Mechanisms of atherogenic effects of bisphenol A

双酚A致动脉粥样硬化作用的机制

基本信息

批准号：
8828205
负责人：
Changcheng Zhou
金额：
$ 18.8万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828205
关键词：
Address Adverse effects Affect Agonist Animal Model Animals ApoE knockout mouse Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biological Biological Monitoring Bone Marrow Transplantation CD36 gene Cardiovascular Diseases Chemicals Chronic Development Dietary Steroid Dose Environment Etiology Exhibits Exposure to Foam Cells Future Genes Goals Health Hormones Human Individual Ligands Link Lipids Mediating Molecular Mus Nuclear Receptors Pathway interactions Pharmacologic Substance Pharmacology Pilot Projects Play Population Production Receptor Activation Risk Risk Assessment Role Specificity Testing Transgenes Transgenic Mice Uncertainty Variant Xenobiotic Metabolism Xenobiotics atherogenesis base bisphenol A blood lipid cardiovascular disorder risk consumer product environmental chemical exposed human population gene environment interaction human population study in vivo leukocyte activation macrophage novel polycarbonate plastic population based pregnane X receptor receptor scavenger receptor sensor species difference

项目摘要

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.

描述（由申请人提供）：这是R21应用程序，旨在研究双酚A（BPA）的动脉粥样硬化作用的机理。 BPA是一种在许多消费产品中广泛用于聚碳酸酯塑料中的基本化学物质，并且人类对BPA的接触无处不在。在多个基于人群的研究中，BPA暴露量更高与心血管疾病（CVD）的风险增加有关。但是，负责这些关联的机制仍然未知。许多环境化学物质可以激活异生元受体妊娠X受体（PXR），而后者又充当异种生物传感器，以调节异种生物代谢，并在整个物种的药理学上表现出很大的差异。最近，我们揭示了PXR在动物模型中的促动脉粥样硬化作用，发现小鼠PXR的慢性激活增加了容易发生动脉粥样硬化的载脂蛋白E缺乏症（APOE-/ - ）小鼠。我们还证明了BPA是人类的有效激活因子，但不是小鼠PXR，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，我们生成了新型的PXR人源化apoe - / - 小鼠（hupxr.apoe - / - ，即用人PXR转基因代替小鼠PXR的Apoe敲除小鼠），可以对人的PXR配体做出反应。我们的中心假设是，通过暴露于BPA的慢性激活PXR会促进泡沫细胞的形成，并增加PXR人源化小鼠中的动脉粥样硬化病变形成，从而增加了暴露的个体中CVD的风险。提出了两个具体目的来检验这一假设：1）与人类暴露有关的剂量，长期暴露于BPA是否会增加PXR人性化apoE - / - 小鼠的动脉粥样硬化？ 2）BPA会通过哪种分子途径影响动脉粥样硬化？拟议的研究是第一个研究BPA暴露对合适动物模型中动脉粥样硬化的影响，并探索BPA在分子水平上诱导CVD的精确分子机制。