Uncovering the Mechanisms of PFAS-induced Immunotoxicity

揭示 PFAS 诱导免疫毒性的机制

基本信息

批准号：
10115847
负责人：
Seth William Kullman
金额：
$ 9.71万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
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/10115847
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 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

项目摘要

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 PFAS 的环境和健康影响”由北卡罗来纳州立大学（北卡罗来纳州）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计划 (SRP) 解决了日益严重的全氟烷基物质和多氟烷基物质 (PFAS) 污染问题由于多种原因，美国 (US) 认为 PFAS 是新出现的污染物，但其中之一是。最紧迫的是，已知存在的近 5,000 种 PFAS 中，只有少数经过评估由于其毒理学潜力，尽管许多社区正受到其存在的影响环境介质，特别是饮用水中的人类接触全氟辛酸 (PFOA) 的研究。和全氟辛烷磺酸 (PFOS)，这两种 PFAS 在人体和人体中检测到的频率和浓度较高环境样本提供了令人信服的证据，表明免疫系统是免疫系统的敏感目标 PFAS。对实验动物模型的额外研究支持了 PFAS 诱导的假设。 PFOA 和 PFOS 具有免疫毒性并改变适应性和先天免疫系统的反应。被认为对人类有免疫危害，但存在一些知识空白：值得注意的是，其机制这些 PFAS 是如何引起免疫毒性的仍然难以捉摸，而且大多数新兴的 PFAS 在多大程度上会引起免疫毒性？扰乱免疫功能的问题在很大程度上是未知的，因此，项目 2 的目标有两个：i) 探索。 PFAS 在特定动物模型以及人类细胞系中诱导免疫毒性的分子变化确定受影响的信号通路和网络，以及 ii) 确定免疫毒理学特征，与少数经过充分研究的 PFAS 相比，PFAS 的新兴关注点包括其机制基础。总体假设是 PFAS 介导的免疫抑制是免疫细胞代谢调节的结果该假设将通过（目标 1）量化 PFAS 暴露对 B 细胞的影响来评估。在小鼠模型中进行发育和抗体生产，并（目标 2）确定 PFAS 暴露的影响该项目将使用斑马鱼体内模型和人类体外细胞系模型来研究吞噬细胞功能。解决了 PFAS 诱导免疫毒性机制已知的重大空白，将改善对已知 PFAS 健康风险、免疫抑制的管理，并加速开发此外，大量未经测试的 PFAS 也意味着快速确定优先级的方法对于告知适当的监管措施至关重要；分子起始事件改变了潜在的免疫反应，以促进基于免疫机制的新型免疫反应最近在北卡罗来纳州和其他地方发现的 PFAS 优先策略。