Mechanisms of atherogenic effects of bisphenol A

描述（由申请人提供）：这是一份R21申请，旨在研究双酚A （BPA）致动脉粥样硬化作用的机制。双酚a是一种基础化学物质，广泛用于许多消费品中的聚碳酸酯塑料中，人类接触双酚a是无处不在的。最近，多项基于人群的研究表明，较高的BPA暴露与心血管疾病（CVD）风险增加有关。然而，导致这些关联的机制尚不清楚。许多环境化学物质可以激活异体受体孕烷X受体（PXR），而PXR又作为异体传感器调节异体代谢，并在不同物种间表现出相当大的药理学差异。最近，我们在动物模型中揭示了PXR的促动脉粥样硬化作用，发现小鼠PXR的慢性激活增加了动脉粥样硬化易感性载脂蛋白E缺陷（ApoE-/-）小鼠的动脉粥样硬化。我们还证明BPA是人类而不是小鼠PXR的有效激活剂，因此，动物模型的选择对于预测BPA的人类风险评估至关重要。因此，我们培育了新型PXR人源化ApoE-/-小鼠（huPXR）。ApoE-/-，即ApoE敲除小鼠，用人类PXR转基因代替小鼠PXR)，可以对人类PXR配体产生反应。我们的中心假设是，暴露于BPA的PXR的慢性激活促进了泡沫细胞的形成，增加了PXR人源化小鼠动脉粥样硬化病变的形成，从而增加了暴露个体患心血管疾病的风险。为了验证这一假设，提出了两个特定的目标：1)长期暴露于与人类暴露剂量相关的BPA是否会增加pxr人源化ApoE-/-小鼠的动脉粥样硬化？2) BPA影响动脉粥样硬化的分子途径是什么？本研究首次在合适的动物模型上研究BPA暴露对动脉粥样硬化的影响，并在分子水平上探索BPA诱导心血管疾病的精确分子机制。

DESCRIPTION (provided by applicant): This is an R21 application intended to investigate the mechanisms of atherogenic effects of bisphenol A (BPA). BPA is a base chemical used extensively in polycarbonate plastics in many consumer products, and human exposure to BPA is ubiquitous. Higher BPA exposure has recently been associated with an increased risk of cardiovascular disease (CVD) in multiple human population-based studies. However, the mechanisms responsible for these associations remain unknown. Many environmental chemicals can activate the xenobiotic receptor pregnane X receptor (PXR) which, in turn, acts as a xenobiotic sensor to regulate xenobiotic metabolism and exhibits considerable differences in its pharmacology across species. Very recently, we revealed PXR's pro-atherogenic effects in animal models and found that chronic activation of mouse PXR increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. We also demonstrated that BPA is a potent activator of human but not mouse PXR, consequently, the choice of animal model is paramount in predicting the human risk assessment of BPA. Therefore, we generated novel PXR- humanized ApoE-/- mice (huPXR.ApoE-/-, i.e., ApoE knockout mice with the human PXR transgene in place of mouse PXR) that can respond to human PXR ligands. Our central hypothesis is that chronic activation of PXR by exposure to BPA promotes foam cell formation and increases atherosclerotic lesion formation in PXR- humanized mice, thereby increasing the risk of CVD in exposed individuals. Two specific aims are proposed to test this hypothesis: 1) Does chronic exposure to BPA at doses relevant to human exposure increase atherosclerosis in PXR-humanized ApoE-/- mice? 2) What molecular pathway does BPA act through to influence atherogenesis? The proposed studies are the first to investigate the effects of BPA exposure on atherosclerosis in a suitable animal model, and to explore the precise molecular mechanisms by which BPA induces CVD at the molecular level.