Department of Hygienic Toxicology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province 150081, PR China.
Department of Environmental Health, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province 150081, PR China.
Ecotoxicol Environ Saf. 2021 Dec 15;226:112862. doi: 10.1016/j.ecoenv.2021.112862. Epub 2021 Oct 5.
To investigate the mechanisms of ATR-induced dopaminergic toxicity by microglia activation and the response of the Keap1/ Nrf2- ARE signaling pathway.
Wistar rats were treated with 50, 100 and 200 mg/kg ATR and BV-2 microglia cells were treated with 50, 100 μM ATR or 100 ng/mL LPS, respectively. Rats behavioral responses and histopathological changes were monitored. Immunohistochemical and immunofluorescence analysis detected Iba-1 and TH cells in rats. Keap1/Nrf2-ARE signaling-related proteins and inflammatory factors from BV-2 cells and rats were detected using ELISA, Western blot and Real-time PCR.
After ATR treatment, the grip strength of Wistar rats was significantly decreased, and anxiety were clearly observed. TH neurons were reduced, however, the number of microglia cells and Iba-1 levels were increased clearly in SN. The release of ROS, TNF-α and IL-Iβ were increased, and levels of SOD and GSH-Px were significantly decreased. Keap1 mRNA expression and protein levels were decreased, while nuclear Nrf2 mRNA expression and protein levels were both increased in vivo and in vitro.
ATR could significantly activate microglia and exacerbate neurotoxicity and neuroinflammation, leading to accelerate dopaminergic neuron cell death by inhibiting Keap1/Nrf2-ARE signaling pathway.
研究 ATR 诱导的小胶质细胞激活和 Keap1/Nrf2-ARE 信号通路反应导致多巴胺能毒性的机制。
Wistar 大鼠分别用 50、100 和 200mg/kg ATR 处理，BV-2 小胶质细胞分别用 50、100μM ATR 或 100ng/mL LPS 处理。监测大鼠的行为反应和组织病理学变化。免疫组织化学和免疫荧光分析检测大鼠中 Iba-1 和 TH 细胞。使用 ELISA、Western blot 和实时 PCR 检测 BV-2 细胞和大鼠中 Keap1/Nrf2-ARE 信号相关蛋白和炎症因子。
ATR 处理后，Wistar 大鼠握力明显下降，焦虑明显。SN 中 TH 神经元减少，然而小胶质细胞和 Iba-1 水平明显增加。ROS、TNF-α 和 IL-Iβ 的释放增加，SOD 和 GSH-Px 水平明显降低。体内和体外 Keap1 mRNA 表达和蛋白水平降低，而核 Nrf2 mRNA 表达和蛋白水平均增加。
ATR 可显著激活小胶质细胞，加重神经毒性和神经炎症，通过抑制 Keap1/Nrf2-ARE 信号通路加速多巴胺能神经元细胞死亡。
