Association between plasma levels of per- and polyfluoroalkyl substances and schizophrenia: A case-control study

Per- and polyfluoroalkyl substances (PFAS) are a class of neurotoxic persistent organic pollutants that may increase the risk of cognitive impairment and dementia, yet their association with schizophrenia (SCZ) remains unclear. This study aimed to investigate the relationship between plasma PFAS levels and the risk of schizophrenia. The concentrations of PFAS in plasma were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). To evaluate the single and combined effects of PFAS exposure on the risk of schizophrenia, we employed multivariable logistic regression, restricted cubic splines (RCS), Bayesian kernel machine regression (BKMR), and generalized weighted quantile sum (gWQS) models. Logistic regression analysis revealed that, compared with the lowest quartile (Q1), the odds ratios (ORs) for PFOS and PFHxS in the highest quartile (Q4) were 0.17 (95% CI:0.09∼0.36) and 0.39 (95% CI:0.21∼0.71), respectively. RCS analysis suggested nonlinear relationships between PFUnDA, PFOS, PFOA, and PFHxS and schizophrenia. In the assessment of mixture exposure effects, the BKMR model indicated an overall negative association between PFAS mixtures and schizophrenia risk, and gWQS analysis further identified PFHxS as the component with the highest weight contribution. Additionally, correlations were observed between the levels of PFUnDA, PFOS, and PFHxS and inflammatory indices in patients with schizophrenia. Future large-scale prospective studies combined with toxicological mechanism research are needed to further validate these findings.