title: Quantitative relationships between lacZ mutant frequency and DNA adduct frequency in Muta™Mouse tissues and cultured cells exposed to 3-nitrobenzanthrone.
abstract: The frequency of stable DNA adducts in a target tissue can be used to assess biologically effective dose; however, the utility of the metric in a risk assessment context depends on the likelihood that the DNA damage will be manifested as mutation. Previously, we employed the Muta™Mouse system to examine the induction of lacZ mutants and DNA adducts following exposure to the well-studied mutagenic carcinogen 3-nitrobenzanthrone (3-NBA). In this follow-up work, we examined the empirical relationships between total adduct frequency and mutant frequency (MF) in tissues and cultured cells following acute 3-NBA exposure. The results show a significant induction of DNA damage and lacZ mutants in liver, colon and bone marrow, as well as FE1 pulmonary epithelial cells. In contrast, lung and small intestine samples had low, but significantly elevated adduct levels, with no significant increases in lacZ MF. Additional analyses showed a significant relationship between the mutagenic efficiency of total adducts, measured as the slope of the relationships between MF and total adduct frequency, and tissue-specific mitotic index (MI). The lack of mutation response in lung, in contrast to the high in vitro MF in FE-1 lung cells, is likely related to the 100-fold difference in MI. The lack of small intestine mutagenic response may be related to limited metabolic capacity, differences in DNA repair, and /or chemically induced apoptosis that has been observed for other potent mutagens. The results indicate that interpretation of adduct frequency values in a risk assessment context can be improved by considering the MI of the target tissue; however, more generalised interpretation is hampered by tissue-specific variations in metabolic capacity and damage processing. The work provides a proof of principle regarding the use of the Muta™Mouse system to critically examine the health risks associated with tissue-specific adduct loads.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture 0803A, 50 Colombine Driveway, Ottawa, Ontario K1A 0K9, Canada and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Tunney's Pasture 0803A, 50 Colombine Driveway, Ottawa, Ontario K1A 0K9, Canada and.
authors.forename: George R
authors.initials: GR
authors.lastname: Douglas
authors.affiliation: King's College London, Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.affiliation: King's College London, Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D007763:Lac Operon / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009154:Mutation; D009928:Organ Specificity; D019076:Transgenes
chemical_list: D001551:Benz(a)Anthracenes; D018736:DNA Adducts; C117220:3-nitrobenzanthrone