环境与职业医学2026，Vol.43Issue(3)：270-277,8.DOI:10.11836/JEOM25370
KDM5A/cGAS-STING介导的小胶质细胞激活参与孕期细颗粒物暴露致子代小鼠大脑皮层损伤
KDM5A/cGAS-STING-mediated microglial activation contributes to prenatal fine particulate matter induced cerebral cortical injury in offspring mice
摘要
Abstract
[Background]Prenatal exposure to fine particulate matter(PM2.5)is closely associated with cortical damage and neuroinflammation in offspring.The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)sig-naling pathway is a key regulator of inflammation and may be subject to epigenetic regulation. [Objective]To investigate the role of cGAS-STING pathway activation in PM2.5-induced cortical damage in offspring mice during pregnancy and the underlying epigenetic regulatory mechanisms. [Methods]Open field tests were used to assess depressive-like behavior in offspring mice.Morphological analysis was conducted to evaluate cortical damage and microglial activation in offspring brains.Real-time fluorescent quantitative PCR(RT-qPCR)and Western blot(WB)were performed to detect changes in the expression of key molecules in the cGAS-STING pathway in cortical tissue.A PM2.5-induced microglial cell injury model was established in BV2 cells.Microglial activation was observed,cell viability was measured using the Cell Counting Kit-8(CCK-8),and the expression levels of inducible nitric oxide synthase(iNOS)and key molecules in the cGAS-STING pathway were detected by RT-qPCR and WB.Bioinformatics analysis was performed to explore the epigenetic regulatory association between the STING signaling pathway and lysine-specific demethylase 5A(KDM5A).Changes in KDM5A mRNA and protein expression,as well as the protein level of histone H3 lysine 4 trimethylation(H3K4me3),were detected in an in vitro PM2.5 injury model.Using small interfering RNA(siRNA)technology,the KDM5A gene was silenced in BV2 cells exposed to PM2.5.The protein expression of H3K4me3 was detected to evaluate improvements in microglial activation,changes in inflammatory markers such as iNOS and mannose receptor(CD206),and al-terations in the cGAS-STING pathway. [Results]Compared with the control group,the total distance of offspring mice in the PM2.5 group was significantly reduced,and both the distance traveled and the time spent in the central area of the open field were significantly decreased(P<0.01,P<0.001),indicating depressive-like behavior in the offspring mice.Compared with the control group,the offspring mice in the PM2.5 group exhibited disorga-nized cortical structure and significantly activated microglia(P<0.01),with significantly increased mRNA and protein levels of cGAS and STING(P<0.05,P<0.01,or P<0.001).The in vitro experiments demonstrated that the PM2.5 treatment induced BV2 cells to polarize toward the M1 phenotype,exhibiting a distinct amoeboid morphology,with upregulated expression of the pro-inflammatory factor iNOS(P<0.05,P<0.01,or P<0.001)and activation of the cGAS-STING pathway(P<0.05,P<0.01).The analysis of RNA-seq data from KDM5A knockout cells revealed significantly downregulated STING expression,suggesting that KDM5A may activate the STING signaling pathway.The in vitro experiments further confirmed that the PM2.5-treated BV2 cells exhibited significantly elevated mRNA and protein levels of KDM5A(P<0.01),while the H3K4me3 protein levels were markedly reduced(P<0.05).After silencing KDM5A in BV2 cells exposed to PM2.5,compared with the PM2.5+siNC group,the PM2.5+siKDM5A group showed no obvious microglial activation and polarized toward the M2 phenotype,with significantly decreased expression levels of iNOS,cluster of differentiation 16(CD16),and interleukin-1β(P<0.05,P<0.01),and significantly increased expression levels of anti-inflammatory factors CD206,YM1,and interleukin-10(P<0.01,P<0.001).Meanwhile,the expression levels of cGAS and STING were also reduced(P<0.05,P<0.01). [Conclusion]KDM5A activates microglia through the cGAS-STING pathway,thereby contributing to PM2.5-induced cortical damage in off-spring mice during pregnancy.关键词
细颗粒物/环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子/小胶质细胞/组蛋白赖氨酸去甲基化酶5A/大脑皮层Key words
fine particulate matter/cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes/microglia/lysine-specific demethylase 5A/cerebral cortex分类
医药卫生引用本文复制引用
聂文珂,周梨,王思齐,宋超,于航,李万伟,栾孟孝,孙露,于丽..KDM5A/cGAS-STING介导的小胶质细胞激活参与孕期细颗粒物暴露致子代小鼠大脑皮层损伤[J].环境与职业医学,2026,43(3):270-277,8.基金项目
山东省自然科学基金面上项目(ZR2021MH031) （ZR2021MH031）
山东省自然科学基金联合基金专项项目(ZR2024LSW019) （ZR2024LSW019）
山东第二医科大学科研创新计划项目(2024BKQ023) （2024BKQ023）
