Integrated in silico and in vivo approaches to investigate effects of BDE-99 mediated by the nuclear receptors on developing zebrafish

Environ Toxicol Chem. 2018 Mar;37(3):780-787. doi: 10.1002/etc.4000. Epub 2017 Dec 13.


One of the most abundant polybrominated diphenyl ethers (PBDEs) is 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), which persists and potentially bioaccumulates in aquatic wildlife. Previous studies in mammals have shown that BDE-99 affects development and disrupts certain endocrine functions through signaling pathways mediated by nuclear receptors. However, fewer studies have investigated the potential of BDE-99 to interact with nuclear receptors in aquatic vertebrates such as fish. In the present study, interactions between BDE-99 and nuclear receptors were investigated by in silico and in vivo approaches. This PBDE was able to dock into the ligand-binding domain of zebrafish aryl hydrocarbon receptor 2 (AhR2) and pregnane X receptor (PXR). It had a significant effect on the transcriptional profiles of genes associated with AhR or PXR. Based on the developed cytoscape of all zebrafish genes, it was also inferred that AhR and PXR could interact via cross-talk. In addition, both the in silico and in vivo approaches found that BDE-99 affected peroxisome proliferator-activated receptor alpha (PPARα), glucocorticoid receptor, and thyroid receptor. Collectively, our results demonstrate for the first time detailed in silico evidence that BDE-99 can bind to and interact with zebrafish AhR and PXR. These findings can be used to elaborate the molecular mechanism of BDE-99 and guide more objective environmental risk assessments. Environ Toxicol Chem 2018;37:780-787. © 2017 SETAC.

Keywords: Aryl hydrocarbon receptor; Cross-talk; Docking; Molecular dynamic simulation; Pregnane X receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Computer Simulation*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Regulatory Networks / drug effects
  • Halogenated Diphenyl Ethers / toxicity*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription, Genetic / drug effects
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • Zebrafish Proteins / chemistry
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • 2,2',4,4',5-brominated diphenyl ether
  • Halogenated Diphenyl Ethers
  • Receptors, Cytoplasmic and Nuclear
  • Zebrafish Proteins