Carcinogenesis Advance Access originally published online on August 31, 2006
Carcinogenesis 2007 28(2):471-478; doi:10.1093/carcin/bgl157
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4-Monochlorobiphenyl (PCB3) induces mutations in the livers of transgenic Fisher 344 rats
Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe (TH) Kaiserstrasse 12, D-76131 Karlsruhe, Germany
1 Department of Occupational and Environmental Health, College of Public Health, The University of Iowa 100 Oakdale Campus-IREH, Iowa City, IA 52242-5000, USA
2 Department of Pathology, The University of Iowa Iowa City, IA 52242, USA
*To whom correspondence should be addressed. Tel: +1 319 335 4650; Fax +1 319 335 4290; Email: gabriele-ludewig{at}uiowa.edu
4-Monochlorobiphenyl (PCB3) is found in small amounts in commercial PCB mixtures, indoor and outdoor air, and in food. In contrast to highly chlorinated congeners that are more resistant to metabolic attack, PCB3 is more readily converted by xenobiotic-metabolizing enzymes to monohydroxy-PCBs and further to dihydroxy-metabolites, which can be oxidized to quinones. Our recent studies demonstrated the initiating action of PCB3 in the livers of male rats. Therefore we hypothesized that PCB3 and/or its metabolite(s) are mutagenic in rat livers in vivo. To investigate the mutagenicity and the types of mutations generated by PCB3, male Fischer 344 BigBlue® rats, transgenic for the lacI gene, were injected intraperitoneally with PCB3 (600 µmol/kg), 4-hydroxy-PCB3 (4-HO-PCB3, 400 µmol/kg), 3-methylcholanthrene (3-MC, 300 µmol/kg, positive control) and corn oil (negative control) once per week, for 4 weeks. Animals were killed 17 days after the last injection and the mutant frequency of the liver lacI gene determined. 3-MC induced a 4-fold increase of the mutant frequency of the lacI gene in the liver. The mutant frequency in PCB3-treated animals was also significantly elevated. In contrast, 4-HO-PCB3 induced a non-significant doubling of the mutant frequency. The mutation spectrum of solvent control mutants was characterized by transitions, whereas in 3-MC-animals, transversion and frameshift mutations predominated. The PCB3-induced mutation spectrum was similar to that of the 3-MC-induced mutants. In contrast, the mutation spectrum of the 4-HO-PCB3 group hardly differed from that of the control animals. This study demonstrates for the first time the mutagenicity of a PCB in vivo.
Abbreviations: BW, body weight; 3-MC, 3-methylcholanthrene; PCB, polychlorinated biphenyl, PCB3, 4-monochlorobiphenyl; pfu, plaque forming unit; PCR, polymerase chain reaction; PND, postnatal day; X-gal, 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside
Received April 27, 2006; revised August 9, 2006; accepted August 15, 2006.
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