title: Increased mitochondrial DNA copy number in occupations associated with low-dose benzene exposure.
abstract: BACKGROUND
  Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses.
  
  
  OBJECTIVE
  Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers.
  
  
  METHODS
  We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari).
  
  
  RESULTS
  In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (-2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008).
  
  
  CONCLUSIONS
  Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.
authors: Department of Occupational and Environmental Health, Università degli Studi di Milano, Milan, Italy. michele.carugno@gmail.com
authors: Michele
authors: M
authors: Carugno
authors: Angela Cecilia
authors: AC
authors: Pesatori
authors: Laura
authors: L
authors: Dioni
authors: Mirjam
authors: M
authors: Hoxha
authors: Valentina
authors: V
authors: Bollati
authors: Benedetta
authors: B
authors: Albetti
authors: Hyang-Min
authors: HM
authors: Byun
authors: Matteo
authors: M
authors: Bonzini
authors: Silvia
authors: S
authors: Fustinoni
authors: Pierluigi
authors: P
authors: Cocco
authors: Giannina
authors: G
authors: Satta
authors: Mariagrazia
authors: M
authors: Zucca
authors: Domenico Franco
authors: DF
authors: Merlo
authors: Massimo
authors: M
authors: Cipolla
authors: Pier Alberto
authors: PA
authors: Bertazzi
authors: Andrea
authors: A
authors: Baccarelli
mesh_terms: D000328:Adult; D000395:Air Pollutants, Occupational / Q000032:analysis / Q000633:toxicity*; D001554:Benzene / Q000032:analysis / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D002947:Cities / Q000453:epidemiology; D003430:Cross-Sectional Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000097:blood / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018628:Gene Dosage / Q000187:drug effects*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000453:epidemiology* / Q000209:etiology; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016273:Occupational Exposure; D060888:Real-Time Polymerase Chain Reaction; D012044:Regression Analysis; D055815:Young Adult
chemical_list: D000395:Air Pollutants, Occupational; D015415:Biomarkers; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004272:DNA, Mitochondrial; D001554:Benzene