Article

Is Muta™Mouse insensitive to clastogens?

GlaxoSmithKline, Department of Genetic Toxicology, Ware, United Kingdom; National Institute of Public Health and the Environment (RIVM), Laboratory for Health Protection Research, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands; Netherlands Centre Alternative to Animal Use (NCA), Utrecht University, The Netherlands
Mutation Research/Genetic Toxicology and Environmental Mutagenesis DOI:10.1016/j.mrgentox.2008.01.008

ABSTRACT Several studies suggest that Muta™Mouse is insensitive to clastogens, including the accompanying paper by Mahabir et al., which describes a study with bleomycin, camptothecin, m-AMSA (4′-(9-acridinylamino)-methanesulfon-m-anisidide) and its ortho-analogue, o-AMSA (4′-(9-acridinylamino)-methanesulfon-o-anisidide). Only camptothecin was clastogenic in Muta™Mouse and none of these four compounds induced mutations at the lacZ locus. However, to improve exposure, dose range-finding studies were performed in CD2F1 mice, the parental strain of Muta™Mouse. Male CD2F1 mice (n = 3) were treated with bleomycin (25–100 mg/kg bw, p.o. and i.p.), camptothecin (1–10 mg/kg bw p.o.) and m-AMSA (10–50 mg/kg bw p.o. and 1–5 mg/kg bw i.p.) for 5 days and blood was sampled on day 3 and/or day 6 for analysis by flow cytometry to determine % MN-RETs. Camptothecin (1 mg/kg bw, day 6) induced a 3.6-fold increase in % MN-RET (P < 0.05) but was toxic at higher doses. All day-3 camptothecin samples were positive (P < 0.05). Bleomycin was negative when administered p.o. but positive at all doses on both days when given i.p. (P < 0.05) whereas m-AMSA was negative when given i.p. or orally. Based on these results, male Muta™Mouse mice (5 per group) were dosed daily with bleomycin (50 mg/kg bw) for 5 days or with camptothecin (5 mg/kg bw) for 2 days. Peripheral blood was sampled 24 h after the final dose in each group and tissues were sampled 37 days later. Both compounds induced significant increases in % MN-RET, but only bleomycin induced a significant increase in MF (6-fold in liver, 4.5-fold in kidney and 2-fold in lung) compared with the untreated control. These studies support the view that Muta™Mouse is insensitive to compounds where the genotoxic mechanism of action is predominantly clastogenesis, but demonstrates that the peripheral blood micronucleus test is a useful adjunct to the transgenic gene-mutation assay.

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Keywords

% MN-RET
 
% MN-RETs
 
1 mg/kg bw
 
3.6-fold increase
 
5 days
 
5 mg/kg bw
 
bleomycin induced
 
CD2F1 mice
 
compounds induced significant increases
 
day 6
 
day-3 camptothecin samples
 
dose range-finding studies
 
final dose
 
four compounds induced mutations
 
higher doses
 
Male CD2F1 mice
 
male Muta™Mouse mice
 
Peripheral blood
 
peripheral blood micronucleus test
 
useful adjunct