Mutagenesis Advance Access published online on July 16, 2008
Mutagenesis, doi:10.1093/mutage/gen037
Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaTMMouse and lung epithelial cells derived from MutaTMMouse
Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG, UK 1Mutagenesis Section, Safe Environments Program, Health Canada, Tunney's Pasture 0803A, Ottawa K1A 0L2, Ontario, Canada 2Division of Molecular Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
FE1 lung epithelial cells derived from MutaTMMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaTMMouse test. 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and urban air pollution. We investigated the mutagenicity and DNA binding of 3-NBA and its main metabolite 3-aminobenzanthrone (3-ABA) in vitro and in vivo in the MutaTMMouse assay. Mice were treated with 3-NBA or 3-ABA (0, 2 or 5 mg/kg body weight/day) by gavage for 28 days and 28 days later lacZ mutant frequency (MF) was determined in liver, lung and bone marrow. For both compounds, dose-related increases in MF were seen in liver and bone marrow, but not in lung; mutagenic activity was 
2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by 32P-post-labelling) were found in liver (230 adducts per 108 nucleotides) with levels 20- to 40-fold lower in bone marrow and lung. With 3-ABA, DNA adduct levels were again highest in the liver, but 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 µg/ml 3-NBA or 3-ABA for 6 h with or without exogenous activation (S9) and harvested after 3 days. For 3-NBA, there was a dose-related increase in MF both with and without S9 mix, which was >10 times higher than observed in vivo. At the highest concentration of 3-ABA (10 µg/ml), we found only around a 2-fold increase in MF relative to controls. DNA adduct formation in FE1 cells was dose-dependent for both compounds, but 10- to 20-fold higher for 3-NBA compared to 3-ABA. Collectively, our data indicate that MutaTMMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaTMMouse testing.
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Received on April 29, 2008; revised on June 10, 2008; accepted on June 16, 2008.