Antiandrogenic Effects of Bisphenol A and Nonylphenol on the Function of Androgen Receptor

Abstract

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.

Investigation of the Effects of Bisphenol A on the Histology and Ultrastructure of Prostate and Seminal Vesicle Glands in Rats

“…It also showed that BPA has adverse effects on the reproductive system in male rats. BPA is reported to have both estrogenic and antiandrogenic effects (6,23,24). Several toxicological studies (25) pointed out that rodents exposed to BPA during the prenatal or perinatal period show a large variety of adverse reproductive outcomes, including decreased epididymal weight and daily sperm production (26,27) and increased prostate weight (28), which is somewhat similar to our findings.…”

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

“…We used several known competitors (unlabeled DHT, BIC, and OHF) of DHT as positive controls (38,51). The IC 50 (the concentration of ligand that were able to inhibit AR-DHT binding by 50%) of DIMN was 1-2 M, while the IC 50 values of unlabeled DHT, OHF, and BIC were 1-2 nM, 0.4 -0.5 M, and 0.9 M, respectively ( Fig.…”

“…Radiolabeled dihydrotestosterone ([ Plasmids-The mammalian expression plasmids of the mouse AR (pcDNA3.AR), mouse GR (pcDNA3.GR), pARE 2 -TATA-Luc, PSA-Luc, MMTV-Luc, GFP-AR, pCR3.1-SRC1, and pSG5-HA-GRIP-1 (SRC-2) have been previously described (35)(36)(37)(38)(39)(40). The pcDNA3.ER␣ (human ER␣ expression plasmid) and ERE-Luc reporter constructs were kindly provided by Dr. J. W. Lee (Baylor College of Medicine) (41).…”

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

“…BPA exposure has also been associated with reproductive dysfunctions, including reduction of testicular weight and sperm count, alterations of hormone levels, and impairment of spermatogenesis (Jin et al, 2013;Pacchierotti et al, 2008;Sakaue et al, 2001;Tiwari and Vanage, 2013;Wang et al, 2016). The mechanism of action of BPA has been investigated with respect to its estrogenic activity, such as effects on steroid hormone synthesis, and androgen receptor (AR) antagonism (Kitamura et al, 2005;Lee et al, 2003;Vinggaard et al, 2008;Zhang et al, 2011). Due to public concern about these potential adverse effects of BPA, the U.S. Food and Drug Administration (FDA) has enforced restrictions on the manufacture and usage of BPA (FDA, 2012(FDA, , 2013.…”