Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.

2.50
Hdl Handle:
http://hdl.handle.net/10146/76175
Title:
Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.
Authors:
Arlt, Volker M.; Gingerich, John; Schmeiser, Heinz H.; Phillips, David H.; Douglas, George R.; White, Paul A.
Abstract:
FE1 lung epithelial cells derived from MutaMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaMouse 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 MutaMouse 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 approximately 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by (32)P-post-labelling) were found in liver (approximately 230 adducts per 10(8) 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 approximately 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 microg/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 microg/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 MutaMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaMouse testing.
Citation:
Mutagenesis 2008, 23 (6):483-490
Journal:
Mutagenesis
Issue Date:
Nov-2008
URI:
http://hdl.handle.net/10146/76175
DOI:
10.1093/mutage/gen037
PubMed ID:
18635558
Additional Links:
http://mutage.oxfordjournals.org/cgi/content/full/23/6/483
Type:
Article
Language:
en
ISSN:
1464-3804
Sponsors:
V.M.A. and D.H.P. are partners of Environmental Cancer Risk, Nutrition and Individual Susceptibility, a network of excellence operating within the European Union 6th Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No. 513943).
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorArlt, Volker M.-
dc.contributor.authorGingerich, John-
dc.contributor.authorSchmeiser, Heinz H.-
dc.contributor.authorPhillips, David H.-
dc.contributor.authorDouglas, George R.-
dc.contributor.authorWhite, Paul A.-
dc.date.accessioned2009-08-04T08:15:30Z-
dc.date.available2009-08-04T08:15:30Z-
dc.date.issued2008-11-
dc.identifier.citationMutagenesis 2008, 23 (6):483-490en
dc.identifier.issn1464-3804-
dc.identifier.pmid18635558-
dc.identifier.doi10.1093/mutage/gen037-
dc.identifier.urihttp://hdl.handle.net/10146/76175-
dc.description.abstractFE1 lung epithelial cells derived from MutaMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaMouse 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 MutaMouse 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 approximately 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by (32)P-post-labelling) were found in liver (approximately 230 adducts per 10(8) 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 approximately 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 microg/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 microg/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 MutaMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaMouse testing.en
dc.description.sponsorshipV.M.A. and D.H.P. are partners of Environmental Cancer Risk, Nutrition and Individual Susceptibility, a network of excellence operating within the European Union 6th Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://mutage.oxfordjournals.org/cgi/content/full/23/6/483en
dc.subjectBenz(a)Anthracenesen
dc.subjectDNA adductsen
dc.subjectLac Operonen
dc.subjectMutagenicity Testsen
dc.subjectMiceen
dc.subject.meshAnimals-
dc.subject.meshBenz(a)Anthracenes-
dc.subject.meshCells, Cultured-
dc.subject.meshDNA Adducts-
dc.subject.meshEpithelial Cells-
dc.subject.meshLac Operon-
dc.subject.meshLung-
dc.subject.meshMice-
dc.subject.meshMice, Transgenic-
dc.subject.meshMutagenicity Tests-
dc.subject.meshMutagens-
dc.titleGenotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.en
dc.typeArticleen
dc.identifier.journalMutagenesisen

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