Exposome-wide analysis of hypertensive disorders of pregnancy and subtypes with subsequent focus on phenols

Hypertensive disorders of pregnancy (HDP) are major pregnancy complications, yet their environmental correlates and associated metabolic profiles remain incompletely characterized. In this prospective study of 1432 pregnant women from the Shanghai Birth Cohort, we integrated exposome-wide prioritization, mixture analyses, untargeted metabolomics, meet-in-the-middle (MITM), and exploratory mediation analyses to investigate prenatal exposures and metabolic profiles associated with HDP, gestational hypertension (GH), and preeclampsia (PE). Eighty-one exposures were ranked using ExWAS, elastic net, random forest, sparse partial least squares, and XGBoost. Among the measured exposure domains, phenols were prominently represented among the top 15 exposures, accounting for eight, seven, and six exposures for HDP, GH, and PE, respectively. Among 10 prioritized phenols, BP-1, BP-8, 4-HBP, and BPS showed generally consistent positive associations, with supportive evidence from weighted quantile sum regression and Bayesian kernel machine regression. In 1156 women with metabolomics data, metabolome-wide association analyses identified metabolic profiles associated with prioritized phenols and HDP outcomes. MITM and exploratory mediation analyses highlighted lipid-related candidate processes, particularly biosynthesis of unsaturated fatty acids and plasmalogen synthesis, which were consistently retained across the outcomes. These findings highlight prenatal phenols as an HDP-associated exposure family and lipid metabolism as a candidate biological link.