Advanced in vitro exposure systems.

Molecular Signature of Asthma-Enhanced Sensitivity to CuO Nanoparticle Aerosols from 3D Cell Model

12. Jun. 2019

DOI: 10.1021/acsnano.9b01823

Ingeborg Kooter1, Marit Ilves 2, Mariska Gröllers-Mulderij 1, Evert Duistermaat 3, Peter C. Tromp 1, Frieke Kuper 1, Pia Kinaret 4,5, Kai Savolainen 6, Dario Greco 4,5, Piia Karisola 2, Joseph Ndika 2, and Harri Alenius 2,7

1The Netherlands Organization for Applied Scientific Research, TNO, P.O. Box 80015, Utrecht 3584 CB, The Netherlands
2Human Microbiome Research, Faculty of Medicine, University of Helsinki, P.O. Box 21, Helsinki 00290, Finland
3Triskelion B.V., P.O. Box 844, Zeist 3704 HE, The Netherlands
4Faculty of Medicine and Life Sciences, University of Tampere, Tampere FI-33014, Finland
5Institute of Biotechnology, University of Helsinki, P.O. Box 56, Helsinki 00014, Finland
6Finnish Institute of Occupational Health, P.O. Box 40, Helsinki 00014, Finland
7Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, Stockholm SE-17176, Sweden

3D human bronchial epithelial cells were cultured at the air−liquid interface that mimics relevant inhalatory exposure were exposed to aerosols of pristine (nCuO) and carboxylated (nCuOCOOH) copper oxide nanoparticles. This paper shows that the existence of asthma enhances sensitivity of the airways to nanoparticle aerosols, possibly as a combined result of a hyperactive airway and inefficient mucociliary clearance mechanisms in asthmatics. The test results are shown in cell viabilty (LDH), Inflammation (IL6, IL8, MCP1) and Transcroptomics.

ABSTRACT: 

More than 5% of any population suffers from asthma, and there are indications that these individuals are more sensitive to nanoparticle aerosols than the healthy population. We used an air−liquid interface model of inhalation exposure to investigate global transcriptomic responses in reconstituted three-dimensional airway epithelia of healthy and asthmatic subjects exposed to pristine (nCuO) and carboxylated (nCuOCOOH) copper oxide nanoparticle aerosols. A dose-dependent increase in cytotoxicity (highest in asthmatic donor cells) and proinflammatory signaling within 24 h confirmed the reliability and sensitivity of the system to detect acute inhalation toxicity. Gene expression changes between nanoparticleexposed versus air-exposed cells were investigated. Hierarchical clustering based on the expression profiles of all differentially expressed genes (DEGs), cell-death-associated DEGs (567 genes), or a subset of 48 highly overlapping DEGs categorized all samples according to “exposure severity”, wherein nanoparticle surface chemistry and asthma are incorporated into the dose−response axis. For example, asthmatics exposed to low and medium dose nCuO clustered with healthy donor cells exposed to medium and high dose nCuO, respectively. Of note, a set of genes with high relevance to mucociliary clearance were observed to distinctly differentiate asthmatic and healthy donor cells. These genes also responded differently to nCuO and nCuOCOOH nanoparticles. Additionally, because response to transition-metal nanoparticles was a highly enriched Gene Ontology term (FDR 8 × 10−13) from the subset of 48 highly overlapping DEGs, these genes may represent biomarkers to a potentially large variety of metal/metal oxide nanoparticles.

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