目的研究慢性氟中毒大鼠脑组织中细胞外信号调节蛋白激酶(Extracellular signal regulated kinases,Ras-Erk1/2)通路主要激酶表达变化及其对转录因子环一磷酸腺苷反应单元结合蛋白(cAMP Responsive Element Binding Protein,CREB)的影响。方法 SD(Sprague dawley)大鼠随机分为3组,即正常组、饮水中小剂量加氟(5 mg/L)组、大剂量加氟(50 mg/L)组,实验期为6个月。实验结束时,用氟离子选择电极法测定大鼠尿氟及血氟含量,尼氏染色检查神经细胞尼氏小体改变,蛋白印迹(Western-blotting)方法检测脑组织中小鸟苷三磷酸结合蛋白(small GTP-binding protein,Ras)、Erk1/2、CREB信号转导激酶的蛋白表达水平,实时荧光定量聚合酶链式反应(Real-time Polymerase Chain Reaction,Re-al-time PCR)方法检测c-fos基因mRNA表达水平。结果与对照组相比,染氟组大鼠有不同程度的氟斑牙及血氟尿氟升高;大脑皮质和海马部位神经细胞尼氏小体减少;脑组织中Ras、phospho-Erk1/2t、otal-Erk1/2及phospho-CREB蛋白表达水平上升(F值分别为19.9、114.59、4.6 9、7.6,P<0.05),以大剂量染氟组尤为明显t,otal-CREB在各组间未见明显改变;大剂量染氟组c-fos基因mRNA表达明显升高,而小剂量染氟组该基因mRNA表达降低。结论过多的氟可引起大鼠脑组织神经细胞损伤,脑组织中Ras-Erk1/2信号激酶通路过度激活可刺激转录因子CREB磷酸化,从而影响c-fos基因的表达,该过程可能参与慢性氟中毒脑损伤机制。 Objective To study the expression of major kinase in the extracellular signal regulated kinases (Ras-Erk1 / 2) pathway in chronic fluorosis rats and its effect on the transcription factor cAMP-responsive Element Binding Protein, CREB). Methods SD rats (Sprague Dawley) were randomly divided into three groups: normal group, medium and low dosage of fluoride (5 mg / L) and high dose of fluoride (50 mg / L) for 6 months. At the end of the experiment, Fluoride ion-selective electrode method was used to determine urinary fluoride and blood fluoride content, Nissl staining was used to examine the change of Nissl body of nerve cell, Western blotting was used to detect the activity of small guanosine triphosphate binding protein protein expression levels of small GTP-binding protein (Ras), Erk1 / 2 and CREB signal transduction kinases, Real-time Polymerase Chain Reaction (Real-time Polymerase Chain Reaction) -fos gene mRNA expression level. Results Compared with the control group, the rats in the fluoride group had different levels of dental fluorosis and increased blood fluorine and fluoride levels; the number of Nissl bodies in the cerebral cortex and hippocampus decreased; the contents of Ras, phospho-Erk1 / 2t , Total-Erk1 / 2 and phospho-CREB (F values ​​were 19.9, 114.59, 4.6 9, 7.6 respectively, P <0.05) No significant changes were observed. The mRNA expression of c-fos gene was significantly increased in high-dose fluoride group, while the mRNA expression was decreased in low-dose fluoride group. Conclusion Excessive fluoride can cause neuronal damage in rat brain. Over-activation of Ras-Erk1 / 2 signal kinase pathway in brain stimulates the phosphorylation of CREB, which may affect the expression of c-fos gene. This process may be involved in chronic Fluorosis poisoning brain injury mechanism.