Open AccessMechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures
Author(s) -
V. Delfosse,
Tiphaine Huet,
Déborah Harrus,
Meritxell Granell,
Maxime Bourguet,
Caroline Gardia-Parège,
Barbara Chiavarina,
Marina Grimaldi,
Sébastien Le Mevel,
Pauline Blanc,
David C.S. Huang,
Jakub Gruszczyk,
Barbara Demeneix,
Sarah Cianférani,
Jean-Baptiste Fini,
Patrick Balaguer,
William Bourguet
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2020551118
Subject(s) - pregnane x receptor , endocrine disruptor , endocrine system , nuclear receptor , xenobiotic , chemistry , transcription factor , biology , microbiology and biotechnology , pharmacology , biochemistry , hormone , enzyme , gene
Significance Many environmental pollutants act as endocrine disruptors that interfere with normal endocrine regulation and promote adverse effects in humans. As a major target of xenobiotics, the pregnane X receptor (PXR) is known to play opposite roles by both facilitating their clearance and mediating their toxic effects. Here, we use structural and functional approaches to describe two converging mechanisms leading to a robust synergistic stimulation of the PXR pathway by mixtures of three chemicals exhibiting very low efficacy when administered separately. This “cocktail effect” relies on two cooperative binding processes that enhance both ligand binding affinity and recruitment of transcriptional coactivators. Our findings show how chemical mixtures may alter physiology and homeostasis at concentrations where individual components are considered safe.