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

项目摘要/摘要 项目3是为新的URI领导的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(陡峭)-正在创建，以帮助超级基金研究计划(SRP)在 解决多氟和全氟烷基物质(PFASs)污染这一新出现的问题。全氟辛烷磺酸 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污染物 由水性灭火泡沫，如鳕鱼角。人类接触全氟辛烷磺酸与 免疫毒性、癌症以及代谢和血脂异常。针对代谢紊乱，全氟辛烷磺酸是 已知对肝脏的高度分配，并已在PFAS血清水平之间建立联系，特别是 全氟辛酸(PFOA)和全氟磺酸(PFOS)与肝脏损伤。虽然很有洞察力，但这两个人 常见的加油站只占污染场地内存在的加油站的一小部分，而且已经 在人类中检测到(例如，格兰杰，陡峭项目2；桑德兰，陡峭项目1)。 对全氟辛烷磺酸生物反应驱动机制的了解仍在不断涌现。这样做的目的是 工作是：(I)解决环境中暴露于全氟辛烷磺酸是否会增加 肥胖引起的脂肪肝和代谢紊乱，以及(Ii)确定物理化学和 有助于生物积累的全氟辛烷磺酸的分配行为。最重要的假设是(1) 接触PFAS将增加饮食诱导的肝脏脂肪变性和炎症，这可能是通过 肥胖增加和脂肪因子分泌改变，以及(2)生物学反应(如肝脏重量) 生物标记物(例如，氧化应激基因表达)可以与蛋白质、脂肪和/或 PFASs的膜分配行为。这些假设将通过(目标1)评估潜力来检验 全氟辛烷磺酸对肝脏脂肪堆积、脂肪生成和脂肪因子分泌的影响，(目标2)评估 出生后和成人暴露全氟辛烷磺酸是肥胖所致肝脏脂肪变性的额外危险因素 脂肪细胞功能障碍，以及(目标3)测定PFASs的物理化学性质及其分配 对脂肪和蛋白质阶段的行为。此外，通过该项目，可持续发展权指导方面存在重大差距 与全氟辛烷磺酸相关的问题将涉及(I)早期全氟辛烷磺酸暴露的结果，(Ii)机械性 除肝脏终点外，暴露于全氟辛烷磺酸的生物标记物；(Iii)美国常见的风险因素 可能影响对全氟辛烷磺酸暴露反应的人群(即饮食；肥胖)，以及(4)准确的测量 预测生物蓄积和毒性所需的物理化学性质。

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.