Prenatal exposure to metal mixtures and newborn birth size in an industrial city: Evidence from cord blood metabolomics.
BACKGROUND Prenatal exposure to metal mixtures may influence newborn birth size, but the underlying metabolic mechanisms remain unclear. This study aimed to evaluate the associations of 19 individual maternal metals and metal mixtures during pregnancy with birth size indicators, specifically birth weight z score (BWZ) and birth length z score (BLZ), and to identify potential metabolic pathways and mediating metabolites based on cord blood metabolomics. METHODS A total of 1059 mother-infant pairs were included in the full cohort. We applied ExWAS, ENET/DSA, WQS, qgcomp, and BKMR to assess both single-metal and joint exposure effects. Exploratory MWAS, pathway enrichment, and mediation analyses were conducted using cord blood metabolomics data. RESULTS In single-metal analyses, Zn, Se, and Mn showed positive associations with BWZ and BLZ, whereas Cu was positively associated with BWZ only; As, Pb, and Cd generally showed inverse associations. In mixture analyses, the negative-direction WQS index was associated with lower BLZ (β = -0.039, P = 0.042). Exploratory metabolomics analyses highlighted lipid-related metabolites, organic acid derivatives, and nucleotide-related metabolites, with enrichment in caffeine metabolism and steroid hormone biosynthesis pathways. Mediation analyses suggested potential indirect effect signals, including As-BWZ via 10-hydroxystearic acid (19.6%), Cu-BWZ via 2-ethyl-2-hydroxybutyric acid (30.8%), and Se-BLZ via 2-ethyl-2-hydroxybutyric acid (21.1%). CONCLUSION In this industrial city cohort, our findings provide evidence linking prenatal metal exposure to newborn birth size and suggest that cord blood metabolic profiles may offer exploratory mechanistic clues for understanding metal-related fetal growth patterns.