Association of co-exposure to EDCs in early pregnancy with threatened abortion: The mediation effect of progesterone

Endocrine-disrupting chemicals (EDCs) are ubiquitous environmental pollutants linked to adverse pregnancy outcomes, but their combined effects on threatened abortion (TA) remain unclear. Progesterone (P4) plays a critical role in maintaining pregnancy, yet its potential modifying effect on EDC-associated TA is underexplored. This study aimed to investigate the association between patterns of EDC co-exposure and TA, and to evaluate the potential mediating effect of P4. A prospective cohort study was conducted among 1,122 pregnant women in China. Urine concentrations of 24 EDCs (including bisphenols, parabens, per- and polyfluoroalkyl substances, and organophosphate flame retardants) were measured, and serum P4 levels were obtained from clinical records. Generalized linear regression model (GLM), LASSO, Bayesian kernel machine regression (BKMR), and quantile g-computation (QGC) were used to assess individual and mixture effects. Mediation analysis was performed to examined the role of P4 in EDC-TA associations. BPB (OR = 1.18, 95 % CI: 1.03, 1.37), BPP (OR = 1.15, 95 % CI: 1.01, 1.30), and BuP (OR = 1.09, 95 % CI: 1.01, 1.17) were positively associated with TA, while DPHP showed a negative association (OR = 0.91, 95 % CI: 0.83, 0.99). Reduced P4 levels significantly increased TA risk (OR = 0.92, 95 % CI: 0.91, 0.94). Mediation analysis revealed that decreased P4 level mediated BPB's harmful effect on TA. Age-stratified analyses showed stronger effedcts of BPP in women ≤ 29 years and BPB effects in those ≥ 30 years. BKMR indicated dose-dependent TA risk elevation at higher mixture exposures (≥ 35th percentile). In conclusion, early-pregnancy co-exposure to specific EDCs increases TA risk, with decreased P4 level mediated BPB's harmful effect on TA. Age modifies susceptibility, highlighting the need for targeted interventions in high-risk subgroups.