Association of metal mixtures during the second trimester with gestational hypothyroidism and its mediation by metabolites.

Exposure to metals has been linked to an increased risk of gestational hypothyroidism (GHT), but the combined effects of metal mixtures and the role of serum metabolites in this relationship remain poorly understood. Therefore, this study aimed to examine the associations between metal exposure and GHT risk and to explore the mediating role of serum metabolites. In a case-control study with 30 pairs of GHT patients and controls matched by age, gestational age, parity, and obesity status, we measured serum metabolites and whole blood metal levels using UPLC-MS/MS and ICP-MS, respectively. Conditional logistic regression was employed to assess the individual effects of metals on GHT risk, while Bayesian kernel machine regression (BKMR) and quantile g-computation evaluated the combined effects of metal co-exposure. Mediation analyses were conducted to investigate the role of serum metabolites in these associations. Arsenic (As), chromium (Cr), nickel (Ni), and selenium (Se) were significantly associated with increased GHT risk (OR: Se = 1.62, Cr = 1.11, Ni = 1.14, As = 1.21). Joint exposure to As, Ni, and Se was positively associated with GHT risk. Mediation analyses revealed that free fatty acids (FFA, 18:5) mediated the associations of Ni and Se with GHT, explaining 31.33 % and 49.16 % of the associations, respectively. Our findings suggest that blood levels of As, Ni, and Se are associated with an increased risk of GHT, and that the Ni- and Se-GHT associations are mediated by FFA (18:5), providing insights into the mechanisms linking metal exposure, serum metabolites, and GHT risk.