ToxSci Advance Access published online on August 8, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm204
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Quinoid Metabolites of 4-monochlorobiphenyl (PCB3) Induce Gene Mutations in Cultured Chinese Hamster V79 Cells
* University of Karlsruhe (TH), Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, Kaiserstraße 12, D-76131 Karlsruhe, Germany
The University of Iowa, College of Public Health, Dept. of Occupational and Environmental Health, 100 Oakdale Campus, Iowa City, IA 52242-5000
* Correspondence: Dr. Leane Lehmann, Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe, Kaiserstraße 12, D-76131 Karlsruhe, Germany, Tel.: +49-721-608-4177; fax +49-721-608-7255, E-mail address: leane.lehmann{at}lmc.uni-karlsruhe.de
Received May 22, 2007; revision received July 17, 2007; accepted July 31, 2007
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Abstract |
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4-Monochlorbiphenyl (PCB3) is a component of commercial 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 (HQ, e.g. 2’,5’-HQ and 3’,4’-HQ), and can be further oxidized to quinones (Q, 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 hydroquinones 3’,4’-HQ and 2’,5’-HQ, and of the quinones 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 sub-micromolar 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.