title: Bisphenol A affects androgen receptor function via multiple mechanisms.
abstract: Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR.
authors.affiliation: DNTP Biomolecular Screening Branch, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, NC, USA. teng1@niehs.nih.gov
authors.forename: Christina
authors.initials: C
authors.lastname: Teng
authors.forename: Bonnie
authors.initials: B
authors.lastname: Goodwin
authors.forename: Keith
authors.initials: K
authors.lastname: Shockley
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Norris
authors.forename: B Alex
authors.initials: BA
authors.lastname: Merrick
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D015741:Metribolone / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010636:Phenols / Q000633:toxicity*; D011944:Receptors, Androgen / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D049452:Green Fluorescent Proteins; D015741:Metribolone; D010636:Phenols; D011944:Receptors, Androgen; C485184:enhanced green fluorescent protein; C006780:bisphenol A; D000098826:Bisphenol A Compounds
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