Prenatal Polychlorinated Biphenyl Mixture Exposure and Neural Tube Defects: Integrated Epidemiological and Experimental Evidence Implicating Pyroptosis

Polychlorinated biphenyls (PCBs) are persistent organic pollutants with reproductive and developmental toxicity, though it remains unclear whether prenatal PCB mixture exposure can lead to neural tube defects (NTDs). We evaluate the effects of real-world PCB mixtures on NTD risk and potential mechanisms by integrating epidemiology, in vivo toxicology, and multiomics. In our case-control study (n = 482), prenatal PCB exposure was estimated from placental concentrations of 13 congeners. Multivariable logistic regression showed that higher levels of PCB-52, PCB-118, and total ΣPCBs were associated with increased NTD risk. Three mixture models associated higher placental PCB mixture levels with elevated NTD risk and identified PCB-52 and PCB-118 as major contributors. Moreover, pregnant mice were dosed with a human-relevant PCB mixture during neurulation, inducing fetal NTDs dose-dependently. Multiomics indicated activation of pyroptosis; targeted assays supported activation of the NLRP3-caspase-1-GSDMD axis with increased IL-18, along with pyroptotic ultrastructural alterations. Overall, we found prenatal PCB mixture exposure was associated with higher NTD risk, and pyroptosis may represent a teratogenic mechanism. Indoor air pollution may be a prenatal exposure source; folic acid supplementation may attenuate PCB-associated NTD risk. This study provides a generalizable framework for real-world mixture risk assessment in birth defect research.