[Role of ferroptosis in cerebellar injury of mice following lead exposure].

ABSTRACT

OBJECTIVE: To investigate the role of ferroptosis in cerebellar injury of mice following lead exposure. METHODS: A total of forty SPF C57 mice were randomly divided into control group, low-dose lead exposure group, middle-dose lead exposure group and high-dose lead exposure group, with 10 mice in each group. Mice in three lead exposure groups were given 0.25, 0.50, 1.00 g/L lead acetate through drinking water for twelve weeks respectively. Lead concentration was detected by inductively coupled plasma mass spectrometer. The motor function was detected by beam walking test and open field test. Pathological changes of cerebellum in mice were observed by H&E staining. Western blotting was used to detect the protein expression of transferrin receptor-1(TFR-1), ferroportin(FPN-1), solute carrier family 7 member 11(SLC7 A11), glutathione peroxidase 4(GPX4), NF-E2-related factor 2(Nrf2) and heme oxygenase-1(HO-1). RESULTS: The lead concentration in cerebellum of mice in low lead group, medium lead group and high lead group were(1.05±0.11), (1.21±0.10) and(1.48±0.1) µg/g, respectively, which were significantly higher than that in the control group. The time to traverse the beam in low lead group, medium lead group and high lead group was 1.34, 1.64 and 2.02 folds of that in control group, respectively. Open field test showed that the central residence time and standing times of mice in low lead group, medium lead group and high lead group were significantly lower than that in control. Purkinje cells in the cerebellum of mice exposed to different doses of lead showed irregular arrangement, small cell bodies and deep staining, especially in the high lead group. The relative levels of iron in low lead group, medium lead group and high lead group was 1.77, 2.29 and 3.77 folds of that in control group, respectively. The content of MDA in cerebellum of mice in three lead exposure groups increased significantly, while the GHS decreased significantly. Compared with the control group, the expression of TFR-1 protein increased significantly in the lead exposure group, while the expression of FPN-1 protein decreased significantly only in the medium lead group and high lead group, which was 60% and 50% of the control group. Compared with the control group, the expressions of oxidative stress regulatory proteins SLC7 A11 and GPX4 in medium lead group and high lead group decreased significantly. Lead exposure significantly decreased the expression of Nrf2 and HO-1 protein in cerebellum, especially in high lead group. CONCLUSION: In this experiment condition, lead may induce ferroptosis in cerebellum of mice, of which, Nrf2/HO-1 signaling pathway might be involved in, and then further result in motor dysfunction of mice.