Effects Of Low-Concentration 1,2-Dichloroethane Subchronic Exposure On Glutamate Metabolism In Hippocampus Of Mice And Its Mechanism

Purpose:1,2-dichloroethane(1,2-DCE)is a halogenated hydrocarbon compound,which is one of the organic solvents commonly used in industry.1,2-DCE is a highly toxic Neurotoxicity,brain tissue is the target organ that mainly accumulates and damages 1,2-DCE.At present,there are few research data on brain tissue damage caused by long-term exposure to low-concentration 1,2-DCE,and further research is urgently needed.Glutamate(Glu)is the most abundant excitatory amino acid neurotransmitter in the central nervous system(CNS)of mammals.It is involved in many important physiological functions in the brain and is related to the corresponding glutamate receptors.(Glutamate receptor(GluR))binds to participate in the induction and maintenance of long-term potentiation(LTP)and other advanced brain neuronal activities.N-methyl-D-aspartate receptor(N-methyl-D-Aspartate receptor(NMDAR),as a very important ionic GluR in CNS,has high permeability to Ca2+ and plays a key role in the induction and maintenance of LTP.The "glutamate-glutamine" cycle is one of the important pathways for the coupling of neuroglia and neurons in the CNS.It maintains the normal metabolism of the neurotransmitter Glu in the CNS,clears the Glu in the synaptic space,and prevents Glu plays a key role in the excitotoxicity of neurons.Astrocyte(AS)is a key site of Glu metabolism in the synaptic cleft and can play an important role in glutamate neurotransmitter transmission.Then,if the 1,2-DCE accumulated in the AS causes any damage to the transporters and metabolic enzymes related to Glu metabolism in the AS,it will seriously interfere with the transmission of glutamate synapses and affect the body Learning and memory function.In this study,female Kunming mice were used as research objects.The effects of prolonged exposure to low concentration of 1,2-DCE on Glu metabolism in the hippocampus of mice were explored.The intellectual damage caused provides experimental reference data.Methods:In this study,healthy and clean female Kunming mice were adaptively fed and randomly divided into a control group and a 1,2-DCE exposure group at 0.225,0.45,and 0.9 g/m3.Static inhalation was used for 3.5 hours per day for 8 weeks.First perform Morris water maze and shuttle box test,then anesthetize the mice,extract hippocampal tissue,and detect glutamine synthetase(GS)and phosphate-activated glutaminase(PAG)in the hippocampus of mice.Activity,distribution,and expression levels.GS,PAG,glutamate/Aspartate transporter(GLAST),glutamate transporter-1(GLT-1)Transcription and protein expression levels of NMDAR subunits GluN1,GluN2A,and GluN2B.Pathological changes were observed in the hippocampal tissue,and calcium specific fluorescence probes were used to determine calcium(calcium,Ca2+)in hippocampal nerve cells of mice content.Results:In the Morris water maze positioning cruise experiment,as the number of training days increased,the escape latency of each group of mice to find a platform continued to shorten,but in the same number of training days,mice in the 1,2-DCE-exposed group The escape latency was longer than in the control group.In the space exploration experiment,the target quadrant dwell time and shuttle target times of the mice also decreased significantly with the increase of the dose measurement;in the shuttle box test,with the increase of the dose,the number of active escapes of the mice in the exposure group Significantly reduced,and the latency of active escape was significantly prolonged.Especially in the high-dose exposure group,both indicators had significant changes;compared with the control group,the mRNA and protein expression levels of GLAST,GLT-1,GS,and PAG in the hippocampus of the exposure group were different.The enzyme activity of GS and PAG also decreased significantly with the increase of the dose;the mRNA and protein expression levels of glutamate receptors GluN1,GluN2A and GluN2B increased with the increase of the dose;The intracellular Ca2+ concentration in the poisoned group was also significantly higher than that in the control group;compared with the control group,the hippocampal pyramidal cells of the exposed group were significantly damaged by HE staining.Conclusions:1.Subchronic exposure to 1,2-DCE at a lower concentration can impair the learning and memory abilities of mice.2.The damage of 1,2-DCE to the learning and memory function of mice may be related to the interference of Glu-Gln circulation in the hippocampus of mice and the neuroexcitation toxicity caused by the accumulation of Glu in synaptic cleft.