Metals and metalloids signatures in early pregnancy suggest cadmium and arsenic as major mixture components associated with gestational diabetes mellitus risk.

Pregnancy is a vulnerable window for environmental pollutant exposure, yet the contribution of metals and metalloids (metal(loid)s) to gestational diabetes mellitus (GDM) remains insufficiently characterized. This prospective cohort study evaluated whether early-pregnancy urinary metal(loid)s were associated with subsequent GDM and explored their predictive and mechanistic value. Among 1,201 pregnant women included in Guilin, China, nine urinary metal(loid)s were measured by inductively coupled plasma mass spectrometry. GDM was diagnosed by a 75-g oral glucose tolerance test at 24-28 gestational weeks. Restricted cubic spline and weighted quantile sum regression assessed dose-response and mixture effects. Machine learning models evaluated early prediction, and network toxicology explored molecular pathways. GDM occurred in 312 participants. Cadmium, arsenic, manganese, thallium, and lead showed nonlinear associations with GDM risk. Cadmium and arsenic dominated the overall mixture effect. Adding urinary metal(loid)s to conventional biochemical indicators modestly improved discrimination, with the XGBoost performing best. Network toxicology identified shared cadmium/arsenic targets enriched in oxidative stress, inflammation, apoptosis, endothelial dysfunction, and insulin-resistance pathways, including AGE-RAGE, HIF-1, TNF, and IL-17 signaling. These findings suggest that early-pregnancy metal(loid)s mixture exposure, particularly cadmium and arsenic, is associated with GDM risk, with arsenic the most consistent contributor across mixture methods and non-linear signals for lead and manganese warranting further investigation. Urinary metal(loid)s may serve as complementary biomarkers for early GDM risk stratification.