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Toxicological Sciences 65, 43-51 (2002)
Copyright © 2002 by the Society of Toxicology

CARCINOGENICITY

Inhibition of Gap-Junctional Intercellular Communication by Environmentally Occurring Polycyclic Aromatic Hydrocarbons

Ludek Bláha*,{dagger}, Petra Kapplová*,{dagger}, Jan Vondrácek*,{ddagger}, Brad Upham§ and Miroslav Machala*,1

* Veterinary Research Institute, Hudcova 70, CZ-62132 Brno, Czech Republic; {dagger} Research Center for Atmospheric and Environmental Chemistry and Ecotoxicology (RECETOX), Masaryk University, CZ-63700 Brno, Czech Republic; {ddagger} Institute of Biophysics, Czech Academy of Sciences, CZ-61265 Brno, Czech Republic; and § Department of Pediatrics and Human Development and the National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824

Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although µM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50–75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.

Key Words: gap-junctional intercellular communication (GJIC); polycyclic aromatic hydrocarbons (PAHs); nongenotoxic carcinogenicity; tumor promotion; in vitro.


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