Trophoblast cell response to periodontal pathogens unveils oxidative stress networks between periodontitis and pre-eclampsia: Mendelian randomization, transcriptomic analysis, and cellular experimental validation.

BACKGROUND: Periodontitis has been associated with an increased risk of pre-eclampsia, but the underlying mechanisms and causal relationship remain unclear. Oxidative stress has been implicated in both conditions, suggesting a potential mechanistic link. OBJECTIVES: To investigate the causal relationship between periodontitis and pre-eclampsia and elucidate shared molecular pathways, with a focus on oxidative stress-related mechanisms. METHODS: We employed a multi-faceted approach combining Mendelian Randomization (MR) analysis, transcriptomic data mining, and in vitro experiments. MR analysis used genome-wide association study data to assess causality. Transcriptomic analysis of public data sets identified cross-talk genes and oxidative stress markers. In vitro experiments using HTR-8/SVneo trophoblast cells treated with Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) validated key findings. RESULTS: MR analysis revealed no significant causal relationship between periodontitis and pre-eclampsia. Transcriptomic analysis identified 31 cross-talk genes, including 10 periodontitis and pre-eclampsia (PD&PE) marker genes and 5 oxidative stress (OS) marker genes. In vitro experiments showed increased expression of OS marker genes (ARG1, FZD1, GCLC, NQO1, and TP53INP1) and elevated reactive oxygen species levels in Pg-LPS-treated trophoblast cells. Antioxidant enzymes (SOD1, CAT, Nrf2, and HO-1) and oxidase (NOX2) were also upregulated, indicating oxidative stress response. CONCLUSIONS: While no direct causal relationship was found, this study reveals shared molecular pathways between periodontitis and pre-eclampsia, particularly through oxidative stress mechanisms. These findings provide new insights into the periodontitis-pre-eclampsia relationship and identify potential targets for therapeutic interventions and biomarker development.