Aryl Hydrocarbon Receptor-Dependent Metabolism Plays a Significant Role in Estrogen-Like Effects of Polycyclic Aromatic Hydrocarbons on Cell Proliferation

Varování

Publikace nespadá pod Lékařskou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.

Autoři	HYZDALOVA M. PIVNIČKA Jakub ZAPLETAL Ondřej VAZQUEZ-GOMEZ G. MATTHEWS J. NEČA Jiří PĚNČÍKOVÁ Kateřina MACHALA M. VONDRÁČEK Jan
Rok publikování	2018
Druh	Článek v odborném periodiku
Časopis / Zdroj	Toxicological sciences
Fakulta / Pracoviště MU	Přírodovědecká fakulta
Citace
www	http://dx.doi.org/10.1093/toxsci/kfy153
Doi	http://dx.doi.org/10.1093/toxsci/kfy153
Klíčová slova	aryl hydrocarbon receptor; polycyclic aromatic hydrocarbons; cytochrome P450 family 1; hydroxylated metabolites; estrogen receptor; cell cycle
Popis	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 benzotalpyrene (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 AhR(KO) 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 AhR(KO) cells, whereas these cells remained sensitive towards both endogenous estrogen 17 beta-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 AhR(KO) cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benzfajanthracene or 3-methylcholanthrene, were diminished in MCF-7 AhR(KO) 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.