Angrish Michelle M, Pleil Joachim D, Stiegel Matthew A, Madden Michael C, Moser Virginia C, Herr David W
a Integrated Sciences and Toxicology Division, NHEERL/ORD , U.S. Environmental Protection Agency, Research Triangle Park , North Carolina , USA.
b Human Exposure and Atmospheric Sciences Division, NERL/ORD , U.S. Environmental Protection Agency, Research Triangle Park , North Carolina , USA.
J Toxicol Environ Health A. 2016;79(4):184-96. doi: 10.1080/15287394.2016.1138923. Epub 2016 Feb 25.
Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine levels that are below or at baseline and relate those dynamic and complex cytokine signatures of exposures with the inflammatory and repair pathways. Thus, highly sensitive, specific, and precise analytical and statistical methods are critically important. Investigators at the U.S. Environmental Protection Agency (EPA) have implemented advanced technologies and developed statistics for evaluating panels of inflammatory cytokines in human blood, exhaled breath condensate, urine samples, and murine biological media. Advanced multiplex, bead-based, and automated analytical platforms provided sufficient sensitivity, precision, and accuracy over the traditional enzyme-linked immunosorbent assay (ELISA). Thus, baseline cytokine levels can be quantified from healthy human subjects and animals and compared to an in vivo exposure response from an environmental chemical. Specifically, patterns of cytokine responses in humans exposed to environmental levels of ozone and diesel exhaust, and in rodents exposed to selected pesticides (such as fipronil and carbaryl), were used as case studies to generally assess the taxonomic applicability of cytokine responses. The findings in this study may aid in the application of measureable cytokine markers in future adverse outcome pathway (AOP)-based toxicity testing. Data from human and animal studies were coalesced and the possibility of using cytokines as key events (KE) to bridge species responses to external stressors in an AOP-based framework was explored.
细胞因子作为细胞间免疫调节信号的低分子量信使蛋白，已成为评估对外部应激源的全身炎症反应的主流临床前标志物。挑战在于对健康受试者中低于或处于基线水平的细胞因子水平进行定量，并将这些暴露的动态且复杂的细胞因子特征与炎症和修复途径联系起来。因此，高灵敏度、特异性和精确性的分析及统计方法至关重要。美国环境保护局（EPA）的研究人员已采用先进技术并开发了统计方法，用于评估人类血液、呼出气冷凝物、尿液样本和小鼠生物介质中的炎症细胞因子组。先进的多重、基于微珠和自动化分析平台比传统的酶联免疫吸附测定（ELISA）提供了足够的灵敏度、精密度和准确性。因此，可以从健康的人类受试者和动物中定量基线细胞因子水平，并与环境化学物质的体内暴露反应进行比较。具体而言，以暴露于环境水平臭氧和柴油尾气的人类以及暴露于选定农药（如氟虫腈和西维因）的啮齿动物中的细胞因子反应模式作为案例研究，以总体评估细胞因子反应的分类适用性。本研究的结果可能有助于在未来基于不良结局途径（AOP）的毒性测试中应用可测量的细胞因子标志物。整合了来自人类和动物研究的数据，并探讨了在基于AOP的框架中使用细胞因子作为关键事件（KE）来桥接物种对外部应激源反应的确可能性。
