title: Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the Muta™Mouse transgenic rodent assay.
abstract: Test batteries to screen chemicals for mutagenic hazard include several endpoints regarded as effective for detecting genotoxic carcinogens. Traditional in vivo methods primarily examine clastogenic endpoints in haematopoietic tissues. Although this approach is effective for identifying systemically distributed clastogens, some mutagens may not induce clastogenic effects; moreover, genotoxic effects may be restricted to the site of contact and/or related tissues. An OECD test guideline for transgenic rodent (TGR) gene mutation assays was released in 2011, and the TGR assays permit assessment of mutagenicity in any tissue. This study assessed the responses of two genotoxicity endpoints following sub-chronic oral exposures of male Muta™Mouse to 9 carcinogenic polycyclic aromatic hydrocarbons (PAHs). Clastogenicity was assessed via induction of micronuclei in peripheral blood, and mutagenicity via induction of lacZ transgene mutations in bone marrow, glandular stomach, small intestine, liver, and lung. Additionally, the presence of bulky PAH-DNA adducts was examined. Five of the 9 PAHs elicited positive results across all endpoints in at least one tissue, and no PAHs were negative or equivocal across all endpoints. All PAHs were positive for lacZ mutations in at least one tissue (sensitivity=100%), and for 8 PAHs, one or more initial sites of chemical contact (i.e., glandular stomach, liver, small intestine) yielded a greater response than bone marrow. Five PAHs were positive in the micronucleus assay (sensitivity=56%). Furthermore, all PAHs produced DNA adducts in at least one tissue. The results demonstrate the utility of the TGR assay for mutagenicity assessment, especially for compounds that may not be systemically distributed.
authors.affiliation: Faculty of Graduate and Postdoctoral Studies, Department of Biology, University of Ottawa, Ottawa, ON, Canada; Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada. Electronic address: alexandra.long@hc-sc.gc.ca.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Long
authors.affiliation: Air Health Science Division, Water and Air Quality Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lemieux
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Faculty of Graduate and Postdoctoral Studies, Department of Biology, University of Ottawa, Ottawa, ON, Canada; Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
mesh_terms: D000818:Animals; D018736:DNA Adducts / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D007763:Lac Operon / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D018736:DNA Adducts; D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; C095911:polycyclic aromatic hydrocarbons-DNA adduct
keywords: Genotoxicity; Micronucleus; Mutation; Muta™Mouse; Polycyclic aromatic hydrocarbon