP (2.7 x 10(-5)), suggesting that the mutagenicity of the latter is derived primarily from compounds in the extract, which itself is responsible for ca. 50% of the weight of DEP. G:C-->A:T transitions were the predominant gpt mutation induced by all three treatments and G:C-->T:A transversions were induced by DEP and DEP extract. Guanine bases centered in nucleotide sequences such as GGA, TGA, CGG, and CGT were the major mutation targets of all three treatments. Thus, our results suggest that the mutagens contained in DEP such as PAH and nitrated PAHs induce mutations and may be responsible for carcinogenesis caused by inhalation of DE.

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“…Another difference appeared when we compared the normalized frequencies of PLAP + cells and mutant rescued transgenes. In young mice, these frequencies were essentially the same (Ono et al, 1995(Ono et al, , 2000Suzuki et al, 1999;Dollé et al, 2000b;Hill et al, 2004). However, in the brain and heart of old mice, the frequency of normalized PLAP + cells was two-to threefold higher than reported in rescue studies on these organs (Ono et al, 2000;Dollé et al, 2000b).…”

Section: Discussionmentioning

confidence: 57%

Mutation in aging mice occurs in diverse cell types that proliferate postmutation

Fischer

Stringer

2008

Aging Cell

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SummaryTo determine the relationship between aging, cell proliferation and mutation in different cell types, hearts, brains and kidneys from G11 PLAP mice between 1 week and 24 months of age were examined. Mutant cells were Regardless of tissue and cell type, PLAP + cells occurred as singletons and in clusters, both of which increased in frequency with age. These data show that age-associated accumulation of mutant cells occurs in diverse cell types and is due to both new mutation and proliferation of mutant cells, even in cell types that tend to not proliferate.

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Target organ and time-course in the mutagenicity of five carcinogens in Muta™Mouse: a summary report of the second collaborative study of the transgenic mouse mutation assay by JEMS/MMS

Cited by 44 publications

References 25 publications

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

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

Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust

Mutation in aging mice occurs in diverse cell types that proliferate postmutation

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