Nontargeted Metabolomics and Machine Learning Reveal Associations Between 6:2 Fluorotelomer Ethoxylate Exposure and Intracranial Aneurysm Risk.

6:2 Fluorotelomer ethoxylates (6:2 FTEOs) are an emerging class of polyfluoroalkyl substances widely used in anti-fog products. Their increasing detection in environmental media and human serum has raised concerns regarding their potential toxicity and associated health risks. The association between 6:2 FTEO exposure and intracranial aneurysm (IA) risk has not been evaluated in any epidemiological study to date. Here, we conducted a case-control study (137 IA patients and 274 healthy controls), quantified seven serum 6:2 FTEO homologues, and performed metabolomic profiling of human serum samples. 6:2 FTEO6, 6:2 FTEO9, and 6:2 FTEO11 dominated the 6:2 FTEO profile in human serum. Serum levels of 6:2 FTEO6, 6:2 FTEO8, and 6:2 FTEO9 showed significant (p < 0.01) associations with IA risk, with adjusted odds ratios comparing the highest versus lowest quartile of 2.68 (95% CI: 1.61-3.70), 2.78 (1.78-3.81), and 1.98 (1.10-3.58), respectively. Weighted quantile sum analysis indicated a significant effect of the combined 6:2 FTEO exposure on IA risk, driven mainly by 6:2 FTEO6. Random forest showed the strongest apparent discrimination, and its top-ranked metabolites were enriched in arachidonic acid metabolism and phosphatidylcholine biosynthesis. In exploratory mediation analyses, the observed indirect-effect estimates for 6:2 FTEO6 and 6:2 FTEO8 were statistically compatible with mediation through arachidonic acid metabolism and phosphatidylcholine biosynthesis. This study is the first to provide epidemiological evidence linking 6:2 FTEO exposure to increased IA risk, and provides hypothesis-generating evidence linking serum 6:2 FTEO concentrations, lipid metabolic perturbations, and IA status.