Mechanisms of atherogenic effects of bisphenol A

双酚A致动脉粥样硬化作用的机制

• 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
• 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

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）：这是一项 R21 申请，旨在研究双酚 A (BPA) 致动脉粥样硬化效应的机制。 BPA 是一种基础化学品，广泛用于许多消费品中的聚碳酸酯塑料，人类接触 BPA 的情况无处不在。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，造成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物质受体孕烷X受体（PXR），而PXR反过来又充当外生物质传感器来调节异生物质代谢，并且其药理学在不同物种之间表现出相当大的差异。最近，我们在动物模型中揭示了 PXR 的促动脉粥样硬化作用，并发现小鼠 PXR 的慢性激活会增加易发生动脉粥样硬化的载脂蛋白 E 缺陷 (ApoE-/-) 小鼠的动脉粥样硬化。我们还证明，BPA 是人类而非小鼠 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，我们产生了新型 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），它可以对人 PXR 配体做出反应。我们的中心假设是，在 PXR 人源化小鼠中，暴露于 BPA 导致的 PXR 慢性激活促进了泡沫细胞的形成并增加了动脉粥样硬化病变的形成，从而增加了暴露个体患 CVD 的风险。提出了两个具体目标来检验这一假设：1) 长期暴露于与人类暴露相关的剂量的 BPA 是否会增加 PXR 人源化 ApoE-/- 小鼠的动脉粥样硬化？ 2) BPA 通过什么分子途径影响动脉粥样硬化形成？该研究首次在合适的动物模型中研究了 BPA 暴露对动脉粥样硬化的影响，并在分子水平上探讨了 BPA 诱发 CVD 的精确分子机制。