Maternal PM2.5 exposure induces preeclampsia-like phenotypes in mice through placental angiogenic dysfunction and lncRNA–RUNX1 dysregulation

Abstract

Preeclampsia (PE) is an idiopathic gestational disorder defined by placental structural abnormalities, systemic inflammatory activation, angiogenic factor imbalance, and endothelial dysfunction. While existing epidemiological studies have established a correlational association between maternal fine particulate matter (PM_2.5) exposure and elevated PE risk, the specific underlying molecular mechanisms driving this association have not been fully elucidated. Using a C57BL/6J mouse model of maternal PM_2.5 exposure via intranasal instillation (3 mg/kg body weight, every other days from gestational day 0.5 to 17.5), we investigated the mechanisms underlying PE-like phenotypes induced by heating-season PM_2.5 from northern China. Exposed pregnant mice exhibited significantly elevated blood pressure at E13.5 and E17.5, accompanied by reduced vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) levels, increased urinary protein, and elevated serum levels of the tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and soluble fms-like tyrosine kinase-1 (sFLT-1). Conversely, the endothelial markers endothelin 1 (ET-1) and nitric oxide (NO) remained unchanged. Placentas from PM_2.5-exposed mice exhibited abnormal architecture and impaired angiogenesis in the labyrinth region. These phenotypes were consistent with key features of PE. Through transcriptomic profiling, bioinformatics analyses, immunofluorescence, quantitative reverse transcription PCR (RT-qPCR), and chromatin/RNA immunoprecipitation assays, we identified the long noncoding RNAs (lncRNAs) NONMMUT087808.1 and NONMMUT044449.2 as potential regulators of placental development and function that are associated with runt-related transcription factor 1 (RUNX1) dysregulation, suggesting a possible contribution to PE-like phenotypes. Taken together, our findings provide experimental evidence linking exposure to heating-season PM_2.5 from northern China with adverse gestational outcomes and highlight the critical need for targeted air pollution mitigation strategies and population-specific health interventions for vulnerable subgroups, including pregnant women.