Modulation of oestrogen receptor signalling by association with the activated dioxin receptor

Nature. 2003 May 29;423(6939):545-50. doi: 10.1038/nature01606.


Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects. Although their anti-oestrogenic actions are well described, dioxins can also induce endometriosis and oestrogen-dependent tumours, implying possible oestrogenic effects. However, the molecular mechanism underlying oestrogen-related actions of dioxins remains largely unknown. A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins. Here we show that the agonist-activated AhR/Arnt heterodimer directly associates with oestrogen receptors ER-alpha and ER-beta. This association results in the recruitment of unliganded ER and the co-activator p300 to oestrogen-responsive gene promoters, leading to activation of transcription and oestrogenic effects. The function of liganded ER is attenuated. Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-alpha-/- ovariectomized mice. Our findings suggest a novel mechanism by which ER-mediated oestrogen signalling is modulated by a co-regulatory-like function of activated AhR/Arnt, giving rise to adverse oestrogen-related actions of dioxin-type environmental contaminants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Binding Sites
  • COS Cells
  • DNA-Binding Proteins*
  • Dioxins / pharmacology
  • Environmental Pollutants / pharmacology
  • Estrogens / pharmacology
  • Female
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Humans
  • Methylcholanthrene / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Ovariectomy
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / chemistry
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Response Elements / genetics
  • Signal Transduction* / drug effects
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Uterus / drug effects


  • ARNT protein, human
  • Arnt protein, mouse
  • DNA-Binding Proteins
  • Dioxins
  • Environmental Pollutants
  • Estrogens
  • Receptors, Aryl Hydrocarbon
  • Receptors, Estrogen
  • Transcription Factors
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Methylcholanthrene