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Bisphenol A affects androgen receptor function via multiple mechanisms.

Publication ,  Journal Article
Teng, C; Goodwin, B; Shockley, K; Xia, M; Huang, R; Norris, J; Merrick, BA; Jetten, AM; Austin, CP; Tice, RR
Published in: Chem Biol Interact
May 25, 2013

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.

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Published In

Chem Biol Interact

DOI

EISSN

1872-7786

Publication Date

May 25, 2013

Volume

203

Issue

3

Start / End Page

556 / 564

Location

Ireland

Related Subject Headings

  • Translocation, Genetic
  • Transfection
  • Toxicology
  • Receptors, Androgen
  • Phenols
  • Microbial Sensitivity Tests
  • Metribolone
  • Humans
  • High-Throughput Screening Assays
  • Green Fluorescent Proteins
 

Citation

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Teng, C., Goodwin, B., Shockley, K., Xia, M., Huang, R., Norris, J., … Tice, R. R. (2013). Bisphenol A affects androgen receptor function via multiple mechanisms. Chem Biol Interact, 203(3), 556–564. https://doi.org/10.1016/j.cbi.2013.03.013
Teng, Christina, Bonnie Goodwin, Keith Shockley, Menghang Xia, Ruili Huang, John Norris, B Alex Merrick, Anton M. Jetten, Christopher P. Austin, and Raymond R. Tice. “Bisphenol A affects androgen receptor function via multiple mechanisms.Chem Biol Interact 203, no. 3 (May 25, 2013): 556–64. https://doi.org/10.1016/j.cbi.2013.03.013.
Teng C, Goodwin B, Shockley K, Xia M, Huang R, Norris J, et al. Bisphenol A affects androgen receptor function via multiple mechanisms. Chem Biol Interact. 2013 May 25;203(3):556–64.
Teng, Christina, et al. “Bisphenol A affects androgen receptor function via multiple mechanisms.Chem Biol Interact, vol. 203, no. 3, May 2013, pp. 556–64. Pubmed, doi:10.1016/j.cbi.2013.03.013.
Teng C, Goodwin B, Shockley K, Xia M, Huang R, Norris J, Merrick BA, Jetten AM, Austin CP, Tice RR. Bisphenol A affects androgen receptor function via multiple mechanisms. Chem Biol Interact. 2013 May 25;203(3):556–564.
Journal cover image

Published In

Chem Biol Interact

DOI

EISSN

1872-7786

Publication Date

May 25, 2013

Volume

203

Issue

3

Start / End Page

556 / 564

Location

Ireland

Related Subject Headings

  • Translocation, Genetic
  • Transfection
  • Toxicology
  • Receptors, Androgen
  • Phenols
  • Microbial Sensitivity Tests
  • Metribolone
  • Humans
  • High-Throughput Screening Assays
  • Green Fluorescent Proteins