title: Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice.
abstract: BACKGROUND
  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. Interestingly, BPA is a potent agonist of human PXR but does not activate mouse or rat PXR signaling, which confounds the use of rodent models to evaluate mechanisms of BPA-mediated CVD risk. This study aimed to investigate the atherogenic mechanism of BPA using a PXR-humanized mouse model.
  
  
  RESULTS
  A PXR-humanized ApoE deficient (huPXR•ApoE(-/-)) mouse line was generated that respond to human PXR ligands and feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. Exposure to BPA significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of huPXR•ApoE(-/-) mice by 104% (P<0.001) and 120% (P<0.05), respectively. By contrast, BPA did not affect atherosclerosis development in the control littermates without human PXR. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR•ApoE(-/-) mice.
  
  
  CONCLUSIONS
  These findings identify a molecular mechanism that could link 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.
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Sui
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Park
authors.forename: Robert N
authors.initials: RN
authors.lastname: Helsley
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Changcheng
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001559:Benzhydryl Compounds / Q000633:toxicity*; D016122:Brachiocephalic Trunk / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010636:Phenols / Q000633:toxicity*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D000098826:Bisphenol A Compounds
chemical_list: D001057:Apolipoproteins E; D001559:Benzhydryl Compounds; D018955:CD36 Antigens; D004785:Environmental Pollutants; D008055:Lipids; D010636:Phenols; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: atherosclerosis; cells; receptors; risk factors
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