ToxSci Advance Access originally published online on October 13, 2004
Toxicological Sciences 2005 83(1):53-63; doi:10.1093/toxsci/kfi009
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Toxicological Sciences vol. 83 no. 1 © Society of Toxicology 2005; all rights reserved.
Aryl Hydrocarbon Receptor-Activating Polychlorinated Biphenyls and Their Hydroxylated Metabolites Induce Cell Proliferation in Contact-Inhibited Rat Liver Epithelial Cells
ek*,
,1
zslav Bryja
,
ina Chramostová*má
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* Laboratory of Cytokinetics, Institute of Biophysics, 612 65 Brno, Czech Republic; Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic; Center of Cell Therapy and Tissue Repair, Charles University, 150 06 Prague, Czech Republic; Department of Molecular Embryology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic; ¶ Institute of Toxicology, Johannes Gutenberg-University, 55131 Mainz, Germany; and || Laboratory of Molecular Embryology, Mendel University Brno, 613 00 Brno, Czech Republic
Received August 13, 2004; accepted October 7, 2004
Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The ‘dioxin-like’ PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the ‘non-dioxin-like’ compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 µM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.
Key Words: cell proliferation; tumor promotion; contact inhibition; PCBs; liver epithelial cells.
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