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是为美国生物医学研究中心提出的两个生物医学研究项目之一 北卡罗来纳州立大学(北卡罗来纳州立大学)领导的“全氟辛烷磺酸对环境和健康的影响”。初级阶段 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)解决了全氟和多氟烷基物质(PFAS)污染日益严重的问题 美国(US)。全氟辛烷磺酸被认为是新出现的令人担忧的污染物，原因有很多，但其中之一 最紧迫的是，在已知的近5000个现有的PFAS中，只有几个得到了评估 因为它们的毒理潜力，尽管许多社区正在受到它们的存在的影响 环境媒体，特别是饮用水。人体暴露于全氟辛酸(PFOA)的研究 和全氟辛烷磺酸(PFOS)，两种在人体内检测到的高频率和高浓度的PFAS 环境样本，提供了令人信服的证据，表明免疫系统是 全氟辛烷磺酸。对实验动物模型的额外研究支持了PFAS诱导 适应性免疫系统和先天免疫系统的免疫毒性和改变反应。而全氟辛酸和全氟辛烷磺酸 它们被认为是对人类的免疫危害，但在认识上存在几个空白：值得注意的是，其机制(S) 这些全氟辛酸是如何导致免疫毒性的仍然难以捉摸，以及大多数出现的全氟辛酸的程度 对免疫功能紊乱的担忧在很大程度上是未知的。因此，项目2的目标有两个：i)探索 部分动物模型和人类细胞系中PFAS诱导免疫毒性的分子变化 为了识别受影响的信号通路和网络，以及ii)确定免疫毒理学特征， 包括机械基础在内，相对于少数几个经过充分研究的全氟辛烷磺酸，新出现的关注的全氟辛烷磺酸。我们的 全球假说认为，PFAS介导的免疫抑制是免疫细胞代谢调节的结果 功能。这一假设将通过(目标1)量化PFAS暴露对B细胞的影响来进行评估 小鼠模型的发育和抗体产生以及(目标2)确定PFAS暴露的影响 用斑马鱼体内模型和人体外细胞系模型研究吞噬细胞功能。这个项目将 解决已知的全氟辛烷磺酸引起免疫毒性的机制方面的重大差距，这 将改善对已知的全氟辛烷磺酸健康风险的管理，抑制免疫，并加速发展 针对受影响个体的免疫疗法。此外，大量未经测试的全氟辛烷磺酸也意味着 快速确定优先顺序的方法对于通知适当的监管措施至关重要；我们的项目将发现 改变免疫反应的分子启动事件促进新的、基于免疫机制的 最近在北卡罗来纳州和其他地方发现了全氟辛烷磺酸的优先战略。

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.