Linking PFAS exposure to thyroid disruption and innate immunity

项目摘要 全氟烷基和多氟烷基物质（PFAS）可以在98%的美国人的血清中检测到， 与几种严重的健康影响有关，包括癌症和炎症性疾病。许多这些健康影响 与先天免疫功能失调有关，但PFAS如何影响先天免疫学广泛 未知初步数据表明，PFAS暴露抑制先天性免疫功能在体外和体内。 此外，PFAS暴露与甲状腺疾病有关，正常的甲状腺激素水平对甲状腺疾病至关重要。 先天免疫功能因此，中心假设是PFAS诱导的免疫毒性是由 甲状腺激素信号减少。这一假设将在以下研究中针对多种结构多样的PFAS进行检验： 人类先天免疫细胞系和甲状腺功能减退症斑马鱼模型。目标1将确定PFAS是否诱导 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将确定是否 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传导。 这项工作将开始，以填补知识空白周围PFAS诱导的毒性，特别是因为它涉及到他们的 免疫毒性及其潜在作用机制。这个项目的成功完成将通知危害 这将有助于识别和风险评估过程，并可能导致改善对环境中PFAS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.