Pentachlorophenol exposure, plasma metabolomic markers, and gestational diabetes mellitus: Association and potential mediation analyses

Pentachlorophenol (PCP) is a pervasive endocrine-disrupting compound present in the environment. Limited research has explored the effects of PCP exposure on gestational diabetes mellitus (GDM), particularly the metabolites-related mechanism. Our study seeks to characterize the interrelationships between PCP exposure, plasma metabolomic markers, and GDM, aiming to elucidate the metabolomic profile mediating PCP-GDM relationship. From a prospective cohort in Changzhou, China, a nested case-control study was conducted, involving 154 GDM cases and 308 controls. We collected fasting blood samples before 16 weeks of gestation and determined PCP levels by UPLC-MS/MS. Plasma metabolomic markers were identified using untargeted metabolomics. Multivariate logistic regression and mediation analysis were used to examine the relationships among PCP exposure, metabolomic markers, and GDM. Using the Mann-Whitney U test, we found that serum PCP levels were significantly higher in GDM cases (median: 0.43 ng/mL, IQR: 0.28-0.77) compared to controls (median: 0.38 ng/mL, IQR: 0.24-0.64; P = 0.041). In the fully adjusted model, which additionally accounted for dietary patterns, the OR (95 %CI) values for GDM across tertiles of serum PCP were 1 (reference), 1.24 (0.73, 2.11), and 2.17 (1.28, 3.68), respectively, indicating a potential dose-response relationship (P trend = 0.004). Furthermore, 152 differential metabolites were identified between groups (FDR <0.05), implicating 4 metabolic pathways: "Nitrogen metabolism", "Alanine, aspartate and glutamate metabolism", "Glycerophospholipid metabolism", and "Pyrimidine metabolism" (FDR <0.1). Mediation analysis revealed that 5 metabolomic markers (such as N-Acetylalanine and 4-Acetamidobutyric acid) significantly mediated the association between PCP and GDM (FDR <0.05), with mediated proportions ranging from 0.15 to 0.31. Together, pregnant women in Eastern China exhibit widespread PCP exposure, with serum PCP levels positively associated with GDM risk. PCP exposure-related metabolomic changes may partially mediate the link between PCP and GDM.