Toxicity of Hydroxylated and Quinoid PCB Metabolites: Inhibition of Gap Junctional Intercellular Communication and Activation of Aryl Hydrocarbon and Estrogen Receptors in Hepatic and Mammary Cells

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Abstract
In the present study, a series of 32 hydroxy- and dihydroxy-polychlorinated biphenyls (OH-PCBs) and PCB-derived quinones were prepared and evaluated for their in vitro potencies to downregulate gap junctional intercellular communication (GJIC) and to activate the aryl hydrocarbon receptor (AhR) and the estrogen receptor alpha (ER) in well-established liver and mammary cell models. The rat liver epithelial cell line WB-F344 was used for in vitro determination of GJIC inhibition; the AhR-inducing activity was determined in the rat hepatoma H4IIE.Luc cells stably transfected with a luciferase reporter gene; ER-mediated activity was measured in two breast carcinoma cell lines, MVLN and T47D.Luc, stably transfected with luciferase under the control of estrogen responsive element. Acute inhibition of GJIC, potentially associated with tumor promotion, was detected after treatment with all OH-PCBs under study, with the persistent OH-PCBs being the strongest ones. Several compounds were found to significantly induce the AhR-mediated activity, including 4'-OH-PCB 79, a metabolite of PCB 77, and 2-(4'-chloro)- and 2-(3',4'-dichloro)-1,4-benzoquinones and 1,4-hydroquinones. Low molecular weight OH-PCBs, such as X-hydroxy, 4'-, and 3',4'dihydroxy-4-chlorobiphenyl, elicited significant estrogenic activity and potentiated effect of 17 estradiol. Antiestrogenic potencies, determined in the presence of 17beta-estradiol, were found for persistent 4-OH-PCB 187, 4-OH-PCB 146, and some low chlorinated PCB derivatives. However, no apparent association between induction of AhR activity and antiestrogenicity was observed. The majority of the OH-PCBs suppressed the 17beta-estradiol response only at cytotoxic concentrations. Spearman's rank correlations were calculated for these biological data and the physicochemical descriptors, hydrophobicity (log P), molar volume, pK(a), log D, and dihedral angle. Significant correlations were found between potency to downregulate GJIC and log P and molar volume (R = - 0.7, p < 0.0001). Antiestrogenic effects were also negatively correlated with hydrophobicity and molar volume. No significant correlations among other biological end points and the physicochemical descriptors were observed for the entire set of compounds. These results show that oxygenated PCB metabolites are capable of multiple adverse effects, including gap junction inhibition, AhR-mediated activity, and (anti)estrogenicity. The inhibition of GJIC by OH-PCBs represents a novel mode of action of both the lower chlorinated and the persisting high molecular weight OH-PCBs.

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