Occupational
Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures of Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters Brooke A Hawkes* Brooke A Hawkes Hawkes Hawkes Hawkes Hawkes Hawkes Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
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 (serum PFAS, years of experience, incumbent versus recruit status) and ALS-relevant miRNA expression in U.S. firefighters. MiRNA expression was quantified from blood collected from 833 firefighters across 15 U.S. sites. 302 of these same firefighters had nine PFAS analytes quantified in serum. 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: Thirteen significant negative associations (p<0.05) were observed for PFAS and miRNA expression, 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 relaxed FDR adjustment for multiple testing (q<0.20). Of these, five were inversely associated with ALS in previous studies, suggesting that increased serum PFAS may be a risk factor for ALS. Twelve miRNAs were associated with incumbency, including miR-195-5p (β = 8.612, 95% CI: 5.028, 12.196) and miR-106b-5p (β = 168.742, 95% CI: 70.176, 267.308); all remained significant after FDR correction. Nine miRNA had a known direction of association with ALS, and in eight of these the directionality with incumbent status was consistent with a higher risk of ALS. MiR-23a-3p was associated with years of firefighting (β = -7.301, 95% CI: -13.246, -1.357), but not after FDR correction. Let-7e-5p was inversely associated with Sm-PFOS, n-PFOS, and incumbency, suggesting a potential combined risk of ALS from increased serum PFAS and firefighting status.
Conclusions: Significant associations between PFAS exposure, firefighting status, and ALS-related miRNAs suggest potential molecular links between occupational exposures and ALS risk, warranting further pathway-focused research.