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: 8638093
• 负责人: Changcheng Zhou
• 金额: $ 22.5万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638093
• 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; public health relevance; receptor; scavenger receptor; sensor; species difference

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.

项目摘要 这是一个R21应用程序，旨在研究双酚A（BPA）致动脉粥样硬化作用的机制。 BPA是一种广泛用于许多消费品中的聚碳酸酯塑料的基础化学品， 暴露于BPA是无处不在的。较高的BPA暴露最近与以下风险增加有关： 心血管疾病（CVD）在多个人群为基础的研究。然而，机制 这些协会的负责人仍然不明。许多环境中的化学物质可以激活 PXR受体，其反过来作为异生物质传感器来调节异生物质 代谢，并在其药理学上表现出相当大的差异，在不同物种。最近，我们 揭示了PXR在动物模型中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是人而不是小鼠PXR的有效激活剂，因此， 模型在预测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ApoE基因敲除小鼠 小鼠PXR），其可以响应于人PXR配体。我们的中心假设是PXR的慢性激活 通过暴露于BPA促进泡沫细胞形成，并增加PXR中动脉粥样硬化病变的形成， 人源化小鼠，从而增加暴露个体中CVD的风险。提出了两个具体目标， 检验这一假设：1）慢性接触BPA的剂量是否与人类接触量有关 PXR人源化ApoE-/-小鼠的动脉粥样硬化？2)BPA通过什么分子途径作用于 影响动脉粥样硬化形成？这项研究首次调查了BPA暴露对 在合适的动物模型中研究动脉粥样硬化，并探索BPA 在分子水平上诱导CVD。