The Molecular Mechanism Underlying The Learning And Memory Deficits In 2,2',4,4'-Tetrabromodiphenyl Ether-Treated Mice

The family of polybrominated diphenyl ethers(PBDEs)has been used as flame retardants in various materials,such as electric appliances,textiles,furnishings,and building materials and it has now been listed as a persistent organic pollution by the Stockholm Convention.PBDEs are quite resistant to physical,chemical,and biologic degradation.Moreover,PBDEs in environmental media can bioaccumulate in the food chain and expose to human beings.Indeed,PBDEs have been detected in human blood,adipose tissue,and breast milk,as well as in the postmortem brain.Because of their long half-lives and bioaccumulation in the environment and human tissue,concerns have been raised about the potential toxicity of PBDEs.2,2?,4,4?-tetrabromodiphenyl ether(BDE-47),one of the most predominant congeners(accounts for 50%),is the predominant congener in all samples,and it is more toxic to human beings than higher brominated congeners.The neurotoxicity and the potential neurotoxic mechanism of BDE-47 has been the focus of attention.However,the exact mechanisms of PBDEs' neurotoxicity still remain elusive.Therefore,adult mouse model of learning and memory deficits induced by BDE-47 was established in this study.Step-through passive avoidance task and Morris water maze(MWM)tests were performed to evaluate the abilities of learning and memory.Using western blotting,frozen sections,immunofluorescence stain,nuclear and cytoplasmic fractionation,brain stereotaxic injection,and lentivirus shRNA knockdown methods and techniques,the potential molecular mechanism underlying the learning and memory deficits induced by BDE-47 was explored.The main achievements of this study are as follows:(1)First,the adult mouse model with learning and memory deficits induced by BDE-47 was established in this study.The short-term memory and spatial leaning and memory abilities of the BDE-47-treated mice were evaluated using the step-through passive avoidance task and MWM test respectively.BDE-47(20 or 40 mg/kg body weight,once a day for 8 weeks)resulted in substantially short-term memory reduction and spatial learning and memory impairments.Although there was no significant difference in body weight,these BDE-47-treated mice had reduced mean brain weight when compared with the control group.(2)This study investigated the role of hippocampal TAR-DNA binding protein-43(TDP-43)protein in BDE-47-induced learning and memory deficits and the underlying molecular mechanism via hippocampus-specific TDP-43 knockdown.We found that the elevation of nuclear TDP-43 induced by BDE-47 caused hippocampal apoptosis and neuron loss,which ultimately led to learning and memory deficits in mice.(3)This study further confirmed the involvement of NLRP3 inflammasome in TDP-43 upregulation in BDE-47-treated mice via hippocampus-special NLRP3 knockdown.Our results clearly demonstrated that NLRP3 inflammasome activation was associated with Parkin deficiency,nuclear TDP-43 upregulation and hippocampal apoptosis,which resulted in impaired learning and learning in BDE-47-treated mice.(4)The molecular mechanism underlying nuclear TDP-43 upregulation mediated by NLRP3 inflammasome was further demonstrated via inhibition of caspase-1 catalytic activity.The selective caspase-1 inhibitor VX765 restored Parkin protein levels,which attenuated nuclear TDP-43 upregulation and cell stress in the hippocampus of BDE-47-treated mice due to Parkin role in nuclear TDP-43 translocation.This study will provide novel mechanistic insights into the neurotoxicity of BDE-47,present further information on environmental risk of PBDEs,and suggest a potential strategy for the prevention or treatment of BDE-47-induced neurotoxicity and brain diseases.