Bisphenol A Increases Atherosclerosis in Pregnane X Receptor‐Humanized ApoE Deficient Mice

Abstract

BackgroundBisphenol 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.Methods and ResultsA 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.ConclusionThese 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.

The role of CD36 receptor in the pathogenesis of atherosclerosis

“…24 Expression of CD36 is enhanced by such pro-inflammatory cytokines as IL-1 (interleukin-1), IL-4 and IL-18, as well as M-CSF (macrophage colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor). [25][26][27][28][29] And increased concentration of proinflammatory cytokines leads to increased expression of CD36 on the surface of macrophages and stimulates the accumulation of ox-LDL. 21,24,30 CD36 expression is reduced by TGF-β (transforming growth factor beta) through phosphorylation of MAPK (mitogen-activated protein kinases), followed by phosphorylation of PPARγ and reduced gene transcription of CD36 in macrophages.…”

Steroid and xenobiotic receptor-mediated effects of bisphenol A on human osteoblasts

“…Therefore, in this study, the high dose of bisphenol A may exert proliferative activity on hFOB cells through the ER pathway. In addition, Sui et al [31] suggested a possible role of bisphenol A in cardiovascular disease in PXR-humanized apolipoprotein-deficient mice. Bisphenol A has also been reported to be the activator of the aryl hydrocarbon receptor (AhR) and SXR in hepatoma cells (HepG2) as well as in human hepatocytes [39].…”

Novel functions of PXR in cardiometabolic disease

“…Interestingly, BPA is a potent agonist for human PXR but not for mouse or rat PXR [14]. To investigate the effects of BPA exposure on atherosclerosis development, a PXR-humanized ApoE deficient mouse model was generated [129]. Feeding study concluded that BPA increased atherosclerosis in ApoE −/− mice in a human PXR-dependent manner [129].…”

“…To investigate the effects of BPA exposure on atherosclerosis development, a PXR-humanized ApoE deficient mouse model was generated [129]. Feeding study concluded that BPA increased atherosclerosis in ApoE −/− mice in a human PXR-dependent manner [129]. BPA-mediated human PXR activation also increased CD36 expression, lipid accumulation and foam cell formation in macrophages of PXR-humanized ApoE −/− deficient mice [129].…”