Association of coexposure to perfluoroalkyl and polyfluoroalkyl compounds and heavy metals with pregnancy loss and reproductive lifespan: The mediating role of cholesterol

Previous studies have demonstrated the toxic effects of per- and polyfluoroalkyl substances (PFASs) and heavy metals on the reproductive system. However, the interactions and combined effects of these substances remain unexplored. This study utilizes data from the National Health and Nutrition Examination Survey to investigate the associations between coexposure to four types of PFASs, lead (Pb), mercury (Hg) and self-reported pregnancy loss and reproductive lifespan in females. Genes associated with these substances and abortion were identified via the Comparative Toxicogenomics Database. The results revealed that Ln-PFOA (IRR=1.88, 95 % CI=1.42-2.50, Ln--: log transformed), Ln-PFOS (IRR=1.58, 95 % CI=1.12-2.22), Ln-PFHxS (IRR=1.99, 95 % CI=1.57-2.52), and Ln-Hg (IRR=1.92, 95 % CI=1.41-2.43) were positively associated with the risk of pregnancy loss. Ln-PFOA (β=1.27, 95 % CI=0.28-2.27), Ln-PFOS (β=1.01, 95 % CI=0.39-1.63), Ln-PFHxS (β=0.71, 95 % CI=0.12-1.63), Ln-PFNA (β=1.15, 95 % CI=0.23-2.08), Ln-Pb (β=3.87, 95 % CI=2.58-5.15), and Ln-Hg (β=1.01, 95 % CI=0.39-1.64) exposures were positively associated with reproductive lifespan. The mixed and overall effects of coexposure to PFASs and heavy metals were positively correlated with the risk of pregnancy loss and reproductive lifespan. Cholesterol partially mediated the association with the risk of pregnancy loss, whereas delay in menopause fully mediated the association with reproductive lifespan. Significant additive interactions were observed between PFOA and Pb and between PFOS, PFHxS, PFNA and Hg at high levels of coexposure. Thirty-nine overlapping genes associated with abortion were identified for these substances, and further analyses revealed that these genes significantly interact and may contribute to abortion through oxidative stress.