Structure–dependent association between Perfluoroalkyl and polyfluoroalkyl substances and hemoglobin in the Chinese population: insights from epidemiological analysis and molecular simulations

The association between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and hemoglobin (Hb) in general population, as well as their structural-functional relationship remains to be elucidated. We examined both individual and joint-level associations of serum PFAS with Hb concentrations using data from the China National Human Biomonitoring Program. Molecular docking and quantum mechanics calculations were further applied to elucidate potential molecular mechanisms. Of 6,883 participants, median serum concentrations of 8 PFAS ranged from 0.15 ng/mL (perfluoroheptanesulfonic acid [PFHpS]) to 5.85 ng/mL (perfluorooctanesulfonic acid [PFOS]). All participants had Hb concentrations within the normal physiological range. PFAS mixture demonstrated negative relationship with the Hb in the general population, with perfluoroundecanoic acid (PFUnDA) emerging as the dominant contributor. Moreover, the effect sizes of inverse associations between perfluorocarboxylic acids (PFCAs) and Hb increased in magnitude with longer carbon chains, especially in females, while no such trend was observed for perfluorosulfonic acids (PFSAs). Notably, the PFOS alternative 6:2 Chlorinated Polyfluorinated Ether Sulfonic Acid (Cl-PFESA) was inversely associated with Hb in females. Stronger associations were observed among females, individuals with lower body mass index, and those with higher meat consumption. Molecular modeling indicated that PFAS preferentially bind to the α subunit rather than the β subunit of Hb, and PFCAs exhibited similar binding affinities to heme comparable to that of oxygen, suggesting potential interference with Hb's oxygen-binding capacity. Our findings revealed structure-dependent associations and interactions between PFAS and Hb, providing important insights for further mechanistic studies on PFAS-related hematotoxicity and highlight the urgent need to control PFAS exposure.