Integrated Exposomics and Metabolomics Reveal Lipid-Mediated Associations of Trace Element and PFAS Co-Exposure with Chronic Cerebral Ischemia

Background/Objectives: The relationship of combined trace-element and per- and polyfluoroalkyl substance (PFAS) exposure with chronic cerebral ischemia (CCI), and the metabolic changes accompanying such exposure, have not been well characterized. We therefore combined exposure assessment with metabolomic profiling to examine pollutant mixtures associated with CCI and to identify candidate metabolic intermediates. Methods: The analysis included 170 participants in a case–control design (85 CCI cases and 85 controls). Plasma was assayed for 19 trace elements and 22 PFASs, together with nontargeted metabolites. Individual and mixture associations were examined using multivariable logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression. Pathway and mediation ansalyses were then used to explore metabolic links. Results: After Benjamini–Hochberg correction, PFNA remained significant in the continuous and upper-quartile analyses, while exposure trends remained significant for PFBS, PFNA, and PFUdA. The mixture analyses also indicated an overall association with CCI, with PFNA making a prominent contribution and showing interaction with As. Metabolomic analysis yielded 41 nominally selected candidate metabolites, many of which were lipid-related. Five lipid candidates showed indirect effects that remained significant after correction across the five mediation tests: Propionylcarnitine, Linoelaidyl carnitine, LysoPC (18:1) isomer 1, LysoPE (22:5), and PE (38:3). Conclusions: The results link CCI with concurrent environmental exposures and indicate that changes in acylcarnitine and glycerophospholipid metabolism may lie on important biological pathways connecting exposure with disease.