The Mechanism Of Subchronic Aluminum Poisoning Impact On Iron Homeostasis In Rats Hippocampus

Aluminum is a chronic and accumulative neurotoxin,and involved in the initiate and progress of various neurodegenerative diseases.Studies have shown that the neurotoxicity of aluminum is related to the oxidative stress caused by iron dyshomeostasis.The maintenance of iron homeostasis requires the normal expression of iron-related proteins and regulatory factors and their interaction with each other to regulate iron uptake,storage and release.However,the effect of aluminum on iron-related proteins and regulatory factors is unclear.In this experiment,the neurotoxicity mechanism of aluminum was investigated from the perspective of iron homeostasis.120 4-week-old male Wistar rats were randomly divided into control group?CG,0 mg/kg B.W.Al Cl₃?,low dose group?LG,50 mg/kg B.W.Al Cl₃?,medium dose group?MG,150 mg/kg B.W.Al Cl₃?and high dose group?HG,450 mg/kg B.W.Al Cl₃?.The model of subchronic aluminum poisoning was established by drinking water contaminated with Al Cl₃ for 90 days.The contents of aluminum and iron in hippocampus of rats,cognitive function,hippocampal histology and oxidative stress were detected to investigate the relationship between the contents of aluminum and iron in the hippocampal tissues and oxidative stress and hippocampal injury.The m RNA and protein expression of iron transporters?Tf R,DMT1 and Fpn1?,iron storage proteins?Fn?and iron regulatory factors?IRPs and hepcidin?was detected to explore the mechanism of aluminum poisoning on hippocampal iron homeostasis in rats.The results showed as follows:?1?The contents of aluminum and iron of all Al Cl₃-exposed groups were significantly increased than those of the CG in the hippocampus?p<0.05,p<0.01?,and iron content is proportional to aluminum content.The results indicated subchronic aluminum poisoning caused aluminum and iron accumulation in the hippocampus of rats.?2?In acquisition trial,the escape latency of the MG and HG was significantly longer than that of the CG?p<0.05,p<0.01?,indicating that aluminum impaired the learning function.In probe trial,the swimming time and path length in target quadrant of the MG and HG were significantly lower than those of the CG?p<0.05,p<0.01?,indicating that aluminum impaired memory function.The results indicated subchronic aluminum poisoning caused cognitive dysfunction of rats.?3?Microstructural observations showed that the hippocampal neurons of the CG and LG were arranged neatly and closely,oval in shape,with a complete and clear structure.The hippocampal neurons of the MG were irregular arranged,with a large number of vacuolated cells.The hippocampal neurons of the HG were loose and disorderly arrangement,the morphology and structure of some neurons were changed,accompanying nucleoli karyopyknosis with dark staining.Quantitative analysis of necrotic neurons in the hippocampal CA1 showed that the loss of neurons in all Al Cl₃-exposed groups was significantly higher than that in the CG?p<0.05,p<0.01?,and showed a dose-dependent effect with aluminum.The results indicated subchronic aluminum poisoning induced microstructure lesion in the hippocampus of rats.?4?Detection of oxidative stress showed that the ROS and MDA content of all Al Cl₃-exposed groups were significantly higher than those of the CG?p<0.05,p<0.01?,and the protein carbonyl content of the MG and HG was significantly higher than that of the CG?p<0.01?.The TAC and SOD activity of all Al Cl₃-exposed groups were significantly lower than those of the CG?p<0.05,p<0.01?,and the CAT activity of the MG and HG was significantly lower than that of the CG?p<0.01?.The results indicated subchronic aluminum poisoning induced oxidative stress in the hippocampus of rats.?5?Detection of iron-related proteins showed that the m RNA expression of DMT1 in the MG and HG was significantly increased than that of the CG?p<0.01?,and the protein expression of DMT1 in all Al Cl₃-exposed groups was significantly increased than that of the CG?p<0.05,p<0.01?.The m RNA and protein expression of Tf R in the MG and HG were significantly decreased than those of the CG?p<0.01?.The m RNA expression of Fpn1 in all Al Cl₃-exposed groups was significantly decreased than that of the CG?p<0.01?,and the protein expression of Fpn1 in the MG and HG was significantly decreased than that of the CG?p<0.01?.The m RNA and protein expression of Ftl in all Al Cl₃-exposed groups were not significantly changed as compared to the CG?p>0.05?.The m RNA and protein expression of Fth in the MG and HG were significantly decreased than those of the CG?p<0.01?.The results indicated subchronic aluminum poisoning disrupted the expression of iron-related proteins in the hippocampus of rats.?6?Detection of iron regulatory factors showed that the m RNA and protein expression of IRP1in all Al Cl₃-exposed groups were not significantly changed as compared to the CG?p>0.05?,and the m RNA and protein expression of IRP2 in all Al Cl₃-exposed groups were significantly decreased than those of the CG?p<0.01?.The m RNA and protein expression of hepcidin in all Al Cl₃-exposed groups were significantly increased than those in the CG?p<0.05,p<0.01?.The results indicated subchronic aluminum poisoning induced abnormal expression of iron regulatory factors in the hippocampus of rats.In conclusion,Al Cl₃ caused the increase of iron content by changing the expression of iron regulatory factors and disrupting iron-related proteins,which in turn lead to oxidative stress and structural damage in the hippocampus,and cognitive dysfunction in rats.