Tissue-specific induction of mutations by acute oral administration of N-methyl-N′-nitro-N-nitrosoguanidine and β-propiolactone to the Muta™Mouse: preliminary data on stomach, liver and bone marrow

Bron, Dominique; Bouilly, Carine; Renault, Dominique; Thybaud, Véronique

doi:10.1016/0165-1161(95)00067-4

Cited by 17 publications

(3 citation statements)

References 18 publications

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“…Dose-response study DMDBC was administered once by s.c. injection at doses ranging from 3 to 180 mg/kg and the liver was sampled 28 days later (Table I). Control MF values are within the range of our previously reported data (11) and are consistent with data reported by others (18,19). The mean MF was slightly increased at 3 and 10 mg/kg (1.2-and 2.0-fold, respectively), and markedly increased at 30, 90 and 180 mg/kg (24.0-, 48.5and 58.2-fold, respectively) suggesting a non-linear response.…”

Section: Resultssupporting

confidence: 92%

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Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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5,9-Dimethyldibenzo[c,g]carbazole (DMDBC) is a synthetic derivative of the environmental pollutant 7H-dibenzo[c,g]carbazole. DMDBC is a potent genotoxic carcinogen specific for mouse liver. Using the MutaMouse lacZ transgenic mouse model and a positive selection assay, we measured lacZ mutant frequency (MF) in the liver 28 days after a single s.c. administration of DMDBC at 3, 10, 30, 90 or 180 mg/kg. MF remained low at 3 and 10 mg/kg, but increased markedly from 30 mg/kg onwards. To investigate the reason for this non-linear response, we examined mechanisms potentially involved in mutation induction in the liver. Genotoxic effects such as DNA adduct formation were detected in 32P-post-labelling studies. Liver sections were examined for microscopic changes and cell proliferation. These parameters, and MF, were studied 2, 4, 7, 14, 21 and 28 days after a single s.c. administration of 10 or 90 mg/kg DMDBC. At 10 mg/kg, a dose found to double the MF on day 28, DNA adducts reached a level of 200-600 adducts per 10(8) nucleotides from day 4 to day 28. No changes in histology or cell proliferation were detected at this low dose. At 90 mg/kg, MF increased gradually from day 7 to day 28 (maximum 44-fold). The DNA adduct level ranged from 400 to 4500 adducts per 10(8) nucleotides on day 2, then stabilized at approximately 400 adducts per 10(8) nucleotides on day 4. An early cytotoxic effect was detected microscopically in centrilobular hepatocytes, and was followed by liver cell proliferation. These data suggest that the marked increase in MF in MutaMouse liver after treatment in vivo with DMDBC at 90 mg/kg may be explained by the induction of replicative DNA synthesis due to a cytotoxic effect, allowing the fixation of persistent DNA adducts into mutations.

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Section: Resultssupporting

confidence: 92%

“…High-molecular-weight genomic DNA was isolated from fresh liver samples as described by Brault et al (11). Five microlitres of DNA was mixed with a λ-phage packaging extract (Transpack; Stratagene, La Jolla, CA) as recommended by the manufacturer.…”

Section: Mutant Frequency Determinationmentioning

confidence: 99%

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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“…In the Muta™mouse assay [131] local effects in the stomach were observed in gavage studies plus systemic effects in the liver, but no mutagenic activity was seen in bone marrow of the Muta™mouse [131]. As expected, no increased incidence in micronuclei was detected in the bone marrow of treated mice [1,4] although clastogenic effects were observed in in vitro studies, in insects and plants (see Additional file 1) indicating chromosomal aberration after direct contact with this alkylating substance.…”

Section: Resultsmentioning

confidence: 99%

Untitled

et al. 2005

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As part of a larger literature study on transgenic animals in mutagenicity testing, test results from the transgenic mutagenicity assays (lacI model; commercially available as the Big Blue® mouse, and the lacZ model; commercially available as the Muta™Mouse), were compared with the results on the same substances in the more traditional mouse bone marrow micronucleus test. 39 substances were found which had been tested in the micronucleus assay and in the above transgenic mouse systems. Although, the transgenic animal mutation assay is not directly comparable with the micronucleus test, because different genetic endpoints are examined: chromosome aberration versus gene mutation, the results for the majority of substances were in agreement. Both test systems, the transgenic mouse assay and the mouse bone marrow micronucleus test, have advantages and they complement each other. However, the transgenic animal assay has some distinct advantages over the micronucleus test: it is not restricted to one target organ and detects systemic as well as local mutagenic effects.

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Efficient detection of deletions induced by a single treatment of mitomycin C in transgenic mousegpt delta using the Spi? selection

Okada

Masumura

Nohmi

et al. 1999

Environ. Mol. Mutagen.

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Tissue-specific induction of mutations by acute oral administration of N-methyl-N′-nitro-N-nitrosoguanidine and β-propiolactone to the Muta™Mouse: preliminary data on stomach, liver and bone marrow

Cited by 17 publications

References 18 publications

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Untitled

Efficient detection of deletions induced by a single treatment of mitomycin C in transgenic mousegpt delta using the Spi? selection

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