Impact of Per/Polyfluoroalkyl pollutants on vascular disease mechanisms

全氟烷基/多氟烷基污染物对血管疾病机制的影响

• 批准号: 10751239
• 负责人: NOYAN GOKCE
• 金额: $ 45.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751239
• 关键词: Acute; Address; Adipose tissue; Affect; Air Pollution; American; American diet; Animals; Area; Atherosclerosis; Attention; Biological Assay; Biopsy; Blood; Blood Vessels; Body Burden; Cardiovascular Diseases; Cardiovascular system; Carpet; Chemicals; Chronic; Classification; Clinical; Clinical Research; Coronary Arteriosclerosis; Cosmetics; Data; Development; Dose; Dyslipidemias; Ecosystem; Elective Surgical Procedures; Endocrine disruption; Endothelium; Environment; Environmental Exposure; Exposure to; Fatty acid glycerol esters; Female; Food; Food Supply; Genes; Goals; Habits; Health; Health Hazards; Health Policy; Heart failure; Hepatocyte; Homeostasis; Human; Hypertension; Immune System Diseases; Impairment; Individual; Industrial Product; Inflammation; Intervention; Ischemia; Lead; Link; Literature; Long-Term Effects; Mediating; Meta-Analysis; Metabolic Diseases; Modeling; Molecular Target; Molecular Toxicology; Mus; Nature; Outcome; PPAR alpha; Paint; Paper; Pathogenesis; Pathway interactions; Persons; Physiological; Physiology; Play; Polishes; Poly-fluoroalkyl substances; Positioning Attribute; Proliferating; Property; Public Health; Publishing; Regulation; Reporting; Research; Role; Stains; Stroke; Systemic disease; Testing; Textiles; Thrombosis; Time; Tissues; Toxic effect; United States; Vascular Diseases; Vascular System; Vasodilation; Vasodilator Agents; Vasomotor; Video Microscopy; Water; Water Supply; Waxes; World Health Organization; adverse birth outcomes; angiogenesis; aqueous; arteriole; bioaccumulation; cardiovascular risk factor; consumer product; drinking; drinking water; environmental toxicology; epidemiologic data; human disease; human tissue; in vivo; innovation; insight; male; man; mouse model; multidisciplinary; novel; pharmacologic; pollutant; response; tool; toxicant

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.

项目概要/摘要 全氟烷基物质和多氟烷基物质 (PFAS) 是人造化学品，常用于 工业和消费品，例如防污和防水织物、食品接触材料、 抛光剂、蜡、油漆和泡沫的半衰期非常长，可以在体内生物累积。 人类，并且在环境中无所不在，包括我们的食品和饮料供应。 提案将重点关注越来越多的证据表明 PFAS 暴露与负面健康有关 我们的初步数据可能在心血管疾病的发病机制中发挥作用。 表明 PFAS 通过损害小动脉来破坏人体血管的关键生理功能 在此应用中，我们将根据我们的知识寻求表征血管舒缩功能和血管生成。 首次研究了不同类别的 PFAS 毒物对人体的因果病理生理作用 为了实现我们的目标，我们将采用补充方法。 利用血管舒张功能和血管生成的生理学研究以及定制的小鼠模型 与人类相关的条件和长期暴露场景以获得对机制的新见解 在目标 1 中，我们将描述 PFAS 污染物对血管疾病的影响。 通过检查内皮依赖性和非依赖性来研究人体脂肪组织微血管 使用视频显微镜观察活体完整小动脉的血管舒张反应，并进行血管生成测定 来自 50 名男性和女性受试者在选择性手术过程中收集的人体脂肪活检。 我们将检验所选 PFAS 对人体血管系统有负面影响的假设。 目标 2 将利用慢性、低剂量、人类相关的暴露来研究特定 PFAS 的能力 诱发男性和女性血管功能障碍和动脉粥样硬化发展的场景 我们将测试表达人类 PPARα 基因并喂养美国饮食的小鼠模型。 假设长期接触特定的 PFAS 毒物会损害血管功能并诱发 我们的方法包括涉及临床的多元化互补团队。 心血管（Gokce 博士）和环境毒理学（Schlezinger 博士）专业知识，并结合 利用活体人类生物样本、分子毒理学和体内小鼠进行生理学研究 慢性暴露模型，用于研究 PFAS 对脉管系统的急性和长期影响。 整个项目解决了最近概述的创新研究未满足的临床需求 EPA 制定了 PFAS 行动承诺战略路线图（2021-2024 年）， 了解 PFAS 污染物如何在调节人类疾病中发挥因果作用。 该项目旨在推动该领域向前发展，并可能导致新干预措施的确定 以及减轻毒物引起的心血管疾病的公共卫生方法。