Bisphenol A and its analogues activate human pregnane X receptor

Area of Science:

• Endocrinology
• Toxicology
• Molecular Biology

Background:

• Bisphenol A (BPA) is a widespread chemical found in consumer products and environmental samples.
• BPA and similar compounds are known endocrine disruptors that can activate the pregnane X receptor (PXR).
• The precise mechanisms by which these chemicals activate PXR are not fully understood.

Purpose of the Study:

• To elucidate the mechanism of interaction and activation of PXR by BPA.
• To assess the PXR binding and activation potential of selected BPA analogues.

Main Methods:

• Utilized cell-based reporter assays to study BPA-PXR interactions.
• Employed in silico ligand-PXR docking studies and site-directed mutagenesis.
• Investigated PXR target gene regulation by BPA and analogues in human LS180 cells.

Main Results:

• BPA and several analogues were identified as potent agonists for human PXR (hPXR), with no effect on mouse PXR.
• Key residues in the hPXR ligand-binding pocket interacting with BPA were identified.
• Structural requirements for BPA analogues to activate hPXR were determined.
• BPA and its analogues demonstrated induction of PXR target gene expression in human cells.

Conclusions:

• The study clarifies the mechanism of BPA interaction and activation of human PXR.
• Findings provide a mechanistic basis for understanding some adverse human health effects associated with BPA exposure.