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.

项目总结