Linking PFAS exposure to thyroid disruption and innate immunity

项目摘要 在98%的美国人的血清中可以检测到全氟烷基物质和多氟烷基物质(PFAS)，并且已经被 与几种严重的健康影响有关，包括癌症和炎症性疾病。其中许多对健康的影响 与先天免疫功能的失调有关，但全氟辛烷磺酸如何影响先天免疫是广泛存在的。 未知。初步数据显示，在体外和体内，PFAS暴露都会抑制先天免疫功能。 此外，接触PFAS与甲状腺疾病有关，正常的甲状腺激素水平对 先天免疫功能。因此，中心假设是PFAS诱导的免疫毒性是通过 甲状腺激素信号减弱。这一假设将在多个结构不同的PFAS中进行测试 人类先天免疫细胞系和甲状腺功能减退的斑马鱼模型。目标1将确定PFAS诱导的 自然杀伤(NK)细胞功能的抑制需要体外甲状腺激素信号传导。目标2将决定是否 PFAS诱导的吞噬细胞功能抑制需要体内和体外甲状腺激素信号转导。 这项工作将开始填补围绕全氟辛烷磺酸引起的毒性的知识空白，特别是当它与它们的 免疫毒性及其潜在的作用机制。该项目的成功完成将通知DASHER 确定和风险评估过程，并可能导致改善对环境中全氟辛烷磺酸的监管。

PROJECT ABSTRACT Per- and polyfluoroalkyl substances (PFASs) can be detected in the serum of 98% of Americans and have been linked to several severe health effects, including cancer and inflammatory diseases. Many of these health effects are linked to dysregulation of innate immune function, but how PFASs impact innate immunology is widely unknown. Preliminary data show that PFAS exposure suppresses innate immune function in vitro and in vivo. Further, PFAS exposure is associated with thyroid disease, and normal thyroid hormone levels are essential for innate immune function. Therefore, the central hypothesis is that PFAS-induced immunotoxicity is mediated by decreased thyroid hormone signaling. This hypothesis will be tested for multiple structurally diverse PFASs in both human innate immune cell lines and a hypothyroid zebrafish model. Aim 1 will determine if PFAS-induced suppression of natural killer (NK) cell function requires thyroid hormone signaling in vitro. Aim 2 will determine if PFAS-induced suppression of phagocyte cell function requires thyroid hormone signaling in vivo and in vitro. This work will begin to fill the knowledge gap surrounding PFAS-induced toxicity, specifically as it relates to their immunotoxicity and their potential mechanisms of action. Successful completion of this project will inform hazard identification and risk assessment processes and may lead to improved regulation of PFASs in the environment.