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.

Department of Chemistry and Toxicology Veterinary Research Institute 62100 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences 61265 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences 61265 Brno Czech Republic Department of Chemistry and Toxicology Veterinary Research Institute 62100 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences 61265 Brno Czech Republic Department of Experimental Biology Faculty of Science Masaryk University 61137 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences 61265 Brno Czech Republic Genomic Medicine and Environmental Toxicology Department Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México C U 04510 Mexico City Mexico

Department of Nutrition Institute of Basic Medical Sciences University of Oslo 0372 Oslo Norway

Citace poskytuje Crossref.org