Associations Between Genome-wide Gene Expression and Ambient Nitrogen Oxides.
We hypothesize that biological perturbations due to exposure to ambient air pollution are reflected in gene expression levels in peripheral blood mononuclear cells.



We assessed the association between exposure to ambient air pollution and genome-wide gene expression levels in peripheral blood mononuclear cells collected from 550 healthy subjects participating in cohorts from Italy and Sweden. Annual air pollution estimates of nitrogen oxides (NOx) at time of blood collection (1990-2006) were available from the ESCAPE study. In addition to univariate analysis and two variable selection methods to investigate the association between expression and exposure to NOx, we applied gene set enrichment analysis to assess overlap between our most perturbed genes and gene sets hypothesized to be related to air pollution and cigarette smoking. Finally, we assessed associations between NOx and CpG island methylation at the identified genes.



Annual average NOx exposure in the Italian and Swedish cohorts was 94.2 and 6.7 µg/m, respectively. Long-term exposure to NOx was associated with seven probes in the Italian cohort and one probe in the Swedish (and combined) cohorts. For genes AHCYL2 and MTMR2, changes were also seen in the methylome. Genes hypothesized to be downregulated due to cigarette smoking were enriched among the most strongly downregulated genes from our study.



This study provides evidence of subtle changes in gene expression related to exposure to long-term NOx. On a global level, the observed changes in the transcriptome may indicate similarities between air pollution and tobacco induced changes in the transcriptome.
From the aDivision of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; bMedical Research Council-Health Protection Agency Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; cDepartment of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden; dDepartment of Biobank Research, Umeå University, Umeå, Sweden; eMolecular and Nutritional Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Florence, Italy; fJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; gHuGeF Foundation, Turin, Italy; hDepartment of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; iEpidemiology Unit, Instituto Tumori, Milan, Italy; and jNational Hellenic Research Foundation, Institute of Biology, Pharmaceutical Chemistry and Biotechnology, Athens, Greece.
Nahid
N
Mostafavi
Jelle
J
Vlaanderen
Lutzen
L
Portengen
Marc
M
Chadeau-Hyam
Lars
L
Modig
Domenico
D
Palli
Ingvar A
IA
Bergdahl
Bert
B
Brunekreef
Paolo
P
Vineis
Dennie G A J
DG
Hebels
Jos C S
JC
Kleinjans
Vittorio
V
Krogh
Gerard
G
Hoek
Panagiotis
P
Georgiadis
Soterios
S
Kyrtopoulos
Roel
R
Vermeulen
D000328:Adult; D000393:Air Pollutants; D000397:Air Pollution / Q000706:statistics & numerical data*; D001943:Breast Neoplasms / Q000453:epidemiology; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007558:Italy / Q000453:epidemiology; D008223:Lymphoma / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009589:Nitrogen Oxides; D012907:Smoking / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D013548:Sweden / Q000453:epidemiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000393:Air Pollutants; C508606:CXCL8 protein, human; C508609:IL10 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D016209:Interleukin-8; D009589:Nitrogen Oxides; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10