Perfluoroalkanoate (PFAS) modulation of the inflammatory response through potent inhibition of arachidonic acid metabolizing cyclooxygenase and cytochrome P450 enzymes

全氟链烷酸酯 (PFAS) 通过有效抑制花生四烯酸代谢环加氧酶和细胞色素 P450 酶来调节炎症反应

• 批准号: 10532243
• 负责人: Jed Noah Lampe
• 金额: $ 22.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532243
• 关键词: Achievement; Alkane 1-monooxygenase; Anabolism; Arachidonic Acids; Biological Assay; Cells; Chemicals; Chronic Disease; Creativeness; Cytochrome P450; Data; Defect; Development; Disease; Environment; Environmental Pollutants; Enzyme Inhibition; Enzymes; Exposure to; Fatty Acids; Fostering; Foundations; Future; Generations; Goals; Health; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Human; Hyperlipidemia; IL8 gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Impairment; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune System; LOX gene; Lipids; Lipopolysaccharides; Liver; Malignant Neoplasms; Mediator; Metabolic; Metabolic Pathway; Metabolism; Molecular; National Institute of Environmental Health Sciences; National Toxicology Program; PTGS1 gene; Pathway interactions; Poly-fluoroalkyl substances; Populations at Risk; Positioning Attribute; Production; Prostaglandin-Endoperoxide Synthase; Public Health; Regulation; Research; Resolution; Rodent; Role; Scheme; Signal Transduction; Stimulus; Testing; Time; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Work; bioaccumulation; cancer risk; cohort; cytokine; falls; immunopathology; immunoregulation; immunotoxicity; improved; inflammatory modulation; inhibitor; insight; lipidomics; novel; prevent; response; substance use; vaccine response

PROJECT SUMMARY The ubiquitous environmental contaminants collectively known as PFAS (Per- and polyfluoroalkyl substances) have been dubbed “forever chemicals” due to their persistence in the environment. In humans, they have been associated with a wide variety of illnesses, including: cancer, immunotoxicities, hepatotoxicity hyperlipidemias, and developmental defects. Despite their toxicological threat to human health, the exact molecular mechanisms by which they exert their effects have remained elusive. A common theme existing between many of these disease states is the disruption of immune system homeostasis, which manifests itself in an increased risk for cancer and other immunotoxicities. Our long-term goal is to delineate the molecular mechanisms related to PFAS-induced innate immune system dysfunction in the liver. The objective of this particular application is to characterize how PFAS, through modulation of key metabolic enzymes, may impact the production of oxylipins by hepatocytes. The impact of these findings will provide mechanistic insight into which innate immune cell mediators contribute to immunosuppression by PFAS. Our central hypothesis is that CYP, COX, and LOX inhibition by PFAS leads to dysregulation of oxylipin synthesis, promoting immune suppression. We will test this hypothesis through employing two specific aims. In our first aim, we will identify the CYP, COX, and LOX oxylipin metabolic pathways inhibited by the PFAS compounds via direct enzyme inhibition assays and a targeted lipidomics approach. This aim will define the impacts of PFAS on the generation of liver-derived inflammatory mediators in exposed individuals. In our second aim, we will characterize the inflammatory response to LPS in PFAS-exposed primary hepatocytes. Here, we will characterize oxylipin metabolism and cytokine production in response to PFAS and LPS exposure to delineate how hepatocytes respond to inflammatory signals after PFAS exposure, thus providing insight into the potential health effects during an immunological challenge. To date, the potential effects of PFAS on hepatic immune responses is not well understood. This proposal will further delineate the molecular mechanisms of PFAS on oxylipin production and immunological challenge, providing a strong foundation for understanding the role of PFAS in immune system dysregulation, which is key to developing treatments for those who have been exposed and preventing the observed immunopathology.

项目摘要 普遍存在的环境污染物统称为PFAS（全氟烷基和多氟烷基 由于其在环境中的持久性，这些物质被称为“永久化学品”。在人类中， 它们与多种疾病有关，包括：癌症、免疫毒性、肝毒性 高血压和发育缺陷。尽管它们对人类健康有毒理学威胁， 它们发挥其作用的分子机制仍然难以捉摸。一个共同的主题 在许多这些疾病状态之间是免疫系统稳态的破坏， 癌症和其他免疫毒性的风险增加。我们的长期目标是描绘出 与PFAS诱导的肝脏先天免疫系统功能障碍相关的机制。的目的 一个特别的应用是表征PFAS如何通过调节关键代谢酶， 肝细胞产生氧脂素。这些发现的影响将提供机械洞察力， 哪些先天性免疫细胞介导剂有助于PFAS的免疫抑制。我们的核心假设是， PFAS对COX、考克斯和LOX的抑制导致氧化脂质合成失调，促进免疫反应。 镇压我们将通过两个具体目标来检验这一假设。在我们的第一个目标中，我们将确定 PFAS化合物通过直接酶抑制的β-羟化酶、考克斯和LOX氧化脂代谢途径 抑制测定和靶向脂质组学方法。这一目标将确定PFAS对 在暴露个体中产生肝源性炎症介质。在我们的第二个目标中，我们将 表征PFAS暴露的原代肝细胞中对LPS的炎症反应。在这里，我们将 表征对PFAS和LPS暴露的反应的氧脂素代谢和细胞因子产生，以描述 PFAS暴露后肝细胞如何对炎症信号作出反应，从而深入了解PFAS的潜在作用。 在免疫挑战期间对健康的影响。迄今为止，PFAS对肝脏免疫功能的潜在影响尚不清楚。 答案不太清楚。这一建议将进一步阐明PFAS的分子机制， oxlipin的产生和免疫学挑战，为理解 PFAS在免疫系统失调中的作用，这是为那些患有免疫系统失调的人开发治疗方法的关键。 暴露并防止观察到的免疫病理学。