南方医科大学学报2024，Vol.44Issue(3)：437-446,10.DOI:10.12122/j.issn.1673-4254.2024.03.04
二甲双胍通过抑制铁死亡改善PM2.5导致的胎盘滋养细胞功能损伤
Metformin ameliorates PM2.5-induced functional impairment of placental trophoblasts by inhibiting ferroptosis
摘要
Abstract
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.关键词
PM2.5/滋养细胞/铁死亡/二甲双胍Key words
PM2.5/trophoblasts/ferroptosis/metformin引用本文复制引用
李淑贤,于淑平,穆亚铭,王凯,刘玉,张美华..二甲双胍通过抑制铁死亡改善PM2.5导致的胎盘滋养细胞功能损伤[J].南方医科大学学报,2024,44(3):437-446,10.基金项目
国家自然科学基金青年项目(82301903) （82301903）
山东省妇幼保健院高层次人才"孵育"计划科研项目(2022RS07) （2022RS07）
山东省妇幼保健院专项资金科研课题(YJKY2022-024)Supported by Natural Science Foundation for the Youth(NSFY)of China(82301903). （YJKY2022-024）
