高齢出産による切迫流産の進行した段階におけるステロイドホルモン生合成の主要経路の解明

Advanced maternal age (AMA, ≥35 years) is increasingly common and is accompanied by rising threatened abortion (AMA-TA) rates, yet its molecular basis remains unclear.

To elucidate AMA-TA mechanisms by integrating metabolomics and transcriptomics, providing a foundation for biomarker and therapeutic discovery.

Untargeted serum metabolomics was performed in 9 AMA-TA patients and 7 age-matched healthy pregnant women. An AMA-TA mouse model was induced by mifepristone (4 mg/kg) to assess embryo resorption, placental morphology, and serum hormones (ELISA). Serum metabolomics and placental transcriptomic profiling (RNA-seq) were then conducted in AMA-TA mice to characterize metabolic and gene expression alterations. Cross-species and multi-omics integration was performed using HomoloGene and MetaboAnalyst 5.0. Key steroid biosynthesis-related genes were finally validated by RT-qPCR.

Human serum metabolomics revealed the differential metabolites were mainly enriched in steroid hormone biosynthesis, lipid metabolism, and amino-acid metabolism. The AMA-TA model showed higher embryo resorption, abnormal placental architecture, and reduced progesterone and chorionic gonadotropin. RNA-seq revealed 111 up- and 1337 downregulated genes enriched in 68 pathways. Consistently, serum metabolomics in AMA-TA mice also showed significant metabolic disturbances, prominently involving steroid hormone biosynthesis. Integrated analysis converged on steroid hormone biosynthesis as a shared key dysregulated pathway. RT-qPCR further confirmed aberrant expression of steroid metabolism-related genes, including upregulation of Akr1d1 and Ugt family genes.

Disruption of steroid hormone biosynthesis represents central molecular feature to AMA-TA. Integrated multi-omics analysis offers mechanistic insight and supports the development of biomarkers and therapeutic targets for AMA-TA.