Prenatal urinary phenanthrene metabolites associated with fetal growth restriction: a nested case-control study with integrated computational toxicology.
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants that can cross the placental barrier, yet evidence linking internal exposure to specific PAH metabolites with fetal growth restriction (FGR) remains scarce and mechanistically unclear. In a nested case-control study within a prospective birth cohort in Guangzhou, China (100 FGR cases and 194 matched controls), we quantified maternal urinary hydroxylated and aminated PAH metabolites in first-trimester samples by HPLC-MS/MS. Conditional logistic regression with machine learning was used to identify PAH metabolites associated with FGR risk and prioritize those most strongly implicated. Network toxicology analyses, combined with molecular docking and in vitro validation in trophoblast cells, were employed to explore the underlying mechanisms. Elevated 1 + 9-hydroxyphenanthrene and 9-aminophenanthrene were significantly associated with increased FGR risk and consistently identified as the strongest contributors. Network toxicology identified 172 overlapping genes between these phenanthrene metabolites and FGR, converging on six core proteins (EGFR, STAT3, NFKB1, PPARG, ESR1, and PTGS2) linked to oxidative stress, inflammation, and cellular homeostasis-processes critically involved in placental development and fetal growth. Molecular docking predicted strong binding affinities (≤ -5.8 kcal/mol) between the phenanthrene metabolites and the identified core targets, providing structural evidence for potential direct interactions. In vitro experiments showed that hydroxylated phenanthrene metabolites downregulated EGFR, whereas 9‑aminophenanthrene upregulated PTGS2, suggesting transcriptional engagement of these targets. These findings identify first‑trimester urinary 1 + 9‑hydroxyphenanthrene and 9‑aminophenanthrene as exposure biomarkers associated with FGR risk and delineate their plausible mechanistic pathways, highlighting the need for component‑specific risk assessment of prenatal PAH exposure.