Prenatal Metal Exposome Reprograms Neonatal Metabolism: Trimester-Dependent Effects on Amino Acid and Carnitine Networks

Pregnant women and newborns are highly vulnerable to metal exposure. However, there is limited evidence regarding how prenatal metal exposome influences newborn metabolic programming. This prospective cohort in 2022–2023 analyzed 432 mother–neonate pairs with complete biospecimens and birth records. We measured maternal urinary concentrations of 18 metals across first and third trimesters as well as neonatal metabolic biomarkers including 12 amino acids, 26 carnitines, thyroid-stimulating hormone (TSH), 17-hydroxyprogesterone (OHP), and glucose-6-phosphate dehydrogenase (G6PD). Multivariable regression, quantile g-computation, and machine learning methods were integrated to evaluate both individual and joint metal effects, with metabolic network and pathway enrichment analyses. Nine neonatal metabolites (tyrosine, glycine, leucine, free carnitine, C3, C5, C5:1, G6PD, and OHP) showed consistent trimester-specific associations with the metal mixtures. Arginine biosynthesis was the primary metal-responsive pathway. First-trimester exposure to zinc, selenium, tin, and chromium inversely correlated with gestational age at birth (β = −0.22 to −0.07; P < 0.05), while zinc and selenium inversely linked to birth weight (β = −83.48 to −51.67; P < 0.05). Mediation analysis revealed G6PD mediated 17.2% (95% CI, 0.11%; 168.00%) of Zn-gestational age association. The present study characterizes distinct metabolic disturbances in newborns associated with trimester-specific metal exposure, establishing novel mechanistic links between metal exposome and adverse birth outcomes.