title: Meta-analysis of transcriptomic responses as a means to identify pulmonary disease outcomes for engineered nanomaterials.
abstract: The increasing use of engineered nanomaterials (ENMs) of varying physical and chemical characteristics poses a great challenge for screening and assessing the potential pathology induced by these materials, necessitating novel toxicological approaches. Toxicogenomics measures changes in mRNA levels in cells and tissues following exposure to toxic substances. The resulting information on altered gene expression profiles, associated pathways, and the doses at which these changes occur, are used to identify the underlying mechanisms of toxicity and to predict disease outcomes. We evaluated the applicability of toxicogenomics data in identifying potential lung-specific (genomic datasets are currently available from experiments where mice have been exposed to various ENMs through this common route of exposure) disease outcomes following exposure to ENMs.
  
  
  
  Seven toxicogenomics studies describing mouse pulmonary responses over time following intra-tracheal exposure to increasing doses of carbon nanotubes (CNTs), carbon black, and titanium dioxide (TiO2) nanoparticles of varying properties were examined to understand underlying mechanisms of toxicity. mRNA profiles from these studies were compared to the publicly available datasets of 15 other mouse models of lung injury/diseases induced by various agents including bleomycin, ovalbumin, TNFα, lipopolysaccharide, bacterial infection, and welding fumes to delineate the implications of ENM-perturbed biological processes to disease pathogenesis in lungs.
  
  
  
  The meta-analysis revealed two distinct clusters-one driven by TiO2 and the other by CNTs. Unsupervised clustering of the genes showing significant expression changes revealed that CNT response clustered with bleomycin injury and bacterial infection models, both of which are known to induce lung fibrosis, in a post-exposure-time dependent manner, irrespective of the CNT's physical-chemical properties. TiO2 samples clustered separately from CNTs and disease models.
  
  
  
  These results indicate that in the absence of apical toxicity data, a tiered strategy beginning with short term, in vivo tissue transcriptomics profiling can effectively and efficiently screen new ENMs that have a higher probability of inducing pulmonary pathogenesis.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Jake
authors.initials: J
authors.lastname: Nikota
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: National Research Centre for the Working Environment, Lerso Parkallé 105, Copenhagen, DK-2100, Denmark.|Department of Public Health, University of Copenhagen, Copenhagen K, DK-1353, Denmark.
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallin
authors.affiliation: National Research Centre for the Working Environment, Lerso Parkallé 105, Copenhagen, DK-2100, Denmark.|Department of Micro- and Nanotechnology, Technical University of Denmark, DK-2800 Kgs., Lyngby, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada. sabina.halappanavar@hc-sc.gc.ca.
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
mesh_terms: D000393:Air Pollutants / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049329:Nanostructures / Q000737:chemistry / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D043922:Toxicogenetics / Q000379:methods / Q000639:trends; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D000393:Air Pollutants
keywords: Carbon black; Carbon nanotubes; Lung disease; Lung fibrosis; Nanomaterials; TiO2 nanoparticles; Toxicogenomics