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.

项目概要 普遍存在的环境污染物统称为 PFAS（全氟烷基和多氟烷基） 物质）因其在环境中的持久性而被称为“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 高脂血症和发育缺陷。尽管它们对人类健康构成毒理学威胁，但确切的 它们发挥作用的分子机制仍然难以捉摸。现有的共同主题 许多这些疾病状态之间的原因是免疫系统稳态的破坏，这本身就表现出来 癌症和其他免疫毒性的风险增加。我们的长期目标是描绘分子 与 PFAS 诱导的肝脏先天免疫系统功能障碍相关的机制。此举的目的 特殊的应用是描述 PFAS 如何通过调节关键代谢酶来影响 肝细胞产生氧脂质。这些发现的影响将为我们提供机制上的见解 其中先天免疫细胞介质有助于 PFAS 的免疫抑制。我们的中心假设是 PFAS 抑制 CYP、COX 和 LOX 导致氧脂素合成失调，促进免疫 抑制。我们将通过两个具体目标来检验这个假设。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 CYP、COX 和 LOX 氧脂素代谢途径 抑制测定和靶向脂质组学方法。该目标将确定 PFAS 对 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 暴露的原代肝细胞对 LPS 的炎症反应。在这里，我们将 描述 PFAS 和 LPS 暴露对氧脂素代谢和细胞因子产生的影响，以描绘 接触 PFAS 后肝细胞如何响应炎症信号，从而深入了解潜在的影响 免疫挑战期间的健康影响。迄今为止，PFAS 对肝脏免疫的潜在影响 反应还没有被很好地理解。该提案将进一步阐明 PFAS 的分子机制 氧脂素的产生和免疫挑战，为理解其作用提供了坚实的基础 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。