Uncovering the Mechanisms of PFAS-induced Immunotoxicity

摘要 （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"由北卡罗来纳州州立大学（NC State）领导。主 拟建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）解决全氟烷基和多氟烷基物质（PFAS）污染日益严重的问题， 美国（US）。PFAS被认为是新兴关注的污染物，原因有很多，但其中之一是 最紧迫的是，在已知存在的近5,000个PFAS中，只有少数几个得到了评估 尽管许多社区正受到其存在的影响， 环境介质，尤其是饮用水。人类暴露于全氟辛酸（PFOA）的研究 和全氟辛烷磺酸（PFOS），这两种PFAS在人体中检出频率和浓度较高， 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。对实验动物模型的进一步研究支持了PFAS诱导 免疫毒性并改变适应性和先天免疫系统的反应。虽然PFOA和PFOS 被认为是对人类的免疫危害，存在一些知识空白：特别是，机制 这些PFAS诱导免疫毒性的机制尚不清楚， 对免疫功能的干扰在很大程度上是未知的。因此，项目2的目标是双重的：i）探索 PFAS在选定动物模型和人类细胞系中诱导免疫毒性的分子变化 以鉴定受影响的信号通路和网络，和ii）确定免疫毒理学特征， 包括机械基础，PFAS的新兴关注相对于少数研究充分的PFAS。我们 总体假设是PFAS介导的免疫抑制是由于免疫细胞代谢的调节， 功能协调发展的将通过（目的1）量化PFAS暴露对B细胞的影响来评价该假设 小鼠模型中的发育和抗体产生，以及（目的2）确定PFAS暴露的影响 使用斑马鱼体内模型和人体外细胞系模型对吞噬细胞功能的影响。该项目将 解决了已知PFAS诱导免疫毒性机制的重大空白， 将改善对已知PFAS健康风险、免疫抑制的管理，并加速 免疫治疗受影响的人。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通知适当的监管措施至关重要;我们的项目将揭示 改变免疫应答的分子起始事件，以促进新的基于免疫机制的 最近在北卡罗来纳州和其他地方检测到的PFAS的优先化策略。

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.