Mechanistic insights into the synergistic activation of the RXR-PXR heterodimer by endocrine disruptor mixtures.

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.

Pesticide toxicity towards microalgae increases with environmental mixture complexity.

Effect-directed analysis (EDA) aims at identifying the compound(s) responsible for toxicity in a complex environmental sample where several dozens of contaminants can be present. In this study, we used an environmental mixture extracted from the Polar Organic Chemical Integrative Sampler (POCIS) previously immersed downstream a landfill (River Ponteils, South West France), to perform an EDA approach using a microalgal bioassay based on the photosynthetic capacities of diatom (Nitzschia palea) cultures. Adverse effects on photosynthetic capacities were recorded when algae were exposed to the entire POCIS extract (> 85% inhibition at the highest concentration tested). This result was coherent with the detection of diuron and isoproturon, which were the 2 most concentrated herbicides in the extract. However, the EDA process did not allow pointing out the specific compound(s) responsible for the observed toxicity but rather suggested that multiple compounds were involved in the overall toxicity and caused mixture effects.