Sources, Transport, Exposure and Effects of PFASs (STEEP)

PFAS 的来源、传输、暴露和影响 (STEEP)

• 批准号: 9258544
• 负责人: Angela L Slitt
• 金额: $ 30.24万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258544
• 关键词: Acids; Address; Adipocytes; Adult; Adverse effects; Age; Automobile Driving; Behavior; Biological; Biological Markers; Breast; Cell Line; Child; Cods; Consumption; Data; Development; Diet; Disease; Dyslipidemias; Environmental Exposure; Environmental Pollutants; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fire - disasters; Functional disorder; Gene Expression; Goals; Health; Hepatic; High Fat Diet; Human; Immunologic Factors; In Vitro; Individual; Industry; Inflammation; Lactation; Lead; Life; Link; Lipids; Liver; Liver diseases; Malignant Neoplasms; Measurement; Measures; Membrane; Metabolic; Metabolic Diseases; Modeling; Mothers; Mus; Obesity; Outcome; Oxidative Stress; Phase; Population; Pregnancy; Property; Proteins; Reporting; Research; Research Project Grants; Risk; Risk Factors; Rodent Model; Role; Sampling; Serum; Site; Source; Structure; Superfund; System; Testing; Tissues; Toxic effect; Toxicokinetics; United States; Water; Weight; Weight Gain; Work; adipokines; analog; aqueous; bioaccumulation; contaminated water; exposed human population; fighting; immunotoxicity; in vivo; interdisciplinary approach; lipid biosynthesis; liver inflammation; liver injury; mother nutrition; neonate; nutrition; obesity risk; perfluorooctanoic acid; postnatal; prenatal; programs; pup; response; wasting

PROJECT SUMMARY/ABSTRACT Project 3 is one of two biomedical projects proposed for new URI-led Center – Sources, Transport, Exposure and Effects of PFASs (STEEP) – that is being created to aid the Superfund Research Program (SRP) in addressing the emerging problem of poly- and perfluorinated alkyl substances (PFASs) contamination. PFASs are considered emerging environmental pollutants, notably found at high concentrations at sites contaminated by aqueous fire fighting foams, such as Cape Cod. Human exposure to PFASs has been linked to immunotoxicity, cancer, as well as metabolic and dyslipidemia. Specific to metabolic disorders, PFASs are known to highly partition to the liver and links have been established between PFAS serum levels, specifically perfluorooctanic acid (PFOA) and perfluorosulfonic acid (PFOS), and liver injury. While insightful, these two common PFASs represent only a fraction of PFASs that exist within the contaminated sites and have been detected in humans (for example by Grandjean, STEEP Project 2; and Sunderland, STEEP Project 1). Understanding the mechanisms driving the biological response to PFASs are still emerging. The goal of this work is to (i) address whether environmental exposure to PFASs contributes an additional increase risk for obesity-induced fatty liver disease and metabolic disorders, and (ii) identify the physicochemical and partitioning behavior of PFASs that contribute to bioaccumulation. The overarching hypotheses are (1) that PFAS exposure will increase diet-induced hepatic steatosis and inflammation, which is potentially via increased adiposity and altered adipokine secretion, and (2) that the biological responses (e.g. liver weight) and biomarkers (e.g. oxidative stress gene expression) can be correlated with the protein, lipid, and/or membrane partitioning behavior of PFASs. These hypotheses will be tested by (Aim 1) evaluating the potential of PFASs to impact hepatic lipid accumulation, adipogenesis and adipokine secretion, (Aim 2) evaluating postnatal and adult PFAS exposure as an additional risk factor for obesity-induced hepatic steatosis and adipocyte dysfunction, and (Aim 3) determining the physicochemical properties of PFASs and their partitioning behavior to fat and in protein phases. Furthermore, through this project significant gaps in ATSDR guidance related to PFASs will be addressed pertaining to (i) outcomes with early in life PFAS exposure, (ii) mechanistic biomarkers for PFAS exposure in addition to liver endpoints, (iii) risk factors common to the United States population that might impact response to PFAS exposure (i.e. diet; obesity), and (iv) accurate measurements of physicochemical properties that are needed to predict bioaccumulation and toxicity.

项目摘要/摘要 项目3是为新Ui-LED中心提议的两个生物医学项目之一 - 来源，运输，曝光 PFAS（陡峭）的影响 - 正在创建以帮助超级基金研究计划（SRP） 解决了多氟化物质（PFASS）污染的新兴问题。 PFASS 被认为是新兴的环境污染物，特别是在污染的地点高浓度下发现 通过战斗泡沫，例如科德角（Cape Cod）。人类接触PFAS已与 免疫毒性，癌症以及代谢和血脂异常。特定于代谢性疾病，PFAS是 已知在PFAS血清水平之间建立了高度分配到肝脏和链接，特别是 全氟辛酸（PFOA）和全氟磺酸（PFO）和肝损伤。虽然有见地，但 常见的PFAS仅代表污染部位中存在的一小部分PFAS，并且已经存在 在人类中检测到（例如，由Grandjean，陡峭的项目2；和Sunderland，陡峭的项目1）。 了解推动PFAS生物学反应的机制仍在出现。目标的目标 工作是（i）解决环境暴露在 肥胖引起的脂肪肝病和代谢疾病，（ii）识别物理和 PFAS的划分行为，导致生物积累。总体假设是（1） PFAS暴露会增加饮食引起的肝脂肪变性和感染，这可能是通过 增加肥胖和脂肪因子分泌的改变，以及（2）生物反应（例如肝脏重量） 和生物标志物（例如氧化应激基因表达）可以与蛋白质，脂质和/或 PFAS的膜分配行为。这些假设将通过（AIM 1）评估潜力来测试 PFASS影响肝脂质积累，脂肪生成和脂肪因子分泌，（AIM 2）评估 产后和成年PFA暴露是肥胖引起的肝脂肪变性和 脂肪细胞功能障碍，（目标3）确定PFASS的物理特性及其分配 脂肪和蛋白质相的行为。此外，通过该项目，ATSDR指导的差距很大 与PFAS有关 除肝脏终点外，PFAS暴露的生物标志物（iii）美国常见的风险因素 可能影响对PFA暴露反应的人群（即饮食；肥胖）和（iv）准确的测量 预测生物积累和毒性所需的物理特性。