ToxSci Advance Access published online on August 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg209
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Veterinary Research Institute, Department of Chemistry and Toxicology, Hudcova 70, 62132 Brno, Czech Republic
* To whom correspondence should be addressed. E-mail: machala{at}vri.cz.
Polychlorinated biphenyls (PCBs), a structurally diverse group of environmental pollutants, are effective promoters in two stage cancer models, which implies that epigenetic mechanisms are involved. Inhibition of gap junctional intercellular communication (GJIC) belongs among critical epigenetic events of tumor promotion. We determined the relative potencies of a series of environmentally relevant PCB congeners to inhibit GJIC in vitro in a rat liver epithelial cell line with pluripotent-oval cell characteristics. The nonplanar PCBs were potent inhibitors of GJIC, whereas the coplanar PCBs did not inhibit GJIC. We then compared the effects of the coplanar PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the noncoplanar PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) with effects of two model GJIC inhibitors, a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In contrast to TPA or EGF, PCB 153 elicited a long-term down-regulation of GJIC (up to 48 h). Using Western blot analysis with phospho-specific antibodies it was found that PCB153 and not PCB126 activated mitogen-activated protein kinases ERK1/2, however in contrast to TPA and EGF, this activation was observed at the time points subsequent to GJIC inhibition. Moreover, blocking of ERK1/2 activation did not prevent the GJIC inhibition induced by PCB153. Therefore, additional intracellular signaling pathways potentially involved in the down-regulation of GJIC by PCBs were screened by using specific chemical probes inhibiting serine/threonine kinases, tyrosine kinases and phospholipases. The selective inhibition of diacylglycerol lipase partially blocked and the selective inhibition of Src kinases and phosphatidylcholine-selective phospholipase C (PC-PLC) completely blocked the inhibitory effects of the noncoplanar PCB on GJIC, indicating that PC-PLC and Src might be upstream regulators of noncoplanar PCB-induced inhibition of GJIC.
© 2003 Society of Toxicology
In Vitro Toxicology and Alternative Testing
Inhibition of Gap Junctional Intercellular Communication by Noncoplanar Polychlorinated Biphenyls: Inhibitory Potencies and Screening for Potential Mode(s) of Action
k Bláha 2,
ek 3,
2 Veterinary Research Institute, Department of Chemistry and Toxicology, Hudcova 70, 62132 Brno, Czech Republic; RECETOX, Masaryk University, Brno, Czech Republic
3 Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic; Veterinary Research Institute, Department of Chemistry and Toxicology, Hudcova 70, 62132 Brno, Czech Republic
4 Department of Pediatrics & Human Development, and the National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI, USA
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