Prenatal exposure to PM2.5 specific constituents and child neurodevelopmental delay: The role of maternal metabolites and mediterranean diet

Prenatal exposure to fine particulate matter (PM 2.5 ) constituents has been associated with impaired neurodevelopment, yet constituent-specific perturbations in maternal metabolism during pregnancy and their associations with child neurodevelopmental outcomes remain unclear. Among 6661 mother–child pairs in the Maternal and Infant Health Cohort in Hefei (MIH‑Hefei), we estimated associations between prenatal exposure to major PM 2.5 constituents and clinically diagnosed neurodevelopmental delay (NDD) using generalized linear regression and multi‑pollutant mixture models. Maternal metabolomic profiles were analyzed to identify pathways associated with each constituent and with NDD, and a meet‑in‑the‑middle (MITM) framework was used to detect overlapping pathways linking exposure and outcome. Effect modification by maternal Mediterranean diet (Med) adherence was tested via interaction terms. The results indicated that higher prenatal exposure to several PM 2.5 constituents was associated with increased NDD risk (ORs (95% CIs) for Q4 vs Q1 were: sulfate (SO₄²⁻), nitrate (NO₃⁻), ammonium (NH₄⁺), organic matter (OM), and black carbon (BC): 1.376 [1.026, 1.844], 1.650[1.204, 2.261], 1.431[1.064,1.923], 1.583 [1.166, 2.148], 1.772 [1.314, 2.389]), and mixture models showed consistent positive associations. Metabolomics and MITM have revealed potential links between the constituent-pathway-outcome axis. Among PM 2.5 constituents, OM and SO₄²⁻ showed the strongest associations with perturbations in four convergent pathways (including glycine, serine, and threonine metabolism and nutrient/energy metabolism pathways). Greater Med adherence modestly attenuated these adverse associations. Overall, specific PM 2.5 constituents may increase NDD risk partly through maternal metabolic dysregulation and Mediterranean‑style dietary patterns during pregnancy may offer limited mitigation.