Impact of Per/Polyfluoroalkyl pollutants on vascular disease mechanisms

项目摘要/摘要 全氟和多氟烷基物质(PFAS)是一种人造化学品，广泛用于 工业和消费品，如防污防水织物、食品接触材料、 抛光剂、蜡、油漆和泡沫。全氟辛烷磺酸的半衰期非常长，可以在 人类，并无处不在的环境中，包括我们的食物和饮用水供应。这 提案的重点将是越来越多的证据表明，接触全氟辛烷磺酸与负面健康有关 结果，并可能在心血管疾病的发病机制中发挥作用。我们的初步数据 显示PFAS通过损害小动脉来扰乱人类血管的关键生理功能 血管运动功能和血管生成。在本申请中，据我们所知，我们将寻求表征 首次研究了不同种类的全氟辛烷磺酸毒物对大鼠的致病作用。 人体血管系统。为了实现我们的目标，我们将采取配套的方法。 利用血管扩张剂功能和血管生成的生理学研究，以及定制的小鼠模型 与人类相关的情况和慢性暴露情景，以获得对 PFAS介导的血管疾病。在目标1中，我们将描述全氟辛烷磺酸污染物对 检测内皮依赖和非内皮依赖的人脂肪组织微血管 应用视频显微镜对活体完整小动脉的血管扩张剂反应，并进行血管生成分析 来自50名男性和女性受试者在择期手术过程中收集的人类脂肪活检。 我们将检验这样一种假设，即选择PFAS对人体血管系统有负面影响。 目标2将使用长期、低剂量、与人类相关的暴露来研究特定的PFAS的能力 在男性和女性中诱发血管功能障碍和动脉粥样硬化的情景 表达人类PPARα基因的小鼠模型，并喂食美国饮食。我们将测试 假设长期接触选定的PFAS毒物会损害血管功能并导致 活体动脉粥样硬化。我们的方法包括一个多样化的互补性团队，包括临床 心血管(Gokce博士)和环境毒理学(Schlezinger博士)的专业知识，并结合 利用活体人类生物脊椎动物的生理学、分子毒理学和活体小鼠的研究 慢性暴露模型研究全氟辛烷磺酸对血管系统的急性和长期影响。这个 正如最近概述的那样，总体项目解决了创新研究未得到满足的临床需求 环境保护局制定的PFAS行动战略路线图(2021-2024年)承诺， 了解全氟辛烷磺酸污染物如何在调节人类疾病方面发挥因果作用。这个整体 项目的定位是推动实地向前发展，并可能导致确定新的干预措施 和公共卫生方法，以减轻毒物引起的心血管疾病。

Project Summary/Abstract Per- and polyfluoroalkyl substances (PFAS) are manmade chemicals that are extensively used in industrial and consumer products such as stain- and water-repellent fabrics, food contact materials, polishes, waxes, paints, and foams. PFAS have exceptionally long half-lives, can bio-accumulate in humans, and are omnipresent in the environment including our food and drinking supplies. This proposal will focus on the growing evidence that PFAS exposures are associated with negative health outcomes and may play a role in the pathogenesis of cardiovascular diseases. Our preliminary data show that PFAS disrupt key physiological functions of human blood vessels by impairing arteriolar vasomotor function and angiogenesis. In this application, we will seek to characterize, to our knowledge for the first time, causal pathophysiological actions of diverse classes of PFAS toxicants upon the human vascular system. To achieve our objectives, we will employ complementary approaches harnessing physiological studies of vasodilator function and angiogenesis, and mouse models tailored to human-relevant conditions and chronic exposure scenarios to gain novel insights into mechanisms of PFAS-mediated vascular disease. In Aim 1, we will characterize the effects of PFAS pollutants on the human adipose tissue microvasculature by examining endothelium-dependent and –independent vasodilator responses using videomicroscopy in live intact arterioles, and perform angiogenic assays from human fat biopsies collected during elective surgical procedures in 50 male and female subjects. We will test the hypothesis that select PFAS have negative effects upon the human vascular system. Aim 2 will investigate the ability of specific PFAS, using chronic, low-dose, human-relevant exposure scenarios to induce the development of vascular dysfunction and atherosclerosis in male and female mouse models that express the human PPARα gene and fed an American diet. We will test the hypothesis that long-term exposure of select PFAS toxicants can impair vascular function and induce atherosclerosis in vivo. Our approach includes a diverse complementary team involving clinical cardiovascular (Dr. Gokce) and environmental toxicology (Dr. Schlezinger) expertise, and combines studies of physiology utilizing live human biospecimens, molecular toxicology, and an in vivo murine chronic exposure model to study acute and long-term effects of PFAS upon the vasculature. The overall project tackles an unmet clinical need for innovative research as outlined by the recently established PFAS Commitments to Action Strategic Roadmap (2021-2024) by the EPA, for understanding how PFAS pollutants can play causal roles in mediating human disease. This overall project is positioned to move the field forward, and may lead to the identification of new interventions and public health approaches to mitigate toxicant-induced cardiovascular diseases.