College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an , 237012, People's Republic of China.
Neurotox Res. 2022 Oct;40(5):1127-1137. doi: 10.1007/s12640-022-00474-x. Epub 2022 Jul 27.
Cadmium (Cd) is a toxic environmental contaminant, which bio-accumulate in animals through the food chain. Cerebellum is one of the primary target organs for Cd exposure. In this study, we established a chronic Cd exposure model; 60 chickens were treated with Cd (0 mg/kg, 35 mg/kg, 70 mg/kg) for 90 days. Clinical manifestations indicated that the chicken was depressed and has unstable gait under Cd exposure. Histopathological results indicated that Cd induced neuronal shrunken and indistinct nucleoli, and the number of Purkinje cells decreased significantly. Cerebellar metal contents were analyzed by ICP-MS. We found that Cd caused Cd and Cu accumulation and decreased the content of Se, Fe, and Zn, suggesting that Cd disturbed metal homeostasis. Besides, Cd treatment group also showed high levels of malondialdehyde (MDA) and hydrogen peroxide (HO) content and inhibited selenoprotein transcriptome, suggesting that Cd exposure resulted in oxidative stress. Notably, low-dose Cd exposure activated MTF1 mRNA and protein expression and its target metal-responsive genes, including MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B which indicate cellular adaptive response against Cd-induced damage. On the other hand, 70 mg/kg Cd downregulated MTF1-mediated metal response, which was involved in Cd-induced cerebellar injury in chicken. In conclusion, our data demonstrated that molecular mechanisms are associated with Cd-induced cerebellar injury due to disturbing MTF1-mediated metal response. This study indicated that the cerebellum is one of the target organs of Cd-induced toxicity. Additionally, Cd exposure induced metal dyshomeostasis in chicken's cerebellum, whereas this study found that lower level of Cd dose triggered the activation of the cytoprotective mechanism through activating the expression of MTF1 which regulate MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B expressions in cerebellum. However, MTF1-mediated metal response was inhibited under the exposure of high dose of Cd, which ultimately caused cerebellar injury. The present study provides a new insight that Cd through disturbed MTF1-mediated metal response disrupts metal homeostasis that induced cerebellar injury.
镉（Cd）是一种有毒的环境污染物，它通过食物链在动物体内生物累积。小脑是 Cd 暴露的主要靶器官之一。在这项研究中，我们建立了慢性 Cd 暴露模型；60 只鸡用 Cd（0mg/kg、35mg/kg、70mg/kg）处理 90 天。临床表现表明，鸡在 Cd 暴露下抑郁且步态不稳定。组织病理学结果表明，Cd 诱导神经元皱缩且核仁不明显，浦肯野细胞数量显著减少。通过 ICP-MS 分析小脑金属含量。我们发现 Cd 导致 Cd 和 Cu 积累，降低 Se、Fe 和 Zn 的含量，表明 Cd 扰乱了金属内稳态。此外，Cd 处理组还表现出高水平的丙二醛（MDA）和过氧化氢（HO）含量，并抑制硒蛋白转录组，表明 Cd 暴露导致氧化应激。值得注意的是，低剂量 Cd 暴露激活了 MTF1mRNA 和蛋白表达及其靶金属反应基因，包括 MT1、MT2、DMT1、ZIP8、ZIP10、TF 和 ATP7B，表明细胞对 Cd 诱导的损伤有适应性反应。另一方面，70mg/kg Cd 下调了 MTF1 介导的金属反应，这与鸡小脑 Cd 诱导损伤有关。总之，我们的数据表明，分子机制与 Cd 诱导的小脑损伤有关，因为它扰乱了 MTF1 介导的金属反应。本研究表明小脑是 Cd 诱导毒性的靶器官之一。此外，Cd 暴露导致鸡小脑金属失调，而本研究发现，较低水平的 Cd 剂量通过激活 MTF1 来触发细胞保护机制的激活，从而调节 MT1、MT2、DMT1、ZIP8、ZIP10、TF 和 ATP7B 在小脑中的表达。然而，在高剂量 Cd 暴露下，MTF1 介导的金属反应受到抑制，最终导致小脑损伤。本研究提供了一个新的见解，即 Cd 通过扰乱 MTF1 介导的金属反应破坏金属内稳态，从而导致小脑损伤。
