Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures previously linked to Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology in sporadic cases. Blood microRNA (miRNA) expression varies between individuals with and without ALS. Firefighters may face elevated ALS risks due to occupational exposures, including elevated serum per- and polyfluoroalkyl substances (PFAS) concentrations. METHODS: This study investigates the association between occupational firefighter characteristics (years of experience, incumbent status (binary; 1=incumbent, 0=recruit), serum PFAS) and ALS-relevant miRNA expression in U.S. firefighters across 10 states. MiRNA expression was quantified from blood collected from 608 firefighters. Serum PFAS concentrations were available for a subset of 302 participants. We identified 19 ALS-related miRNAs using miRWalk's Disease Ontology. Adjusted linear regression models estimated associations between exposures and miRNA expression, controlling for demographic and occupational factors. RESULTS: In analyses of firefighter occupational characteristics (n=608), incumbent firefighters had significantly altered expression in ten ALS-related miRNAs compared to new recruits (p<0.05) and all remained significant after false discovery rate (FDR) adjustment for multiple testing (q<0.20). Years of firefighting was associated with lower expression of multiple miRNAs, including hsa-miR-23a-3p (β = -11.276, 95% CI: -18.870, -3.682), and this association remained significant after FDR correction. In PFAS analyses (n=302), higher serum PFAS concentrations were associated with 13 significant PFAS-miRNA associations (p<0.05) involving ALS-related miRNAs, including Sm-PFOS and hsa-let-7i-5p (β = -0.169, 95% CI: -0.287, -0.052), hsa-let-7c-5p (β = -0.128, 95% CI: -0.218, -0.037), and hsa-let-7e-5p (β = -0.113, 95% CI: -0.210, -0.017); PFNA and hsa-let-7c-5p (β = -0.126, 95% CI: -0.214, -0.037); and PFHxS and hsa-let-7i-5p (β = -0.126, 95% CI: -0.223, -0.029). Six remained significant after FDR adjustment (q < 0.20). Hsa-let-7e-5p was significantly lower in firefighters with higher Sm-PFOS, n-PFOS, and in incumbent firefighters. CONCLUSIONS: Significant associations between PFAS exposure, firefighting status, and ALS-related miRNAs suggest that PFAS exposure and firefighting characteristics are associated with miRNA expression patterns previously linked to ALS, warranting further investigation into potential biological pathways.