Defining estrogenic mechanisms of bisphenol A analogs through high throughput microscopy-based contextual assays

Chem Biol. 2014 Jun 19;21(6):743-53. doi: 10.1016/j.chembiol.2014.03.013. Epub 2014 May 22.


Environmental exposures to chemically heterogeneous endocrine-disrupting chemicals (EDCs) mimic or interfere with hormone actions and negatively affect human health. Despite public interest and the prevalence of EDCs in the environment, methods to mechanistically classify these diverse chemicals in a high throughput (HT) manner have not been actively explored. Here, we describe the use of multiparametric, HT microscopy-based platforms to examine how a prototypical EDC, bisphenol A (BPA), and 18 poorly studied BPA analogs (BPXs), affect estrogen receptor (ER). We show that short exposure to BPA and most BPXs induces ERα and/or ERβ loading to DNA changing target gene transcription. Many BPXs exhibit higher affinity for ERβ and act as ERβ antagonists, while they act largely as agonists or mixed agonists and antagonists on ERα. Finally, despite binding to ERs, some BPXs exhibit lower levels of activity. Our comprehensive view of BPXs activities allows their classification and the evaluation of potential harmful effects. The strategy described here used on a large-scale basis likely offers a faster, more cost-effective way to identify safer BPA alternatives.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / chemistry*
  • Benzhydryl Compounds / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / antagonists & inhibitors*
  • Estrogen Receptor beta / metabolism
  • HeLa Cells
  • High-Throughput Screening Assays*
  • Humans
  • MCF-7 Cells
  • Microscopy
  • Phenols / adverse effects
  • Phenols / chemistry*
  • Phenols / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Benzhydryl Compounds
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Phenols
  • bisphenol A