Joint effects of prenatal endocrine disrupting chemicals and heavy metal mixture on birth size and maternal complication in the Korea children's environmental health cohort study

Background: Prenatal exposure to mixtures of heavy metals and endocrine-disrupting chemicals (EDCs) may adversely affect birth outcomes, but their joint effects remain understudied. Methods: This study analyzed 4715 Korean mother-infant pairs from the Ko-CHENS cohort. Maternal whole blood was used to measure three heavy metals (lead, cadmium, mercury), while urine samples were collected to quantify 15 non-persistent EDCs, including phthalate metabolites, bisphenols, and parabens. Birth size was assessed using INTERGROWTH-21st z-scores. Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) were applied to evaluate mixture effects. Results: Individual chemical analyses revealed significant negative associations between birth weight and MEOHP (β = −0.146, p = 0.034), MCOP (β = −0.057, p = 0.023), MtP (β = −0.032, p = 0.021), and Cd (β = −0.141, p = 0.023). Birth length showed similar patterns with MEOHP and MCOP. Weight-for-length was negatively associated with BPS (β = −0.100, p = 0.008) and Pb (β = −0.253, p = 0.048). WQS analysis demonstrated significant negative mixture effects on birth length (β = −0.052, p = 0.040) and weight-for-length (β = −0.108, p = 0.017). BKMR revealed threshold-dependent relationships, with adverse effects becoming significant when exposure levels exceeded the 50th percentile. Heavy metals emerged as primary drivers of mixture effects, while subgroup analyses showed no significant effects from phthalate or phenol mixtures alone. Conclusions: Prenatal exposure to environmental chemical mixtures significantly reduces birth size through threshold-dependent mechanisms. Heavy metals are key contributors to adverse mixture effects, highlighting the need for cumulative risk assessment approaches in environmental health policy.