Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders

Introduction: Neurologist-assessed parkinsonism signs are prevalent among workers exposed to manganese (Mn)-containing welding fume. Neuroinflammation may possibly play a role. Inducible nitric oxide synthase, coded by NOS2, is involved in inflammation, and particulate exposure increases the gene's expression through methylation of CpG sites in the 5' region. Methods: We assessed DNA methylation at three CpG sites in the NOS2 exon 1 from blood from 201 welders. All were non-Hispanic Caucasian men 25-65 years old who were examined by a neurologist specializing in movement disorders. We categorized the workers according to their Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) scores as parkinsonism cases (UPDRS3≥15; n=49), controls (UPDRS3<6; n=103), or intermediate (UPDRS3 ≥6 to < 15; n=49). Results: While accounting for age, examiner and experimental plate, parkinsonism cases had lower mean NOS2 methylation than controls (p-value for trend=0.04), specifically at CpG site 8329 located in an exonic splicing enhancer of NOS2 (p-value for trend=0.07). These associations were not observed for the intermediate UPDRS3 group (both p-value for trend≥0.59). Conclusions: Inflammation mediated by inducible nitric oxide synthase may possibly contribute to the association between welding fume and parkinsonism, but requires verification in a longitudinal study.