Maternal metabolomics linking prenatal exposure to fine particulate matter and birth weight: a cross-sectional analysis of the MADRES cohort.

Background: Prenatal exposure to air pollution has been associated with an increased risk of low birth weight. Disrupted metabolism may serve as an underlying mechanism, but the specific metabolic pathways involved remain unclear.

Methods: In the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, 382 third-trimester maternal serum samples were analyzed for untargeted metabolomics using liquid chromatography with Fourier transform high-resolution mass spectrometry. Ambient concentrations of fine particulate matter (PM_2.5), particulate matter ≤ 10 μm in diameter (PM₁₀), nitrogen dioxide (NO₂), and ozone (O₃) were estimated using inverse-distance-squared weighted spatial interpolation based on daily residential histories. Birth weight was retrieved from medical records. Linear regression identified metabolomic features associated with air pollution exposure or birth weight, followed by Mummichog pathway enrichment and mediation analyses for the selected features.

Results: Second-trimester PM_2.5 exposure was associated with lower birth weight. Fourteen metabolic pathways were significantly associated with second-trimester PM_2.5 exposure, with C21-steroid hormone biosynthesis and metabolism showing the most significant association. Sixteen metabolic pathways were significantly associated with birth weight, with vitamin A (retinol) metabolism being the most significantly enriched pathway. Seven pathways were associated with both PM_2.5 exposure and birth weight, including C21-steroid hormone biosynthesis and metabolism, bile acid biosynthesis, tyrosine metabolism, ascorbate (vitamin C) and aldarate metabolism, vitamin D3 (cholecalciferol) metabolism, vitamin A (retinol) metabolism, and pyrimidine metabolism. Overweight or obese women exhibited more metabolomic features and metabolic pathways associated with PM_2.5 exposure compared to underweight or normal-weight women. No associations were observed between PM₁₀, NO₂, or O₃ and birth weight.

Conclusions: Maternal metabolic pathways involving steroid metabolism, oxidative stress and inflammation, vitamin metabolism, and DNA damage may link prenatal PM_2.5 exposure to lower birth weight, with overweight or obese women potentially more susceptible to these metabolic disruptions.