In silico binding of 4,4'-bisphenols predicts in vitro estrogenic and antiandrogenic activity

Otakuye Conroy-Ben, Isabel Garcia, Sondra S. Teske

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Bisphenols, anthropogenic pollutants, leach from consumer products and have potential to be ingested and are excreted in waste. The endocrine disrupting effects of highly manufactured bisphenols (BPA, BPS, and BPF) are known, however the activities of others are not. Here, the estrogenic and androgenic activities of a series of 4,4'-bisphenols that vary at the inter-connecting bisphenol bridge were determined (BPA, BPB, BPBP, BPC2, BPE, BPF, BPS, and BPZ) and compared to in silico binding to estrogen receptor-alpha and the androgen receptor. Bioassay results showed the order of estrogenicity (BPC2 (strongest)>BPBP>BPB>BPZ>BPE>BPF>BPA>BPS, r2=0.995) and anti-androgenicity (BPC2 (strongest)>BPE, BPB, BPA, BPF, and BPS, r2=0.996) correlated to nuclear receptor binding affinities. Like testosterone and the anti-androgen hydroxyflutamide, bisphenol fit in the ligand-binding domain through hydrogen-bonding at residues Thr877 and Asn705, but also interacted at either Cys784/Ser778 or Gln711 through the other phenol ring. This suggests the 4,4'-bisphenols, like hydroxyflutamide, are androgen receptor antagonists. Hydrogen-bond trends between ERα and the 4,4'-bisphenols were limited to residue Glu353, which interacted with the -OH of one phenol and the -OH of the A ring of 17β-estradiol; hydrogen-bonding varied at the -OH of ring D of 17β-estradiol and the second phenol -OH group. While both estrogen and androgen bioassays correlated to in silico results, conservation of hydrogen-bonding residues in the androgen receptor provides a convincing picture of direct antagonist binding by 4,4'-bisphenols.

Original languageEnglish (US)
JournalEnvironmental Toxicology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

androgen
Hydrogen Bonding
Phenol
Computer Simulation
Hydrogen bonds
Androgen Receptors
Biological Assay
Androgens
Bioassay
hydrogen
Estradiol
phenol
Androgen Receptor Antagonists
Estrogen Receptor alpha
Cytoplasmic and Nuclear Receptors
bioassay
Consumer products
Testosterone
Hydrogen
Estrogens

Keywords

  • Binding affinity
  • Bisphenols
  • Endocrine disruption
  • Yeast estrogen/androgen screen

ASJC Scopus subject areas

  • Toxicology
  • Management, Monitoring, Policy and Law
  • Health, Toxicology and Mutagenesis

Cite this

In silico binding of 4,4'-bisphenols predicts in vitro estrogenic and antiandrogenic activity. / Conroy-Ben, Otakuye; Garcia, Isabel; Teske, Sondra S.

In: Environmental Toxicology, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Bisphenols, anthropogenic pollutants, leach from consumer products and have potential to be ingested and are excreted in waste. The endocrine disrupting effects of highly manufactured bisphenols (BPA, BPS, and BPF) are known, however the activities of others are not. Here, the estrogenic and androgenic activities of a series of 4,4'-bisphenols that vary at the inter-connecting bisphenol bridge were determined (BPA, BPB, BPBP, BPC2, BPE, BPF, BPS, and BPZ) and compared to in silico binding to estrogen receptor-alpha and the androgen receptor. Bioassay results showed the order of estrogenicity (BPC2 (strongest)>BPBP>BPB>BPZ>BPE>BPF>BPA>BPS, r2=0.995) and anti-androgenicity (BPC2 (strongest)>BPE, BPB, BPA, BPF, and BPS, r2=0.996) correlated to nuclear receptor binding affinities. Like testosterone and the anti-androgen hydroxyflutamide, bisphenol fit in the ligand-binding domain through hydrogen-bonding at residues Thr877 and Asn705, but also interacted at either Cys784/Ser778 or Gln711 through the other phenol ring. This suggests the 4,4'-bisphenols, like hydroxyflutamide, are androgen receptor antagonists. Hydrogen-bond trends between ERα and the 4,4'-bisphenols were limited to residue Glu353, which interacted with the -OH of one phenol and the -OH of the A ring of 17β-estradiol; hydrogen-bonding varied at the -OH of ring D of 17β-estradiol and the second phenol -OH group. While both estrogen and androgen bioassays correlated to in silico results, conservation of hydrogen-bonding residues in the androgen receptor provides a convincing picture of direct antagonist binding by 4,4'-bisphenols.",
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