title: Inducible nitric oxide synthase gene methylation and parkinsonism in manganese-exposed welders.
abstract: BACKGROUND
  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.
authors: University of Washington, Department of Neurology, Seattle, WA, USA; University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA. Electronic address: ssn@uw.edu.
authors: Susan
authors: S
authors: Searles Nielsen
authors: University of California San Diego, Department of Family and Preventive Medicine, La Jolla, CA, USA.
authors: Harvey
authors: H
authors: Checkoway
authors: Washington University, Department of Neurology, St. Louis, MO, USA.
authors: Susan R
authors: SR
authors: Criswell
authors: University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA.
authors: Federico M
authors: FM
authors: Farin
authors: University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA.
authors: Patricia L
authors: PL
authors: Stapleton
authors: University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA; University of Washington, Department of Biostatistics, Seattle, WA, USA.
authors: Lianne
authors: L
authors: Sheppard
authors: Washington University, Department of Neurology, St. Louis, MO, USA; University of the Witwatersrand, School of Public Health, Parktown, South Africa.
authors: Brad A
authors: BA
authors: Racette
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation; D006801:Humans; D008297:Male; D008345:Manganese / Q000009:adverse effects*; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009784:Occupational Diseases / Q000139:chemically induced*; D016273:Occupational Exposure / Q000009:adverse effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D014896:Welding
chemical_list: D008345:Manganese; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: DNA methylation; Manganese; Nitric oxide synthase type II; Occupational exposure; Parkinsonian disorders; Welding
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