Gestational homocysteine exposure induces preeclampsia-like phenotypes and alters fetal neurodevelopmental gene expression via impaired decidualization.

AIMS: Preeclampsia is a major cause of maternal and perinatal morbidity, yet the pathogenic role of clinical metabolic marker homocysteine (Hcy) remains poorly defined. This study aimed to verify whether gestational Hcy exposure triggers preeclampsia-like phenotypes, clarify underlying decidualization-related mechanisms, and investigate the rescue effect of folate supplementation.

MATERIALS AND METHODS: We treated pregnant mice with 100 mg/kg/day Hcy beginning at 0.5 dpc, and monitored preeclampsia-like phenotypes including hypertension and proteinuria while measuring placental and fetal indicators. We established pseudopregnancy models to assess decidualization capacity, quantified decidual marker levels via qPCR, and performed RNA-seq for placental transcriptome profiling. We also set a folate co-administration group to explore rescue effects.

KEY FINDINGS: Gestational Hcy induced typical preeclampsia-like phenotypes and markedly impaired decidualization in both pregnant and pseudopregnant mice, alongside downregulated Prl8a2, Wnt4, Dtprp, Hoxa10 and Bmp2. Hcy-suppressed genes were largely enriched in fetal neurodevelopment pathways including neuronal migration and axonogenesis. Folate supplementation effectively reversed maternal abnormal phenotypes and rescued defective placentation.

SIGNIFICANCE: Gestational Hcy disrupts decidualization to drive preeclampsia-like phenotypes and impairs fetal neurodevelopment. Folate relieves Hcy-mediated gestational damage, serving as a promising preventive intervention for hyperhomocysteinemia-related pregnancy complications. Our findings support routine prenatal Hcy screening and personalized folate supplementation for high-risk pregnant populations.