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

全氟和多氟烷基物质(PFAS)是一类普遍存在的人造化学品，用于其 工业和消费品(厨具、服装、地毯)以及消防中的表面活性剂性质 泡沫。全氟辛烷磺酸高度耐降解，导致它们在环境和环境中的生物积累。 人类。正因为如此，目前全氟辛烷磺酸在人体内的血液浓度是 比其他遗留污染物高出数量级。接触全氟辛烷磺酸与增加 心脏代谢性疾病的危险因素(即循环胆固醇升高)或主要临床结果 与动脉粥样硬化有关，包括中风和心脏病发作。然而，目前还没有研究报告关于 暴露于PFAS是否会导致动脉粥样硬化的发生。这样做的首要目标是 建议是确定接触PFAS是否会导致动脉粥样硬化，并确定潜在的 PFAS诱导动脉粥样硬化危险因素发展的机制。我们已经在我们的 低密度脂蛋白受体缺陷小鼠(LDLR-/-)饲喂致动脉粥样硬化饲料的初步研究 暴露于5种与环境相关的全氟辛烷磺酸(全氟辛烷磺酸、全氟辛烷磺酸和全氟辛烷磺酸)的简单混合物中 7周后循环中胆固醇和胆汁酸增加，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，尤其是回肠胆汁酸转运蛋白。 重摄取顶端钠依赖胆汁酸转运体(ASBT)。因此，这一点的中心假设 有观点认为，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。为了验证这一假设，我将使用Ldlr-/-小鼠，这是 对动脉粥样硬化进行机械研究，因为这种转基因模型具有胆固醇特征 这与在人类中看到的情况非常相似，也是一个对饮食操纵敏感的模型。实验 在目标1中提出将通过监测高脂血症小鼠的动脉粥样硬化的发展 主动脉和主动脉根部的病变发展，量化脂质、甾醇和胆汁酸水平，以及 转录剪裁侧写。AIM 2将研究PFAS介导的 循环胆固醇和动脉粥样硬化。在Aim 2中提出的实验将探索ASBT抑制 调节循环中的胆固醇和胆汁酸，以及动脉粥样硬化的发展。总而言之， 这些数据将描述暴露于全氟辛烷磺酸和动脉粥样硬化风险增加之间的新机制。这 拟议的工作将对耐受性良好的药物的使用产生广泛的影响 对全氟辛烷磺酸介导的毒性的干预。

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.