title: Network Analysis Reveals Similar Transcriptomic Responses to Intrinsic Properties of Carbon Nanomaterials in Vitro and in Vivo.
abstract: Understanding the complex molecular alterations related to engineered nanomaterial (ENM) exposure is essential for carrying out toxicity assessment. Current experimental paradigms rely on both in vitro and in vivo exposure setups that often are difficult to compare, resulting in questioning the real efficacy of cell models to mimic more complex exposure scenarios at the organism level. Here, we have systematically investigated transcriptomic responses of the THP-1 macrophage cell line and lung tissues of mice, after exposure to several carbon nanomaterials (CNMs). Under the assumption that the CNM exposure related molecular alterations are mixtures of signals related to their intrinsic properties, we inferred networks of responding genes, whose expression levels are coordinately altered in response to specific CNM intrinsic properties. We observed only a minute overlap between the sets of intrinsic property-correlated genes at different exposure scenarios, suggesting specific transcriptional programs working in different exposure scenarios. However, when the effects of the CNM were investigated at the level of significantly altered molecular functions, a broader picture of substantial commonality emerged. Our results imply that in vitro exposures can efficiently recapitulate the complex molecular functions altered in vivo. In this study, altered molecular pathways in response to specific CNM intrinsic properties have been systematically characterized from transcriptomic data generated from multiple exposure setups. Our computational approach to the analysis of network response modules further revealed similarities between in vitro and in vivo exposures that could not be detected by traditional analysis of transcriptomics data. Our analytical strategy also opens a possibility to look for pathways of toxicity and understanding the molecular and cellular responses identified across predefined biological themes.
authors.forename: Pia
authors.initials: P
authors.lastname: Kinaret
authors.forename: Veer
authors.initials: V
authors.lastname: Marwah
authors.forename: Vittorio
authors.initials: V
authors.lastname: Fortino
authors.forename: Marit
authors.initials: M
authors.lastname: Ilves
authors.affiliation: Finnish Institute of Occupational Health , Helsinki, Finland 00251.
authors.forename: Henrik
authors.initials: H
authors.lastname: Wolff
authors.forename: Lasse
authors.initials: L
authors.lastname: Ruokolainen
authors.forename: Petri
authors.initials: P
authors.lastname: Auvinen
authors.affiliation: Finnish Institute of Occupational Health , Helsinki, Finland 00251.
authors.forename: Kai
authors.initials: K
authors.lastname: Savolainen
authors.affiliation: Institute of Environmental Medicine (IMM), Karolinska Institutet , 171 77 Stockholm, Sweden.
authors.forename: Harri
authors.identifier: 0000-0003-0106-8923
authors.initials: H
authors.lastname: Alenius
authors.forename: Dario
authors.identifier: 0000-0001-9195-9003
authors.initials: D
authors.lastname: Greco
mesh_terms: D000818:Animals; D002460:Cell Line; D030541:Databases, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D012343:RNA, Transfer / Q000235:genetics*; D059467:Transcriptome
chemical_list: D037742:Nanotubes, Carbon; D012343:RNA, Transfer
keywords: carbon nanomaterials; gene networks; mechanism of action; network response modules; pathways of toxicity; toxicogenomics; transcriptomics