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）致动脉粥样硬化作用的机制。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，人类暴露于BPA是普遍存在的。最近，在多项基于人群的研究中，较高的BPA暴露与心血管疾病（CVD）风险增加有关。然而，负责这些联系的机制仍然不明。许多环境化学物质可以激活异生素受体--异生素X受体（PXR），PXR作为异生素感受器调节异生素代谢，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，并发现小鼠PXR的慢性激活增加了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。我们还证明了BPA是人类而不是小鼠PXR的有效激活剂，因此，动物模型的选择在预测BPA的人类风险评估中至关重要。因此，我们产生了新的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），其可以对人PXR配体产生应答。我们的中心假设是，暴露于BPA的PXR慢性激活促进泡沫细胞形成，并增加PXR人源化小鼠动脉粥样硬化病变的形成，从而增加暴露个体的CVD风险。提出了两个具体的目标来检验这一假设：1）在PXR人源化ApoE-/-小鼠中，以与人类暴露相关的剂量长期暴露于BPA是否会增加动脉粥样硬化？2)BPA通过什么样的分子途径影响动脉粥样硬化的发生？这些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，并在分子水平上探索了BPA诱导CVD的精确分子机制。