Abstract 285: Bisphenol A Increases Atherosclerosis Mediated by the Human Pregnane X Receptor

Abstract

Objective: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) in multiple large-scale human population studies but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor (PXR) which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro-atherogenic effects in animal models upon activation. BPA is a potent agonist of human PXR but has no effects on mouse or rat PXR activity, which confounds the use of rodent models to evaluate mechanisms of BPA-mediated CVD risk. This study aims to investigate the atherogenic mechanism of BPA using a novel PXR-humanized mouse model. Approach and Results: We generated PXR-humanized ApoE deficient (huPXR•ApoE -/- ) mice that respond to human PXR ligands and therefore constitute a model to study the atherogenic effects of BPA. Feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. We found that exposure to BPA increased atherosclerosis in huPXR•ApoE -/- mice but not their control littermates. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR•ApoE -/- mice. Conclusions: Our findings provide a molecular mechanism linking BPA exposure to increased risk of CVD in exposed individuals. PXR is therefore a relevant target for future risk assessment of BPA and related environmental chemicals in humans.