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

全氟烷基和多氟烷基物质（PFAS）是一类普遍存在的人造化学品，用于其 在工业和消费品（炊具、服装、地毯）以及消防中的表面活性剂性能 泡沫。PFAS具有高度的抗降解性，导致其在环境中的生物累积性， 人类正因为如此，PFAS目前在人体内循环的血液浓度为 比其他传统污染物更高。暴露于PFAS与增加 心脏代谢疾病的危险因素（即，循环胆固醇增加）或主要临床结局 与动脉粥样硬化有关的疾病，包括中风和心脏病发作。然而，目前还没有研究报告 暴露于PFAS是否会诱导动脉粥样硬化的发展。本报告的总体目标 建议是确定PFAS暴露是否诱导动脉粥样硬化，并表征潜在的 导致PFAS诱导的动脉粥样硬化危险因素发展的机制。我们已经在我们的 初步研究表明，低密度脂蛋白受体缺陷小鼠（Ldlr -/-）喂养致动脉粥样硬化饮食， 暴露于5种与环境相关的PFAS（PFOS、PFOA、PFNA、PFHxS和GenX）的简单混合物， 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暴露导致回肠胆汁酸转运蛋白的诱导，尤其是回肠 再摄取顶端钠依赖性胆汁酸转运蛋白（ASBT）。因此，这个问题的核心假设 有人认为PFAS暴露通过ASBT介导的胆汁相关机制诱导动脉粥样硬化 酸的运输和排泄。为了验证这一假设，我将利用Ldlr -/-小鼠，这是金标准， 机械地研究动脉粥样硬化，因为这种基因修饰的模型具有胆固醇特征， 这与人类中所见的非常相似，并且是一种对饮食控制敏感的模型。实验 目的1中提出的方法将通过监测高脂血症小鼠动脉粥样硬化的发展， 主动脉和主动脉根部的病变发展，定量脂质、固醇和胆汁酸水平，以及 转录组学分析目的2将研究PFAS介导的增加 循环胆固醇和动脉粥样硬化。目标2中提出的实验将探索ASBT抑制如何 调节循环胆固醇和胆汁酸，以及动脉粥样硬化的发展。总的来说， 这些数据将描述PFAS暴露与动脉粥样硬化风险增加之间的新机制。这 拟议的工作将对使用耐受性良好的药物作为有效药物产生广泛的影响。 针对PFAS介导的毒性的干预措施。

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.