Role of KDM5A regulating Notch signaling pathway in injury of off-spring mouse cerebral cortex caused by PM2.5 exposure during pregnancy
AIM:To investigate the role and mechanism of histone demethylase lysine-specific demethylase 5A(KDM5A)in regulating the Notch signaling pathway in particulate matter 2.5(PM2.5)-induced cortical damage in off-spring mice.METHODS:A pregnancy PM2.5 exposure model was established using intratracheal nebulization.Pregnant mice were randomly divided into PBS control group and PM2.5 exposure group.The cortices of offspring mice were isolated 14 d after birth.Golgi staining,electron microscopy and other methods were used to detect damage to neurons and chroma-tin in the cortex.Western blot,RT-qPCR and immunofluorescence staining were used to detect the mRNA and protein ex-pression of KDM5A in the cortex,and the distribution of KDM5A co-localized with neural cells.A PM2.5-treated PC12 cell injury model was established to detect changes in cell viability and the expression of proteins related to cell proliferation and apoptosis.Further,Western blot,RT-qPCR and immunofluorescence staining were used to detect the mRNA and pro-tein expression of KDM5A,the distribution of KDM5A co-localized with neurons,and changes in the protein level of his-tone H3K4me3.Bioinformatics methods were used to predict the interaction between KDM5A and Notch1,which was fur-ther validated by transfection experiments.In both in vivo and in vitro PM2.5 exposure models,changes in key molecules of the Notch signaling pathway and the co-expression of Notch1 with neural cells in the cortices of 14-day-old offspring mice and PC12 cells were detected.RESULTS:Prenatal PM2.5 exposure during pregnant led to a reduction in the number of neurons and decreased dentritic complexity in the cerebral cortex of offspring at 14 d after birth.It also caused abnormal chromatin condensation within neuronal nuclei,decreased mRNA and protein expression of KDM5A protein in the cortex,increased H3K4me3 protein levels(P＜0.05),and a significant reduction in KDM5A/NeuN double-positive cells.Expo-sure to PM2.5 also resulted in decreased viability and proliferation,and increased apoptosis of PC12 cells,with reduced ex-pression of KDM5A mRNA and protein,increased H3K4me3 protein expression(P＜0.05),and a reduction in the num-ber of KDM5A/MAP-2 double-positive cells.Bioinformatics analysis and transfection experiments in PC12 cells revealed that Notch1 is a downstream target gene of KDM5A.Further in vivo and in vitro experiments found that PM2.5 exposure lead to decreased mRNA and protein expression of key Notch signaling molecules Notch1,Jagged1 and Hes1,and reduced numbers of Notch1/NeuN and Notch1/MAP-2 double-positive cells.CONCLUSION:Exposure to PM2.5 can lead to abnor-mal expression of KDM5A in the offspring's cerebral cortex,which may cause neuronal damage by down-regulating the Notch signaling pathway,a downstream target.This could be one of the significant factors contributing to the neurodevelop-mental disorders in offspring exposed to PM2.5 during pregnancy.
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