ToxSci Advance Access originally published online on August 8, 2007
Toxicological Sciences 2007 100(1):88-98; doi:10.1093/toxsci/kfm204
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Quinoid Metabolites of 4-Monochlorobiphenyl Induce Gene Mutations in Cultured Chinese Hamster V79 Cells
* Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe (TH), Kaiserstraße 12, D-76131 Karlsruhe, Germany
Department of Occupational and Environmental Health, College of Public Health, University of Iowa, 100 Oakdale Campus, Iowa City, Iowa 52242-5000
1 To whom correspondence should be addressed. Fax: +49-721-608-7255. E-mail: leane.lehmann{at}lmc.uni-karlsruhe.de.
Received May 22, 2007; accepted July 31, 2007
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Abstract |
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4-Monochlorobiphenyl (PCB3) is a component of commercial polychlorinated biphenyl (PCB) products and is an airborne environmental pollutant. Our recent study with transgenic Fischer 344 rats revealed the mutagenic potential of PCB3 in the livers of male rats. PCB3 is converted in vitro to hydroxylated metabolites, to hydroquinones (HQs, e.g., 2',5'-HQ and 3',4'-HQ), and can be further oxidized to quinones (Qs, e.g., 2',5'-Q and 3',4'-Q). This raises the question whether the mutagenic potential of PCB3 is due to the mutagenicity of PCB3 itself or of one of the metabolites. In this study, we investigated the mutagenicity of PCB3, of the monohydroxylated metabolites 2'-hydroxy (HO)-, 3'-HO-, and 4'-HO, of the HQs 3',4'-HQ and 2',5'-HQ and of the Qs 3',4'-Q and 2',5'-Q in cultured Chinese hamster V79 cells. The induction of gene mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene locus by selection with 6-thioguanine. The induction of chromosome and genome mutations was assessed using the micronucleus assay and immunochemical differentiation of micronuclei containing whole chromosomes (kinetochore positive) and DNA fragments (kinetochore negative). The induction of chromosome and genome mutations, detected as micronuclei, was only observed at higher, cytotoxic concentrations of monohydroxylated, catecholic, and quinoid metabolites of PCB3. However, both PCB3-Qs induced a significant increase in the mutant frequency of the hprt gene and did so at submicromolar concentrations. Thus, the present study demonstrates for the first time the mutagenicity of PCB3 metabolites in mammalian cells and identifies quinoid metabolites of PCB3 as potential ultimate mutagens.
Key Words: 4-monochlorobiphenyl; PCB; HPRT mutation; V79 cells.