College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
Toxicology. 2021 Jun 15;457:152790. doi: 10.1016/j.tox.2021.152790. Epub 2021 Apr 21.
Cadmium (Cd), an environmental pollutant, causes several adverse reactions in animals. High dose of Cd has serious cytotoxicities, including the induction of programmed cell necrosis, autophagy and apoptosis, which has aroused wide public concern. The balance of cytokine network is affected by Th1/Th2 balance which is closely related to immune response and the occurrence, development, treatment and outcome of various diseases. Cd can induce severe apoptosis, but the relationship between Cd induced apoptosis and Th1/Th2 balance has not been clarified. In this study, we established a pig Cd poisoning model, exposing to CdCl for 40 days (20 mg Cd/kg diet). Firstly, deviation of Th1/Th2 balance was observed by fluorescence staining, and apoptosis was observed by TUNEL staining. Then, real-time fluorescence quantitative analysis and Western blot were used to detect the expression of related proteins. The results show that Cd can interfere with the balance of Th1/Th2 and shift the balance towards Th1. In addition, through the experiments, we found that Cd exposure can increase the expression of glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP78), marker proteins of unfolded protein response (UPR). Cd exposure can increase the expression of pancreatic endoplasmic reticulum kinase (PERK), CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF-6), cysteinyl aspartate specific proteinase (Caspase12), indicating the three branches (ATF6, PERK and IRE-1) of endoplasmic reticulum stress (ER-stress) were activated. Moreover, we found that the expression of pro-apoptosis genes in the downstream pathway of ER-stress increased. In summary, our results indicated that Cd exposure upregulated the expression of pro-apoptosis related genes and caused apoptosis via the activation of the ER-stress signaling pathways in pancreas cells. And these negative effects were correlated with the equilibrium drift of Th1/Th2, increase in the expression and secretion of Th1 cytokines.
镉（Cd）是一种环境污染物，会在动物体内引起多种不良反应。高剂量的镉具有严重的细胞毒性，包括诱导程序性细胞坏死、自噬和细胞凋亡，这引起了广泛的公众关注。细胞因子网络的平衡受到 Th1/Th2 平衡的影响，而 Th1/Th2 平衡与免疫反应以及各种疾病的发生、发展、治疗和结果密切相关。镉可诱导严重的细胞凋亡，但镉诱导的细胞凋亡与 Th1/Th2 平衡之间的关系尚未阐明。在本研究中，我们建立了猪镉中毒模型，用 CdCl 暴露 40 天（20mgCd/kg 饮食）。首先，通过荧光染色观察 Th1/Th2 平衡的偏差，通过 TUNEL 染色观察细胞凋亡。然后，通过实时荧光定量分析和 Western blot 检测相关蛋白的表达。结果表明，镉可干扰 Th1/Th2 平衡并使其向 Th1 倾斜。此外，通过实验发现，镉暴露可增加未折叠蛋白反应（UPR）的标志物葡萄糖调节蛋白 94（GRP94）和葡萄糖调节蛋白 78（GRP78）的表达。镉暴露可增加内质网激酶（PERK）、CCAAT 增强子结合蛋白同源蛋白（CHOP）、肌醇需求酶 1（IRE-1）、激活转录因子 6（ATF-6）、半胱氨酸天冬氨酸特异性蛋白酶 12（Caspase12）的表达，表明内质网应激（ER-stress）的三条分支（ATF6、PERK 和 IRE-1）被激活。此外，我们发现 ER-stress 下游途径中促凋亡基因的表达增加。总之，我们的结果表明，镉暴露通过激活内质网应激信号通路上调了凋亡相关基因的表达，并导致胰腺细胞凋亡。并且这些负面影响与 Th1/Th2 的平衡漂移、Th1 细胞因子的表达和分泌增加有关。
