MTF-1调控的金属稳态在镉致鸡肝损伤中的作用及分子机制

镉是环境中广泛存在的重金属污染物，主要在肝脏中蓄积并发挥毒性效应。金属元素稳态平衡是肝脏发挥功能的物质基础，金属元素稳态失衡会导致肝损伤。MTF-1作为机体中唯一的金属转录调控因子，在金属元素稳态调控中发挥重要作用。然而MTF-1介导的金属元素稳态调控在环境剂量镉致肝脏损伤中的作用及分子机制仍不清楚。本项目以前期发现的镉导致鸡肝脏金属元素紊乱的现象为依据，以鸡肝脏和原代鸡肝细胞为研究对象，并建立MTF-1基因敲除和过表达原代鸡肝细胞模型，检测肝脏与肝细胞损伤、金属含量及价态、MTF-1信号传导通路、MTF-1对金属转运/结合基因启动子活性的调控等。从机体-器官-细胞-金属元素四个层次，揭示金属元素稳态失衡在镉致鸡肝损伤中的作用及MTF-1调控的金属元素稳态在镉致鸡肝脏损伤中的分子机制。本项目从新的视角揭示环境剂量镉的肝毒性机制，为镉毒性的防治提供新靶点，并为比较医学提供借鉴。

Cadmium, a widespread heavy metal pollutant, mainly accumulates in liver and exerts its toxic effect. Metal homeostasis is necessary to maintain liver function. Metal homeostasis disorder can cause liver damage. MTF-1 is the metal transcriptional factor that plays an important role in regulating metal homeostasis. However, the mechanism of environmental-dose cadmium-induced metal homeostasis disorder remains unclear. In this project, based on the former investigation of cadmium-induced hepatic metal homeostasis disorder, we choose chicken livers and primary hepatocytes as experimental objects. MTF-1 gene knockout and overexpression hepatocytes model are built. Liver damage, metal content and valence, MTF-1 signaling pathway-related molecules and MTF-1mediated metal transport/binding gene promoter activity are detected in this study. This study will clarify the relevance and molecular mechanism of MTF-1 mediated metal homeostasis regulation in environmental-dose cadmium-induced hepatotoxicity at organism-organ-cell-metal element four levels. These results provide a new target for the prevention of cadmium-induced hepatotoxicity and the reference for further research in the comparative medicine.