Association of combined exposure to air pollutants during ovarian stimulation, follicular fluid metabolites, and IVF/ICSI outcomes: A prospective cohort study.

The impact of ambient air pollution on female fertility, particularly under real-world multipollutant exposure scenarios and regarding embryo quality, remains poorly understood. The underlying biological mechanisms have yet to be fully elucidated. Follicular fluid (FF) metabolites, reflecting the oocyte microenvironment, may provide mechanistic insights into air pollution toxicity. In this prospective cohort study, 688 women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) were enrolled. Individual-level exposures to six air pollutants [particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5); particulate matter with aerodynamic diameter ≤ 10 μm (PM10); ozone (O3); nitrogen dioxide (NO2); sulfur dioxide (SO2); carbon monoxide (CO)] were averaged over each participant's controlled ovarian stimulation (COS) window. Composite air pollution scores (CAPS) were constructed for IVF/ICSI outcomes. Untargeted FF metabolomics was performed using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry. Associations between pollutant exposure, CAPS, and IVF/ICSI outcomes were assessed using generalized linear models, and mediation analysis was conducted to identify FF metabolites involved. Elevated levels of O3 and PM2.5 were associated with lower proportions of fertilization and best-quality embryo. PM2.5 was also inversely associated with clinical pregnancy and live birth proportions. CAPS demonstrated consistent negative associations, especially in nulliparity, IVF treatment, and gonadotropin-releasing hormone antagonist protocol participants, with variations across age and body mass index. Mediation analysis identified four FF metabolites-pregnenolone, 7-dehydrodesmosterol, oleic acid, and deoxyuridine monophosphate-as partial mediators. These metabolites participate in steroid biosynthesis, oxidative balance, and DNA damage pathways, providing novel mechanistic insights into the reproductive toxicity of ambient air pollution.