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