Uncovering the Mechanisms of PFAS-induced Immunotoxicity

揭示 PFAS 诱导免疫毒性的机制

• 批准号: 10337308
• 负责人: Seth William Kullman
• 金额: $ 14.92万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-28 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337308
• 关键词: Acids; Adaptive Immune System; Address; Affect; Air; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; B-Cell Development; B-Lymphocytes; Bioenergetics; Biological; Biological Assay; Biomedical Research; Cause of Death; Cell Line; Cell physiology; Cells; Chemical Structure; Chemicals; Chemotaxis; Chronic Disease; Communities; Data; Deposition; Dermal; Development; Disease; Embryo; Environment; Environmental Health; Environmental Pollution; Environmental Risk Factor; Event; Experimental Animal Model; Exposure to; Flow Cytometry; Food; Frequencies; Future; Goals; Hazardous Substances; Health; Hepatotoxicity; Human; Human Cell Line; Immune; Immune System Diseases; Immune response; Immune system; Immunize; Immunosuppression; Immunotherapy; Impairment; In Vitro; Individual; Industrial Product; Industrialization; Infection; Innate Immune System; Knowledge; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Natural Immunity; North Carolina; Organism; Outcome; Phagocytes; Phagocytosis; Plasma Cells; Poly-fluoroalkyl substances; Production; Public Health; Reactive Oxygen Species; Research; Research Project Grants; Resistance; Respiration; Risk; Sampling; Serum; Signal Pathway; Signaling Protein; Site; Source; Stains; Superfund; T-Lymphocyte; Testing; Toxic effect; Toxicology; United States; Universities; Water; Work; Zebrafish; adaptive immunity; base; bioaccumulation; consumer product; developmental toxicity; disorder risk; drinking water; experience; exposed human population; hazard; immune function; immune health; immunoregulation; immunotoxicity; improved; in vivo; in vivo Model; macrophage; metabolome; metabolomics; mouse model; neutrophil; novel; perfluorooctane sulfonate; programs; rapid technique; reproductive toxicity; response; tool; transcriptome; vaccine response

ABSTRACT (Biomedical Research) Research Project 2 Biomedical Research Project 2 is one of two biomedical research projects proposed for the “Center for Environmental and Health Effects of PFAS” being led by North Carolina State University (NC State). The primary goal of the proposed Center is to provide highly relevant data and information to help the Superfund Research Program (SRP) address the growing problem of per- and polyfluoroalkyl substance (PFAS) contamination across the United States (US). PFAS are considered contaminants of emerging concern for myriad reasons, but one of the most pressing is that only a handful of the nearly 5,000 PFAS that are known to exist have been evaluated for their toxicologic potential, even though numerous communities are being impacted by their presence in environmental media, especially drinking water. Studies of humans exposed to perfluoroocatonic acid (PFOA) and perfluorooctane sulfonate (PFOS), two PFAS detected with high frequency and concentration in human and environmental samples, have provided compelling evidence that the immune system is a sensitive target of PFAS. Additional work with experimental animal models supports the hypothesis that PFAS induce immunotoxicity and alter responses of both the adaptive and innate immune systems. While PFOA and PFOS are presumed to be immune hazards to humans, several gaps in knowledge exist: notably, the mechanism(s) by which these PFAS induce immunotoxicity remain elusive, and the extent to which most PFAS of emerging concern perturb immune function is largely unknown. Therefore, the objectives of Project 2 are twofold: i) explore molecular changes underlying PFAS-induced immunotoxicity in select animal models as well as human cell lines to identify impacted signaling pathways and networks, and ii) determine the immunotoxicological profile, including mechanistic underpinnings, of PFAS of emerging concern relative to the few well-studied PFAS. Our global hypothesis is that PFAS-mediated immune suppression results from modulation of immune cell metabolic functions. This hypothesis will be evaluated by (Aim 1) quantifying the impact of PFAS exposure on B cell development and antibody production in a mouse model and (Aim 2) identifying the impact of PFAS exposure on phagocytotic cell function using a zebrafish in vivo model and human in vitro cell line models. This project will address significant gaps in what is known about the mechanisms by which PFAS induce immunotoxicity, which will improve management of a known PFAS health risk, immune suppression, and accelerate development of immune therapies for affected individuals. Additionally, the large number of untested PFAS also means that methods for rapid prioritization are critical for informing appropriate regulatory measures; our project will uncover molecular initiating events underlying altered immune responses to facilitate novel, immune-mechanism-based prioritization strategies for PFAS recently detected in North Carolina and elsewhere.

抽象的 （生物医学研究）研究项目2 生物医学研究项目2是为“中心”提出的两个生物医学研究项目之一 PFA的环境和健康影响”由北卡罗来纳州立大学（NC州）领导。 拟议中心的目标是提供高度相关的数据和信息，以帮助超级基金研究 程序（SRP）解决了跨越跨性别和多氟烷基物质（PFAS）污染的日益严重的问题 美国（美国）。由于多种原因，PFA被认为是新兴关注的污染物，但 最紧迫的是，已经评估了已知存在的近5,000个PFA中的少数 为了毒理学的潜力，即使许多社区受到其在内的存在的影响 环境媒体，尤其是饮用水。对暴露于全氟环酸（PFOA）的人类的研究 和全氟辛烷磺酸盐（PFO），两个PFA在人类和 环境样本提供了令人信服的证据，表明免疫系统是 PFA。与实验动物模型的其他工作支持了PFA的影响的假设 免疫毒性和改变适应性和先天免疫系统的反应。而PFOA和PFO 被预览是对人类的免疫危害，知识存在几个差距：值得注意的是，机制 这些PFA诱导免疫毒性仍然难以捉摸，以及大多数出现的PFA的程度 关注的扰动免疫功能在很大程度上未知。因此，项目2的目标是双重的：i）探索 PFAS诱导的免疫毒性的分子变化在某些动物模型以及人类细胞系中 确定受影响的信号通路和网络，ii）确定免疫毒理学特征， 包括机械基础，相对于少数研究的PFA，新兴关注的PFA。我们的 全球假设是PFAS介导的免疫抑制是由免疫细胞代谢的调节引起的 功能。该假设将通过（AIM 1）量化PFAS暴露对B细胞的影响来评估该假设 小鼠模型中的开发和抗体产生，（目标2）识别PFAS暴露的影响 使用斑马鱼在体内模型和人体体外细胞系模型上进行吞噬细胞功能。这个项目将 解决有关PFA诱导免疫毒性的机制已知的显着差距，这些机制 将改善对已知PFAS健康风险，免疫抑制的管理以及加速的发展 受影响个体的免疫疗法。此外，大量未经测试的PFA还意味着 快速优先级的方法对于告知适当的监管措施至关重要。我们的项目将发现 分子引发的事件改变了免疫反应的改变，以促进新型，免疫机制 最近在北卡罗来纳州和其他地方发现了PFA的优先级策略。