A nested case-control study of air pollution and congenital heart defects via circulating proteins

Prenatal air pollution exposure is linked to congenital heart defects (CHD), while the underlying molecular mechanisms remain poorly understood. Here we showed that maternal exposure to PM2.5, PM10, and NO2 was significantly associated with increased CHD risk during the periconception period, with NO2 exhibiting the strongest effect. Moreover, a supervised sparse partial least square model identified pollutant-specific protein signatures in both maternal serum and umbilical cord serum. These protein fingerprints could effectively reflect the levels of air pollution and were significantly associated with CHD outcomes. Notably, our study revealed that FGF-4, VEGF-D, MSP, and Angiogenin may be involved in air pollution-associated cardiac malformations. Overall, this study promotes the understanding of the association between air pollution and CHD by identifying susceptible populations and underlying molecular mechanisms, providing a scientific basis for mitigation policies and prenatal healthcare. Prenatal exposure to air pollution has been linked to risk of congenital heart defects (CHD). Here the authors report that periconception exposure, especially to NO₂, is associated with higher CHD risk and distinct maternal and cord blood protein signatures.