Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor.
By using a yeast detection system for androgenic and antiandrogenic effects of chemicals, we identified bisphenol A (BPA) and nonylphenol (NP) as antiandrogens. In this study, we report molecular mechanisms for the antiandrogenic action of BPA and NP. In the ARhLBD-activating signal cointegrator 1 (ASC1) yeast two-hybrid system, which reflects the androgen-dependent interaction between androgen receptor (AR) and its coactivator, ASC1, BPA and NP acted as potent AR antagonists comparable to a known strong antagonist, cyproterone acetate. Ligand competition assays revealed that [3H]5alpha-dihydroxytestosterone (DHT) binding to AR is inhibited a maximum of 30 and 40% at approximately 5 nM of NP and 50 nM of BPA, respectively. In addition, the nuclear translocation of green fluorescent protein (GFP)-AR fusion protein in the presence of testosterone was affected by the addition of BPA and NP, which cause rather dispersed distribution of GFP-AR between the nuclear and the cytoplasmic compartments. Furthermore, in transient transfection assays, BPA and NP inhibited androgen-induced AR transcriptional activity. Taken together, the results suggest that BPA and NP affect multiple steps of the activation and function of AR, thereby inhibiting the binding of native androgens to AR, AR nuclear localization, AR interaction with its coregulator, and its subsequent transactivation. These data may help us better understand the biological alterations induced by these environmental compounds.
Lee
Hyun Ju
HJ
Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea.
Chattopadhyay
Soma
S
Gong
Eun-Yeung
EY
Ahn
Ryun Sup
RS
Lee
Keesook
K
D000726:Androgen Antagonists / Q000633:toxicity*; D001559:Benzhydryl Compounds; D002467:Cell Nucleus / Q000378:metabolism; D005453:Fluorescence; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics; D010636:Phenols / Q000633:toxicity*; D011869:Radioligand Assay; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000098826:Bisphenol A Compounds
D000726:Androgen Antagonists; D001559:Benzhydryl Compounds; D049452:Green Fluorescent Proteins; D008024:Ligands; D008164:Luminescent Proteins; D010636:Phenols; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; C025256:nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds