Exposure to PFAS mixture induces atherosclerosis via modulation of bile acid transport

接触 PFAS 混合物会通过调节胆汁酸转运诱导动脉粥样硬化

• 批准号: 10678129
• 负责人: Katherine Roth
• 金额: $ 7.18万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678129
• 关键词: ASBT protein; Acceleration; Acids; Animals; Aorta; Atherogenic Diet; Atherosclerosis; Bile Acids; Biology; Blood; Cardiometabolic Disease; Cardiovascular Models; Carpet; Chemicals; Cholesterol; Clinical; Clothing; Cross-Sectional Studies; Data; Development; Diet; Diet Research; Dietary Cholesterol; Disease model; Environment; Excretory function; Exposure to; Female; High Density Lipoproteins; Human; Industrial Product; Inflammatory; LDL Cholesterol Lipoproteins; Laboratories; Lead; Length; Lesion; Link; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Mediating; Medicine; Modeling; Monitor; Mus; Myocardial Infarction; Oils; Outcome; Pathologic; Pattern; Pharmacologic Substance; Phenotype; Poly-fluoroalkyl substances; Population; Postdoctoral Fellow; Process; Property; Proteins; Publishing; Reporting; Research; Resistance; Risk Factors; Rodent; Sterols; Stroke; Testing; Toxic Environmental Substances; Toxic effect; Training; Very low density lipoprotein; Wild Type Mouse; Work; absorption; atherosclerosis risk; bile acid metabolism; bile acid transporter; bioaccumulation; cardiometabolism; career; cholesterol absorption; consumer product; dietary manipulation; drinking water; effective intervention; epidemiology study; experimental study; hypercholesterolemia; lipoprotein cholesterol; magnetic beads; male; man; member; mouse model; pollutant; post-doctoral training; research faculty; reuptake; skills; surfactant; transcriptomic profiling; unpublished works

Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals utilized for their surfactant properties in industrial and consumer products (cookware, clothing, carpets) as well as in firefighting foams. PFAS are highly resistant to degradation, leading to their bioaccumulation in the environment and in humans. Because of this, PFAS are currently circulating in humans at blood concentrations that are magnitudes higher than other legacy contaminants. Exposure to PFAS have been associated with increased risk factors for cardiometabolic disease (i.e., increased circulating cholesterol), or major clinical outcomes related to atherosclerosis that include stroke and heart attack. However, no studies have yet reported on whether exposure to PFAS can induce the development of atherosclerosis. The overarching objective of this proposal is to determine if PFAS exposure induces atherosclerosis and to characterize the underlying mechanisms leading to PFAS-induced development of atherosclerosis risk factors. We have shown in our preliminary studies that Low Density Lipoprotein Receptor deficient mice (Ldlr -/-) fed an atherogenic diet and exposed to a simple mixture of 5 environmentally relevant PFAS (PFOS, PFOA, PFNA, PFHxS, and GenX) for 7 weeks resulted in increased circulating cholesterol and bile acids as well as decreased bile acid excretion. We also observed that PFAS exposure results in induction of ileal bile acid transporters, especially the ileal reuptake apical sodium dependent bile acid transporter (ASBT). Therefore, the central hypothesis of this proposal is that PFAS exposure induces atherosclerosis through mechanisms related to ASBT-mediated bile acid transport and excretion. To test this hypothesis, I will utilize Ldlr -/- mice, which is the gold standard for mechanistically investigating atherosclerosis because this genetically modified model has cholesterol profiles that closely mirror those seen in humans and is a model sensitive to dietary manipulation. Experiments proposed in Aim 1 will investigate the development of atherosclerosis in hyperlipidemic mice by monitoring lesion development in the aorta and aortic roots, quantifying lipid, sterol, and bile acid levels, and transcriptomic profiling. Aim 2 will investigate mechanisms underlying the PFAS-mediated increases in circulating cholesterol and atherosclerosis. Experiments proposed in Aim 2 will explore how ASBT inhibition modulates circulating cholesterol and bile acids, as well as the development of atherosclerosis. Collectively, these data will describe new mechanisms linking exposure to PFAS and increased risk of atherosclerosis. This proposed work will have broad implications for the use of well-tolerated pharmaceuticals as effective interventions against PFAS-mediated toxicity.

每种和多氟烷基物质（PFA）是一类无处不在的人造化学物质 工业和消费产品（炊具，服装，地毯）以及消防的表面活性剂特性 泡沫。 PFA对降解具有高度抵抗力，导致其在环境和 人类。因此，PFA目前以血液浓度在人类中循环 大小高于其他遗产污染物。暴露于PFA与增加有关 心脏代谢疾病的危险因素（即循环胆固醇增加）或主要的临床结果 与动脉粥样硬化有关，包括中风和心脏病发作。但是，尚无研究 暴露于PFA是否会诱导动脉粥样硬化的发展。这个总体目标 建议是确定PFAS暴露是否诱导动脉粥样硬化并表征基础 导致PFA引起的动脉粥样硬化风险因素的发展的机制。我们在我们的 初步研究，低密度脂蛋白受体缺乏小鼠（LDLR - / - ）喂养动脉粥样硬化饮食和 暴露于5种环境相关的PFA（PFO，PFOA，PFNA，PFHXS和GENX）的简单混合物中 7周导致循环胆固醇和胆汁酸增加以及胆汁酸排泄减少。 我们还观察到，PFAS暴露会导致回肠胆汁酸转运蛋白，尤其是回肠转运蛋白 再摄取顶端钠依赖性胆汁酸转运蛋白（ASBT）。因此，这一点的中心假设 建议是PFAS暴露通过与ASBT介导的胆汁有关的机制诱导动脉粥样硬化 酸的运输和排泄。为了检验该假设，我将使用LDLR - / - 小鼠，这是金标准 机械学研究动脉粥样硬化，因为该转基因模型具有胆固醇谱 这密切反映了在人类中看到的，并且是对饮食操纵敏感的模型。实验 AIM 1中提出的将通过监测高脂血症小鼠的动脉粥样硬化的发展。 主动脉和主动脉根的病变发育，量化脂质，固醇和胆汁酸水平，以及 转录组分析。 AIM 2将研究PFA介导的增加的基础机制 循环胆固醇和动脉粥样硬化。 AIM 2中提出的实验将探讨ASBT抑制 调节循环胆固醇和胆汁酸，以及动脉粥样硬化的发展。共同 这些数据将描述将暴露与PFAS接触和动脉粥样硬化风险增加的新机制。这 拟议的工作将对使用耐受性良好的药物具有广泛的影响 针对PFAS介导的毒性的干预措施。