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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.

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