title: Screening of bisphenol A, triclosan and paraben analogues as modulators of the glucocorticoid and androgen receptor activities.
abstract: A homeostasis of the glucocorticoid and androgen endocrine system is essential to human health. Their disturbance can lead to various diseases, for example cardiovascular, inflammatory and autoimmune diseases, infertility, cancer. Fifteen widely used industrial chemicals that disrupt endocrine activity were selected for evaluation of potential (anti)glucocorticoid and (anti)androgenic activities. The human breast carcinoma MDA-kb2 cell line was utilized for reporter gene assays, since it expresses both the androgen and the glucocorticoid-responsive reporter. Two new antiandrogens, 4,4'-sulfonylbis(2-methylphenol) (dBPS) and 4,4'-thiodiphenol (THIO), and two new antiglucocorticoids, bisphenol Z and its analog bis[4-(2-hydroxyethoxy)phenyl] sulfone (BHEPS) were identified. Moreover, four new glucocorticoid agonists (methyl paraben, ethyl paraben, propyl paraben and bisphenol F) were found. To elucidate the structure-activity relationship of bisphenols, we performed molecular docking experiments with androgen and glucocorticoid receptor. These docking experiments had shown that bulky structures such as BHEPS and bisphenol Z act as antiglucocorticoid, because they are positioned toward helix H12 in the antagonist conformation and could therefore be responsible for H12 conformational change and the switch between agonistic and antagonistic conformation of receptor. On the other hand smaller structures cannot interact with H12. The results of in vitro screening of fifteen industrial chemicals as modulators of the glucocorticoid and androgen receptor activities demand additional in vivo testing of these chemicals for formulating any relevant hazard identification to human health.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Katra
authors.initials: K
authors.lastname: Kolšek
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič Raščan
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: marija.sollner@ffa.uni-lj.si.
authors.forename: Marija
authors.initials: M
authors.lastname: Sollner Dolenc
mesh_terms: D001559:Benzhydryl Compounds / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D010226:Parabens / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000031:analogs & derivatives*
chemical_list: D001559:Benzhydryl Compounds; D010226:Parabens; D010636:Phenols; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D014260:Triclosan
keywords: Androgen receptor; Bisphenol A; Glucocorticoid receptor; Parabens; Triclocarban; Triclosan