PFNA dominates the association between PFAS mixture exposure and hypertension risk: The mediating role of estradiol in the U.S. adults

This study aimed to investigate the association between per- and polyfluoroalkyl substances (PFAS) mixture exposure and hypertension risk, and to assess the mediating role of estradiol. We investigated these questions in 5175 adults from the U.S. National Health and Nutrition Examination Survey (NHANES 2011–2020). Serum concentrations of six PFAS and estradiol were quantified. Using weighted quantile sum (WQS) regression, we evaluated the joint effect of the PFAS mixture on hypertension (2017 ACC/AHA criteria). Restricted cubic splines (RCS) characterized exposure–response shapes, and causal mediation analysis tested estradiol as a potential mechanistic pathway. After full adjustment, perfluorononanoic acid (PFNA) exhibited the strongest association with hypertension (odds ratio per ln-unit increase, 1.16; 95% CI, 1.06–1.27). WQS regression identified PFNA as the primary driver of the mixture effect (weighted contribution, 37.5%). Crucially, estradiol significantly mediated 4.68% of the association between PFNA and hypertension, and 4.22% for perfluorooctanoic acid (PFOA). Sex-stratified analyses revealed that the associations of PFNA and PFOA with hypertension were significant only in females. All analyses accounted for the complex survey design and were adjusted for sociodemographic, lifestyle, and clinical factors. Our integrated analytical approach identifies PFNA, a long-chain PFAS, as a key driver of hypertension risk within environmental PFAS mixtures. The finding that estradiol reduction mediates this association provides novel evidence for an endocrine-disruption mechanism and explains observed female-specific susceptibility. These results highlight the importance of compound-specific prioritization and sex-aware frameworks in environmental risk assessment.