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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：
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
项目类别：
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

项目摘要

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.

项目总结