氯化蒽(Cl-Ants),持久性有机污染物,在环境中被广泛检测到,由于频繁的呼吸道暴露而造成潜在的肺毒性风险。然而,缺乏直接证据和对其毒性机制的全面了解。基于我们先前对Cl-蚂蚁免疫毒性风险的发现,本研究建立了模拟肺免疫微环境的三维共培养球体模型。目的是探讨肺的免疫毒性及其机制,考虑到Cl-Ants的免疫反应性增强和频繁的肺暴露。结果表明,Cl-蚂蚁暴露导致球状体尺寸减小,巨噬细胞向外迁移增加,降低细胞活力,升高8-OHdG水平,抗感染平衡受到干扰,和改变细胞因子的产生。具体来说,氯取代基数与Cl-Ants引起的球状体指示剂破坏程度相关,与单氯化Ant相比,二氯化Ant具有更强的免疫毒性作用。此外,我们确定了与细胞活力相关的关键调节基因(ALDOC和ALDOA),细菌反应(TLR5和MAP2K6),和GM-CSF生产(CEBPB)。总的来说,这项研究提供了低剂量Cl-PAHs肺免疫毒性的初步体外证据,提高对Cl-蚂蚁结构相关毒性的理解,改进环境污染物的外部毒性评估方法,这对未来的监测和评估具有重要意义。
Chlorinated
anthracenes (Cl-Ants), persistent organic pollutants, are widely detected in the environment, posing potential lung toxicity risks due to frequent respiratory exposure. However, direct evidence and a comprehensive understanding of their toxicity mechanisms are lacking. Building on our prior findings of Cl-Ants\' immunotoxic risks, this study developed a three-dimensional coculture spheroid model mimicking the lung\'s immune microenvironment. The objective is to explore the pulmonary immunotoxicity and comprehend its mechanisms, taking into account the heightened immune reactivity and frequent lung exposure of Cl-Ants. The results demonstrated that Cl-Ants exposure led to reduced spheroid size, increased macrophage migration outward, lowered cell viability, elevated 8-OHdG levels, disturbed anti-infection balance, and altered cytokine production. Specifically, the chlorine substituent number correlates with the extent of disruption of spheroid indicators caused by Cl-Ants, with stronger immunotoxic effects observed in dichlorinated Ant compared to those in monochlorinated Ant. Furthermore, we identified critical regulatory genes associated with cell viability (ALDOC and ALDOA), bacterial response (TLR5 and MAP2K6), and GM-CSF production (CEBPB). Overall, this study offers initial in vitro evidence of low-dose Cl-PAHs\' pulmonary immunotoxicity, advancing the understanding of Cl-Ants\' structure-related toxicity and improving external toxicity assessment methods for environmental pollutants, which holds significance for future monitoring and evaluation.