Mechanisms of atherogenic effects of bisphenol A

项目摘要 这是一种R21应用，旨在研究双酚A(BPA)致动脉粥样硬化的机制。 双酚A是一种基础化学品，广泛用于聚碳酸酯塑料中的许多消费品，以及人类 接触双酚A无处不在。最近，更高的双酚A暴露与增加的风险有关。 心血管疾病(CVD)在多个以人类为基础的人群研究中。然而，这些机制 对这些协会负责的人仍然不得而知。许多环境化学物质都能激活外来生物。 受体孕烷X受体(PXR)作为异生感受器调节异生 并在不同物种的药理作用上表现出相当大的差异。就在最近，我们 在动物模型中揭示了PXR的促动脉粥样硬化作用，并发现小鼠PXR的慢性激活 增加易患动脉粥样硬化的载脂蛋白E缺陷(ApoE-/-)小鼠的动脉粥样硬化。我们也 证明BPA是人类PXR的有效激活剂，而不是小鼠PXR，因此选择动物 在预测双酚A的人体风险评估中，模型是至关重要的。因此，我们产生了新颖的PXR- 人源化ApoE-/-小鼠(huPXR？ApoE-/-)，即用人PXR转基因取代ApoE基因敲除小鼠 小鼠PXR)，可以对人类PXR配体产生反应。我们的中心假设是PXR的慢性激活 暴露于双酚A可促进泡沫细胞的形成并增加动脉粥样硬化病变的形成。 使小鼠人性化，从而增加接触者患心血管疾病的风险。提出了两个具体目标，以 验证这一假设：1)长期接触双酚A的剂量与人类接触的剂量相关，是否会增加 PXR人源化ApoE-/-小鼠的动脉粥样硬化？2)BPA通过什么分子途径发挥作用 影响动脉粥样硬化的形成？拟议的研究是第一次调查暴露于双酚A对 建立合适的动脉粥样硬化动物模型，并探讨双酚A参与动脉粥样硬化的确切分子机制 在分子水平上诱导CVD。

Project Summary 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.