{"title":"[二甲双胍通过抑制铁蜕变改善PM2.5诱导的胎盘滋养细胞功能损伤]。","authors":"S Li, S Yu, Y Mu, K Wang, Y Liu, M Zhang","doi":"10.12122/j.issn.1673-4254.2024.03.04","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism.</p><p><strong>Methods: </strong>Sixteen pregnant Kunming mice were randomly assigned into two groups (<i>n</i>=8) for intratracheal instillation of PBS or PM2.5 suspension at 1.5, 7.5, and 12.5 days of gestation. The pregnancy outcome of the mice was observed, and placental zonal structure and vascular density of the labyrinth area were examined with HE staining, followed by detection of ferroptosis-related indexes in the placenta. In cultured human trophoblasts (HTR8/SVneo cells), the effects of PM2.5 exposure and treatment with metformin on cell viability, proliferation, migration, invasion, and tube formation ability were evaluated using CCK8 assay, EDU staining, wound healing assay, Transwell experiment, and tube formation experiment; the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting.</p><p><strong>Results: </strong>M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight (all <i>P</i><0.001). PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis. In cultured HTR8/SVneo cells, PM2.5 significantly inhibited proliferation, migration, invasion, and angiogenesis of the cells by causing ferroptosis. Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation, migration, invasion, and angiogenesis of the cells, and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity, reduced MDA and Fe<sup>2+</sup> levels, and upregulated GPX4 and SLC7A11 protein expression (<i>P</i><0.05 or 0.01).</p><p><strong>Conclusion: </strong>PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice, and metformin can effectively alleviate PM2.5-induced trophoblast impairment.</p>","PeriodicalId":18962,"journal":{"name":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006689/pdf/","citationCount":"0","resultStr":"{\"title\":\"[Metformin ameliorates PM2.5-induced functional impairment of placental trophoblasts by inhibiting ferroptosis].\",\"authors\":\"S Li, S Yu, Y Mu, K Wang, Y Liu, M Zhang\",\"doi\":\"10.12122/j.issn.1673-4254.2024.03.04\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism.</p><p><strong>Methods: </strong>Sixteen pregnant Kunming mice were randomly assigned into two groups (<i>n</i>=8) for intratracheal instillation of PBS or PM2.5 suspension at 1.5, 7.5, and 12.5 days of gestation. The pregnancy outcome of the mice was observed, and placental zonal structure and vascular density of the labyrinth area were examined with HE staining, followed by detection of ferroptosis-related indexes in the placenta. In cultured human trophoblasts (HTR8/SVneo cells), the effects of PM2.5 exposure and treatment with metformin on cell viability, proliferation, migration, invasion, and tube formation ability were evaluated using CCK8 assay, EDU staining, wound healing assay, Transwell experiment, and tube formation experiment; the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting.</p><p><strong>Results: </strong>M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight (all <i>P</i><0.001). PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis. In cultured HTR8/SVneo cells, PM2.5 significantly inhibited proliferation, migration, invasion, and angiogenesis of the cells by causing ferroptosis. Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation, migration, invasion, and angiogenesis of the cells, and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity, reduced MDA and Fe<sup>2+</sup> levels, and upregulated GPX4 and SLC7A11 protein expression (<i>P</i><0.05 or 0.01).</p><p><strong>Conclusion: </strong>PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice, and metformin can effectively alleviate PM2.5-induced trophoblast impairment.</p>\",\"PeriodicalId\":18962,\"journal\":{\"name\":\"Nan fang yi ke da xue xue bao = Journal of Southern Medical University\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-03-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006689/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nan fang yi ke da xue xue bao = Journal of Southern Medical University\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.12122/j.issn.1673-4254.2024.03.04\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.12122/j.issn.1673-4254.2024.03.04","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
摘要
目的研究二甲双胍对PM2.5诱导的胎盘滋养细胞功能损伤的保护作用,并探讨其潜在机制:16只妊娠昆明小鼠随机分为两组(n=8),分别在妊娠1.5、7.5和12.5天气管内灌注PBS或PM2.5悬浮液。观察小鼠的妊娠结局,用 HE 染色法检查胎盘带状结构和迷宫区的血管密度,然后检测胎盘中与铁败坏相关的指标。在培养的人滋养细胞(HTR8/SVneo细胞)中,使用CCK8检测法、EDU染色法、伤口愈合检测法、Transwell实验和管形成实验评估了PM2.5暴露和二甲双胍处理对细胞活力、增殖、迁移、侵袭和管形成能力的影响;使用ELISA和Western印迹法分析了铁变态反应相关蛋白的细胞表达:结果:妊娠期小鼠暴露于M2.5会导致胎儿体重和胎儿数量显著下降,胎儿死亡率增加,胎盘重量减少(所有P2+水平),GPX4和SLC7A11蛋白表达上调(PConclusion:妊娠期暴露于PM2.5会导致不良妊娠结局以及小鼠胎盘滋养细胞的铁变态反应和功能损伤,而二甲双胍能有效缓解PM2.5诱导的滋养细胞损伤。
[Metformin ameliorates PM2.5-induced functional impairment of placental trophoblasts by inhibiting ferroptosis].
Objective: To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism.
Methods: Sixteen pregnant Kunming mice were randomly assigned into two groups (n=8) for intratracheal instillation of PBS or PM2.5 suspension at 1.5, 7.5, and 12.5 days of gestation. The pregnancy outcome of the mice was observed, and placental zonal structure and vascular density of the labyrinth area were examined with HE staining, followed by detection of ferroptosis-related indexes in the placenta. In cultured human trophoblasts (HTR8/SVneo cells), the effects of PM2.5 exposure and treatment with metformin on cell viability, proliferation, migration, invasion, and tube formation ability were evaluated using CCK8 assay, EDU staining, wound healing assay, Transwell experiment, and tube formation experiment; the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting.
Results: M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight (all P<0.001). PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis. In cultured HTR8/SVneo cells, PM2.5 significantly inhibited proliferation, migration, invasion, and angiogenesis of the cells by causing ferroptosis. Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation, migration, invasion, and angiogenesis of the cells, and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity, reduced MDA and Fe2+ levels, and upregulated GPX4 and SLC7A11 protein expression (P<0.05 or 0.01).
Conclusion: PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice, and metformin can effectively alleviate PM2.5-induced trophoblast impairment.