Associations between perfluoroalkyl substances and multiple sclerosis in U.S. cohorts compared with NMOSD, MOGAD, and
Farren B S Briggs1, Federico Montini2, Charles F Spurlock3
1Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
Background And Objectives:
Perfluoroalkyl substances (PFAS) are persistent environmental contaminants with endocrine and neuroimmune properties, yet relevance to multiple sclerosis (MS) remains unclear. Recent European data suggested MS-PFAS associations may vary by sex. We evaluated sex-stratified and disease-specific PFAS-MS associations in U.S. cohorts and explored endocrine and transcriptomic correlates.
Methods:
Liquid chromatography-mass spectrometry-derived serum PFHxS, PFOA, and PFOS were quantified in 439 participants (226 MS, 106 healthy controls [HC], 59 neuromyelitis optica spectrum disorder [NMOSD], 48 myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD]) across two U.S. cohorts. PFAS levels were compared across diagnostic groups with sex stratification. Exposure-risk models estimated MS odds. Among MS-HC females, associations between PFAS and sex-steroid metabolites were evaluated, and PFAS-correlated gene-expression signatures were examined in a subset of MS females.
Results:
PFHxS was consistently elevated in MS females compared with HC, NMOSD, and MOGAD females, while PFOA showed a similar but less uniform pattern; male associations were imprecise. Exposure-risk models demonstrated dose-response and non-linear associations for PFHxS, with directionally similar patterns for PFOA; PFHxS was the primary contributor in mixture analyses. PFOS associations were weaker and less consistent. Exploratory analyses observed significant MS × PFOA interactions for several steroid metabolites, and PFAS-correlated genes showed tentative enrichment of neuronal membrane pathways.
Conclusions:
Across two U.S. cohorts, PFHxS demonstrated consistent association with MS, particularly among females, while PFOA showed a similar but less uniform pattern. Exploratory findings suggest plausible pathways linking PFAS exposure to MS. Multi-ethnic and longitudinal studies are needed to expand generalizability and clarify temporality and causality.
