PFAS accelerate atherosclerosis through modulation of bile acid metabolism

PFAS 通过调节胆汁酸代谢加速动脉粥样硬化

基本信息

批准号：
10658104
负责人：
Michael Curtis Petriello
金额：
$ 164.42万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658104
关键词：
ASBT protein Acceleration Aorta Arterial Fatty Streak Atherogenic Diet Atherosclerosis Bile Acids Blood Cardiometabolic Disease Cardiovascular Diseases Cause of Death Chemicals Cholesterol Clinical Community Health Coronary heart disease Correlation Studies Data Dietary Cholesterol Enterohepatic Circulation Environment Excretory function Experimental Models Exposure to Female Genes Goals Health Surveys High Density Lipoproteins Human Image Label Lead Length Lesion Link Lipids Low Density Lipoprotein Receptor Low-Density Lipoproteins Measures Mediating Mediation Methods Modeling Monitor Mus Myocardial Infarction Oils Outcome Output Pathologic Pathway interactions Pattern Pharmacologic Substance Phytosterols Poly-fluoroalkyl substances Property Publishing Reporting Risk Factors Rodent Rodent Model Role Sampling Serum Sterols Stroke Testing Time Toxic effect Toxicity Tests Toxicokinetics United States Very low density lipoprotein Wild Type Mouse absorption arm atherosclerosis risk bile acid metabolism cardiometabolic risk cardiovascular disorder risk cholesterol absorption cohort consumer product design dietary epidemiology study ileum lipoprotein cholesterol male man perfluorooctane sulfonate pollutant preclinical study reuptake surfactant

项目摘要

PROJECT SUMMARY Cardiovascular diseases are the leading cause of death in the United States and worldwide, and atherosclerotic heart disease is particular burdensome. Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals that have been associated with increased risk factors for cardiometabolic disease (i.e., increased circulating cholesterol), or major outcomes related to atherosclerosis including stroke/heart attacks in epidemiological studies. No studies have reported on PFAS accelerated atherosclerosis using rodent models. Recent rodent studies have shown PFAS can increase circulating cholesterol, but these studies have relied primarily on wildtype mice which display lipoprotein cholesterol fraction patterns (VLDL, LDL, HDL) that are opposite of humans, and which do not develop lesions within the aorta. To circumvent this problem and to have an experimental model from which results can be directly extrapolated to humans, we will use Low Density Lipoprotein Receptor deficient mice (Ldlr -/-), which have lipid profiles like humans, to determine if PFAS- mediated increases in cholesterol levels lead to pathological atherosclerosis. Recently, we published that wildtype mice fed an atherogenic diet and exposed to a simple mixture of 5 environmentally relevant PFAS (PFOS, PFOA, PFNA, PFHxS, and GenX) for 12 weeks resulted in increased circulating cholesterol and bile acids. In preliminary studies, we followed the same exposure paradigm and observed increased circulating cholesterol in Ldlr -/- mice. Here, we propose to extend our initial observations using a simple PFAS mixture to a full factorial design and examine atherosclerotic lesion formation. Circulating cholesterol levels can be modulated through mechanisms related to dietary cholesterol absorption, de-novo cholesterol synthesis, and fecal excretion. Our preliminary studies show that Ldlr -/- mice exposed to the mixture show decreased bile acid excretion and induction of reuptake transporters in the ileum (especially apical sodium dependent bile acid transporter; ASBT). Our proposed studies will use pharmaceuticals selective for ASBT and mass labeled sterols to confirm ASBT induction is critical. Finally, to validate some of these observations in a human cohort, we recently measured PFAS in serum from the Anniston Community Health Surveys (ACHS) and we reported that residents were highly exposed to PFOS, and we now propose to measure bile acids in stored samples. We will use mixture methods to show 1) PFAS mixtures statistically correlate with increased cholesterol, and 2) these associations are mediated through increases in circulating bile acids. We hypothesize that PFAS accelerate atherosclerosis by altering cholesterol excretion as bile acids. Our specific aims are: 1) To test the hypothesis that mixtures of environmentally relevant PFAS accelerate atherosclerosis in Ldlr -/- mice. 2) To test the hypothesis that PFAS disrupts bile acid reuptake leading to increases in circulating cholesterol through ASBT- related mechanisms. 3) To examine the association between PFAS mixtures and circulating bile acids and test if that the association between PFAS mixtures and cholesterol can be explained by increases in these.

项目概要心血管疾病是美国和世界范围内导致死亡的主要原因，而动脉粥样硬化心脏病尤其造成负担。全氟烷基物质和多氟烷基物质 (PFAS) 是一类普遍存在的物质与心脏代谢疾病危险因素增加相关的人造化学物质（即循环胆固醇增加），或与动脉粥样硬化相关的主要结果，包括中风/心脏病发作流行病学研究。目前还没有关于使用啮齿动物模型研究 PFAS 加速动脉粥样硬化的研究报道。最近的啮齿动物研究表明 PFAS 可以增加循环胆固醇，但这些研究依赖于主要针对显示脂蛋白胆固醇分数模式（VLDL、LDL、HDL）的野生型小鼠，这些模式是与人类相反，并且不会在主动脉内发生病变。为了规避这个问题并有一个实验模型，其结果可以直接外推到人类，我们将使用低密度脂蛋白受体缺陷小鼠 (Ldlr -/-) 具有与人类相似的脂质分布，以确定 PFAS 是否介导的胆固醇水平升高导致病理性动脉粥样硬化。最近，我们发布了野生型小鼠喂食致动脉粥样硬化饮食并暴露于 5 种环境相关 PFAS 的简单混合物（PFOS、PFOA、PFNA、PFHxS 和 GenX）持续 12 周会导致循环胆固醇和胆汁增加酸。在初步研究中，我们遵循相同的暴露范式并观察到循环增加 Ldlr -/- 小鼠中的胆固醇。在这里，我们建议使用简单的 PFAS 混合物来扩展我们的初步观察完整的因子设计并检查动脉粥样硬化病变的形成。循环胆固醇水平可通过与膳食胆固醇吸收、胆固醇从头合成相关的机制进行调节，粪便排泄。我们的初步研究表明，暴露于混合物的 Ldlr -/- 小鼠胆汁酸减少回肠中再摄取转运蛋白的排泄和诱导（尤其是顶端钠依赖性胆汁酸）运输者； ASBT）。我们提出的研究将使用选择性 ASBT 和质量标记甾醇的药物确认 ASBT 诱导至关重要。最后，为了在人类队列中验证其中一些观察结果，我们最近测量了安尼斯顿社区健康调查 (ACHS) 血清中的 PFAS，我们报告称居民高度暴露于全氟辛烷磺酸，我们现在建议测量储存样本中的胆汁酸。我们将使用混合方法来证明 1) PFAS 混合物在统计上与胆固醇升高相关，以及 2) 这些这种关联是通过循环胆汁酸的增加来介导的。我们假设 PFAS 会加速通过改变胆固醇以胆汁酸的形式排泄来预防动脉粥样硬化。我们的具体目标是：1）检验假设与环境相关的 PFAS 混合物会加速 Ldlr -/- 小鼠的动脉粥样硬化。 2) 测试假设 PFAS 会破坏胆汁酸再摄取，通过 ASBT 导致循环胆固醇增加相关机制。 3) 检查 PFAS 混合物与循环胆汁酸之间的关联并进行测试如果 PFAS 混合物与胆固醇之间的关联可以通过这些混合物的增加来解释。