Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that interact in a complex manner with both the aryl hydrocarbon receptor (AhR) and estrogen receptors (ER). Their potential endocrine-disrupting activities may depend on both inhibitory AhR-ER cross-talk and on AhR-dependent metabolic production of estrogenic PAH metabolites. Here, we analyzed the impact of AhR on estrogen-like effects of PAHs, such as benzo[a]pyrene (BaP), in particular, on control of cell cycle progression/cell proliferation. Using AhR knockout variant of estrogen-sensitive human breast cancer MCF-7 cells (MCF-7 AhRKO cells), we observed that the AhR-dependent control of cytochrome P450 family 1 (CYP1) expression played a major role in formation of estrogenic BaP metabolites, most notably 3-OH-BaP, which contributed to the ER-dependent induction of cell cycle progression/cell proliferation. Both BaP metabolism and the BaP-induced S-phase transition/cell proliferation were inhibited in MCF-7 AhRKO cells, whereas these cells remained sensitive towards both endogenous estrogen 17β-estradiol or hydroxylated BaP metabolites. BaP was found to increase the activity of ER-dependent luciferase reporter gene in wild-type MCF-7 cells; however, unlike its hydroxylated metabolite, BaP failed to stimulate luciferase activity in MCF-7 AhRKO cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benz[a]anthracene or 3-methylcholanthrene, were diminished in MCF-7 AhRKO cells. Ectopic expression of human CYP1A1 and CYP1B1 enzymes partly restored both BaP metabolism and its effects on cell proliferation. Taken together, our data suggest that the AhR-dependent metabolism of PAHs contributes significantly to the impact of PAHs on cell proliferation in estrogen-sensitive cells.

• MeSH
• Cell Culture Techniques MeSH
• Cell Cycle drug effects   genetics   MeSH
• Cytochrome P-450 CYP1A1 genetics   metabolism   MeSH
• Cytochrome P-450 CYP1B1 genetics   metabolism   MeSH
• Endocrine Disruptors metabolism   toxicity   MeSH
• Gene Expression drug effects   MeSH
• Genetic Vectors MeSH
• Gene Knockdown Techniques MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Plasmids MeSH
• Polycyclic Aromatic Hydrocarbons metabolism   toxicity   MeSH
• Cell Proliferation drug effects   genetics   MeSH
• Receptors, Aryl Hydrocarbon genetics   metabolism   MeSH
• Receptors, Estrogen genetics   metabolism   MeSH
• Genes, Reporter MeSH
• Transfection MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CYP1A1 protein, human MeSH Browser
• CYP1B1 protein, human MeSH Browser
• Cytochrome P-450 CYP1A1 MeSH
• Cytochrome P-450 CYP1B1 MeSH
• Endocrine Disruptors MeSH
• Polycyclic Aromatic Hydrocarbons MeSH
• Receptors, Aryl Hydrocarbon MeSH
• Receptors, Estrogen MeSH

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

• Keywords
• Airborne polychlorinated biphenyls, Endocrine disruption, HydroxyLated PCBs, Metabolism of xenobiotics, Tumor promotion,
• MeSH
• Cell Line MeSH
• Endocrine Disruptors metabolism   toxicity   MeSH
• Epithelial Cells drug effects   MeSH
• Hydroxylation MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants toxicity   MeSH
• Humans MeSH
• Neoplasms metabolism   MeSH
• Polychlorinated Biphenyls metabolism   toxicity   MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Receptors, Steroid metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endocrine Disruptors MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants MeSH
• Polychlorinated Biphenyls MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear MeSH
• Receptors, Steroid MeSH

PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.

• Keywords
• Androgen receptor, Atropisomer, Chiral, Constitutive androstane receptor, Estrogen receptors, Polychlorinated biphenyl, Pregnane X receptor,
• MeSH
• Biotransformation MeSH
• Humans MeSH
• Polychlorinated Biphenyls chemistry   MeSH
• Receptors, Cytoplasmic and Nuclear chemistry   metabolism   MeSH
• Stereoisomerism MeSH
• Receptors, Steroid chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2,3,6,2',3',6'-hexachlorobiphenyl MeSH Browser
• Polychlorinated Biphenyls MeSH
• Receptors, Cytoplasmic and Nuclear MeSH
• Receptors, Steroid MeSH