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.

项目概要/摘要 项目 3 是为 URI 主导的新中心提议的两个生物医学项目之一 - 来源、运输、暴露 PFAS 的影响和影响 (STEEP)——该项目的创建是为了帮助超级基金研究计划 (SRP) 解决新出现的多氟烷基物质和全氟烷基物质 (PFAS) 污染问题。 PFAS 被认为是新出现的环境污染物，特别是在受污染地点以高浓度发现 使用水性灭火泡沫，例如 Cape Cod。人类接触 PFAS 与 免疫毒性、癌症以及代谢和血脂异常。针对代谢紊乱，PFAS 是 已知 PFAS 高度分布于肝脏，并且已建立 PFAS 血清水平之间的联系，特别是 全氟辛酸（PFOA）和全氟磺酸（PFOS）与肝损伤。这两个人虽然见解独到， 常见的 PFAS 仅代表污染场地内存在的 PFAS 的一小部分，并且已被 在人类中检测到（例如 Grandjean，STEEP 项目 2；以及 Sunderland，STEEP 项目 1）。 对 PFAS 生物反应驱动机制的了解仍在不断涌现。此举的目标 工作的目的是 (i) 解决 PFAS 的环境暴露是否会导致额外增加风险 肥胖引起的脂肪肝疾病和代谢紊乱，以及 (ii) 确定理化和代谢紊乱 PFAS 的分配行为有助于生物蓄积。总体假设是 (1) PFAS 暴露会增加饮食引起的肝脂肪变性和炎症，这可能是通过 肥胖增加和脂肪因子分泌改变，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（目标 1）评估潜力进行检验 PFAS 对肝脏脂质积累、脂肪生成和脂肪因子分泌的影响，（目标 2）评估 产后和成人 PFAS 暴露是肥胖引起的肝脂肪变性的另一个危险因素 脂肪细胞功能障碍，以及（目标 3）确定 PFAS 的理化特性及其分配 对脂肪和蛋白质相的行为。此外，通过该项目，ATSDR 指导中存在重大差距 与 PFAS 相关的问题将涉及 (i) 生命早期 PFAS 暴露的结果，(ii) 机制 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 PFAS 暴露反应的人群（即饮食、肥胖），以及 (iv) 准确测量 预测生物蓄积性和毒性所需的物理化学特性。