Department of Biology, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
Department of Life and Nanopharmaceutical Science, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
Ecotoxicol Environ Saf. 2021 Mar 15;211:111947. doi: 10.1016/j.ecoenv.2021.111947. Epub 2021 Jan 25.
The chicken (Gallus gallus), which has three aryl hydrocarbon receptor (AHR) isoforms (ckAHR1, ckAHR2, and ckAHR1β) and two AHR nuclear translocator (ARNT) isoforms (ckARNT1 and ckARNT2), is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and can serve as an avian model to gain an understanding of the mechanism underlying dioxin toxicity. To elucidate the mechanism of TCDD-induced immunotoxicity in avian species, we treated chicken embryos in ovo with graded concentrations of TCDD (1.5, 2.5, 3.0, 3.3, 3.5, and 4.0 μM). Initially, we measured mRNA expression levels of ckAHR and ckARNT isoforms and analyzed the T cell populations and transcriptome in the thymuses of TCDD-treated chicken embryos. Quantitative polymerase chain reaction analysis revealed that mRNA expressions of ckAHR1 and ckARNT2 were dominant in the thymus. Severe weight loss and thymus atrophy were observed in the TCDD-treated embryos. Immunophenotyping analyses demonstrated significant increases in CD4CD8CD25 and CD4CD8CD25 regulatory T cells (Tregs) populations following TCDD exposure, suggesting that TCDD suppresses T cell-mediated immune responses in chicken embryos. In addition, thymic transcriptome analyses intimated that alteration of the signaling pathways related to erb-b2 receptor tyrosine kinase 4 (ERBB4) and wnt family member 5A (WNT5A), and bone morphogenetic protein (BMP) may be associated with the TCDD-induced thymus atrophy. We also observed significantly altered expression levels of genes including interleukine 13 receptor subunit alpha 2 (IL13RA2), transforming growth factor beta 1 (TGFβ1), collagen type III alpha 1 chain (COL3A1), and collagen type IX alpha 3 chain (COL9A3), implying immunosuppression, fibrosis development, and collagen deposition. Collectively, these findings suggest that TCDD exposure activates the ckAHR1-ckARNT2 signaling pathway and suppresses immune responses through the prompted differentiation to CD4CD8CD25 and CD4CD8CD25 Tregs and altered expressions of immune-related genes in the thymus of chicken embryos.
鸡（Gallus gallus）有三种芳基烃受体（AHR）同工型（ckAHR1、ckAHR2 和 ckAHR1β）和两种 AHR 核转位蛋白（ARNT）同工型（ckARNT1 和 ckARNT2），对 2,3,7,8-四氯二苯并对二恶英（TCDD）非常敏感，可作为禽类模型来了解二恶英毒性的作用机制。为了阐明禽类中 TCDD 诱导的免疫毒性机制，我们用不同浓度的 TCDD（1.5、2.5、3.0、3.3、3.5 和 4.0 μM）对鸡胚进行了体内处理。首先，我们测量了 ckAHR 和 ckARNT 同工型的 mRNA 表达水平，并分析了 TCDD 处理的鸡胚胸腺中的 T 细胞群和转录组。实时定量聚合酶链反应分析显示 ckAHR1 和 ckARNT2 的 mRNA 表达在胸腺中占主导地位。TCDD 处理的胚胎出现严重的体重减轻和胸腺萎缩。免疫表型分析表明，TCDD 暴露后 CD4CD8CD25 和 CD4CD8CD25 调节性 T 细胞（Tregs）群体显著增加，表明 TCDD 抑制鸡胚中的 T 细胞介导的免疫反应。此外，胸腺转录组分析表明，与 erb-b2 受体酪氨酸激酶 4（ERBB4）和 Wnt 家族成员 5A（WNT5A）以及骨形态发生蛋白（BMP）相关的信号通路的改变可能与 TCDD 诱导的胸腺萎缩有关。我们还观察到包括白细胞介素 13 受体亚单位α 2（IL13RA2）、转化生长因子β 1（TGFβ1）、III 型胶原α 1 链（COL3A1）和 IX 型胶原α 3 链（COL9A3）在内的基因表达水平发生显著改变，提示免疫抑制、纤维化发展和胶原蛋白沉积。总之，这些发现表明 TCDD 暴露通过激活 ckAHR1-ckARNT2 信号通路，以及通过促使向 CD4CD8CD25 和 CD4CD8CD25 Tregs 的分化，以及鸡胚胸腺中免疫相关基因表达的改变，抑制免疫反应。
