Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
Environ Pollut. 2021 Oct 15;287:117302. doi: 10.1016/j.envpol.2021.117302. Epub 2021 May 4.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known immunotoxic environmental pollutant. However, most immunotoxicology studies of TCDD were based on the animal models and the inner mechanisms have just focused on a few genes/proteins. In this study, the immune functions of THP-1-derived macrophages was measured with in-vitro bioassays after 24-h exposure of TCDD including environmentally relevant concentrations. RNA-seq and Weighted Gene Co-expression Network Analysis were used to characterize the immunotoxicity molecular mechanisms. Our study is the first report on the TCDD-induced effects of cell adhesion, morphology, and multiple cytokines/chemokines production on THP-1 macrophages. After TCDD treatment, we observed an inhibited cell adherence, probably attributed to the suppressed mRNA levels of adhesion molecules ICAM-1, VCAM-1 and CD11b, and a decrease in cell pseudopodia and expression of F-actin. The inflammatory cytokines TNF-α, IL-10 and other 8 cytokines/chemokines regulating granulocytes/T cells and angiogenesis were disrupted by TCDD. Alternative splicing event was found to be a sensitive target for TCDD. Using WGCNA, we identified 10 hub genes (TNF, SRC, FGF2, PTGS2, CDH2, GNG11, BDNF, WNT5A, CXCR5 and RUNX2) highly relevant to these observed phenotypes, suggesting AhR less important in the effects TCDD have on THP-1 macrophages than in other cells. Our findings broaden the understanding of TCDD immunotoxicity on macrophages and provide new potential targets for clarifying the molecular mechanisms.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种众所周知的免疫毒性环境污染物。然而，大多数 TCDD 的免疫毒理学研究都是基于动物模型，并且内在机制仅集中在少数几个基因/蛋白质上。在这项研究中，通过体外生物测定法测量了 THP-1 衍生的巨噬细胞的免疫功能，包括在环境相关浓度下 24 小时暴露于 TCDD 后。RNA-seq 和加权基因共表达网络分析用于表征免疫毒性的分子机制。我们的研究首次报道了 TCDD 对 THP-1 巨噬细胞的细胞黏附、形态和多种细胞因子/趋化因子产生的诱导作用。在 TCDD 处理后，我们观察到细胞黏附受到抑制，这可能归因于黏附分子 ICAM-1、VCAM-1 和 CD11b 的 mRNA 水平降低，以及细胞伪足减少和 F-肌动蛋白表达减少。TNF-α、IL-10 和其他 8 种调节粒细胞/T 细胞和血管生成的细胞因子/趋化因子被 TCDD 破坏。替代性剪接事件被发现是 TCDD 的一个敏感靶标。使用 WGCNA，我们鉴定了 10 个与这些观察到的表型高度相关的枢纽基因（TNF、SRC、FGF2、PTGS2、CDH2、GNG11、BDNF、WNT5A、CXCR5 和 RUNX2），这表明 AhR 在 TCDD 对 THP-1 巨噬细胞的影响中不如在其他细胞中重要。我们的发现拓宽了对巨噬细胞中 TCDD 免疫毒性的认识，并为阐明分子机制提供了新的潜在靶点。
