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.

项目总结/摘要 项目3是为URI领导的新中心提出的两个生物医学项目之一-来源，运输，暴露 和PFASs的影响（STEEP）-这是为了帮助超级基金研究计划（SRP）， 解决新出现的多氟烷基和全氟烷基物质污染问题。PFASs 被认为是新出现的环境污染物，特别是在受污染的地点发现的高浓度 水灭火泡沫，如科德角。人类接触PFAS与以下因素有关： 免疫毒性、癌症以及代谢和血脂异常。对于代谢紊乱，PFAS是 已知其高度分配至肝脏，并且已在PFAS血清水平之间建立了联系， 全氟辛酸（PFOA）和全氟磺酸（PFOS）以及肝损伤。虽然有见地，这两个 常见的PFASs仅代表污染场地内存在的PFASs的一小部分， 在人类中检测到的（例如Grandjean，STEEP项目2;和桑德兰，STEEP项目1）。 了解推动对PFAS生物反应的机制仍在不断出现。这个目标 工作是（i）解决PFAS的环境暴露是否会导致风险额外增加 肥胖引起的脂肪肝疾病和代谢紊乱，和（ii）确定理化和 促进生物累积的PFASs的分配行为。总体假设是（1）， PFAS暴露将增加饮食诱导的肝脏脂肪变性和炎症，这可能是通过 增加的肥胖和改变的脂肪因子分泌，和（2）生物学反应（例如肝脏重量） 并且生物标志物（例如氧化应激基因表达）可以与蛋白质、脂质和/或 PFASs的膜分配行为。这些假设将通过（目标1）评估 PFAS影响肝脏脂质蓄积、脂肪形成和脂肪因子分泌，（目的2）评估 出生后和成人PFAS暴露是肥胖诱导的肝脂肪变性的额外风险因素， 脂肪细胞功能障碍，以及（目的3）确定PFASs的理化性质及其分配 脂肪和蛋白质阶段的行为。此外，通过这一项目， 与PFAS相关的问题将涉及（i）生命早期PFAS暴露的结局，（ii） 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 预测生物累积性和毒性所需的物理化学特性。