ArticleProceedings of the National Academy of Sciences of the United States of America2021
Mechanistic insights into the synergistic activation of the RXR-PXR heterodimer by endocrine disruptor mixtures.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 68 citations in OpenAlex.
- Impact of glyphosate and its mixture with 2,4-D and dicamba on gut biochemical function, intestinal barrier integrity and microbiome composition in adult rats with prenatal commencement of exposure.Archives of toxicology · 2026Article
- Differential expression of PPAR isoforms in streptozotocin induced model of sporadic alzheimer's disease in zebrafish.Molecular biology reports · 2026Article
- Relevance and challenges of exposome studies for environmental health research.Environmental health : a global access science source · 2026Review
- Prioritising research on endocrine disruption in the marine environment: a global perspective.Biological reviews of the Cambridge Philosophical Society · 2026Review
- Epoxy tetrahydrophthalimides as potential bioactive agents: synthesis and computational study.Pest management science · 2025Article
- Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.Oncogenesis · 2025Article
- Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation.Journal of medicinal chemistry · 2025Article
- A two-in-one expression construct for biophysical and structural studies of the human pregnane X receptor ligand-binding domain, a pharmaceutical and environmental target.Acta crystallographica. Section F, Structural biology communications · 2025Article
- An abundant ginger compound furanodienone alleviates gut inflammation via the xenobiotic nuclear receptor PXR in mice.Nature communications · 2025Article
- Engineered nanofiber scaffolds prime chromatin reorganization to sensitize cells for long-term and low-dose chemical hazard detection.Frontiers in pharmacology · 2025Article
- Computationally-Assisted Discovery and Assignment of a New Class of 6/6/5/5 Fused-Ring Diterpene Acting as Pregnane X Receptor Ligands fromJournal of natural products · 2024Article
- Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- First characterization of the nuclear receptor superfamily in the Mediterranean musselPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Article
- Review
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- Basic concepts of mixture toxicity and relevance for risk evaluation and regulation.Archives of toxicology · 2023Article
- Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions.Nature communications · 2023Article
- Article
- Expanding the Library of 1,2,4-Oxadiazole Derivatives: Discovery of New Farnesoid X Receptor (FXR) Antagonists/Pregnane X Receptor (PXR) Agonists.Molecules (Basel, Switzerland) · 2023Article
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Humans are chronically exposed to mixtures of xenobiotics referred to as endocrine-disrupting chemicals (EDCs). A vast body of literature links exposure to these chemicals with increased incidences of reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, chemicals have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects. Our previous work shed light on a mechanism by which a binary mixture of xenobiotics activates PXR in a synergistic fashion. Structural analysis revealed that mutual stabilization of the compounds within the ligand-binding pocket of PXR accounts for the enhancement of their binding affinity. In order to identify and characterize additional active mixtures, we combined a set of cell-based, biophysical, structural, and in vivo approaches. Our study reveals features that confirm the binding promiscuity of this receptor and its ability to accommodate bipartite ligands. We reveal previously unidentified binding mechanisms involving dynamic structural transitions and covalent coupling and report four binary mixtures eliciting graded synergistic activities. Last, we demonstrate that the robust activity obtained with two synergizing PXR ligands can be enhanced further in the presence of RXR environmental ligands. Our study reveals insights as to how low-dose EDC mixtures may alter physiology through interaction with RXR-PXR and potentially several other nuclear receptor heterodimers.
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