BACKGROUND: Benzene is an established leukemogen at high-exposure levels. While low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses. OBJECTIVES: To determine in a large multi-center 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; explore potential links between mtDNAcn and leukemia-related epigenetic markers. METHODS: We measured blood relative mtDNAcn by real-time PCR in 341 individuals selected from various occupational groups with low-level benzene exposures (>100 times lower than the OSHA/EU 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 policemen, 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 farther referents (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 in 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: MtDNAcn was increased at low-benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.
Increased Mitochondrial DNA Copy Number in Occupations Associated with Low-Dose Benzene Exposure.
BONZINI, MATTEO;
2011-01-01
Abstract
BACKGROUND: Benzene is an established leukemogen at high-exposure levels. While low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses. OBJECTIVES: To determine in a large multi-center 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; explore potential links between mtDNAcn and leukemia-related epigenetic markers. METHODS: We measured blood relative mtDNAcn by real-time PCR in 341 individuals selected from various occupational groups with low-level benzene exposures (>100 times lower than the OSHA/EU 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 policemen, 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 farther referents (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 in 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: MtDNAcn was increased at low-benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.
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