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 pro-inflammatory signaling within 24 h confirmed the reliability and sensitivity of the system to detect acute inhalation toxicity. Gene expression changes between nanoparticle-exposed 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.
Highlights
Asthma is a chronic respiratory disease with extremely high susceptibility to environmental exposures such as allergens,[1] chemicals,[2] and particulate air pollutants.[3−5] Asthmatic airways are typically chronically inflamed and extremely hyper-reactive, with symptoms such as recurrent wheezing, coughing, and shortness of breath
Cytotoxicity was highest in asthmatic donor cells, and pristine nCuO appears to be more cytotoxic than COOH-functionalized nCuO
We identified genes related to asthma by microarray-based comparative transcriptomics on total RNA isolated from asthmatic and healthy donor cells that had only been exposed to control air
Summary
Asthma is a chronic respiratory disease with extremely high susceptibility to environmental exposures such as allergens,[1] chemicals,[2] and particulate air pollutants.[3−5] Asthmatic airways are typically chronically inflamed and extremely hyper-reactive, with symptoms such as recurrent wheezing, coughing, and shortness of breath. Accurate and scalable ex vivo test methods which are still applicable to human exposures and can be used to evaluate the potential health hazards associated with ENM in a timely manner, are needed. Three-dimensional cocultures for nanoparticle exposure at an air−liquid interface that mimics the human lung have recently been developed.[8,9] Using this system in combination with adverse outcome assays, in vitro simulation of particle exposure and potential health hazard has been successfully performed for airborne particles and fibers.[10−14]. Unraveling the mechanistic interplay between nanoscale materials and asthma has been far limited to a handful of studies.[19] As such, employing an in vitro 3D human bronchial epithelial model in tandem with extensive downstream transcriptomic assessment in healthy and vulnerable individuals with a disease-compromised respiratory system is the subject of this study. As such, employing an in vitro 3D human bronchial epithelial model in tandem with extensive downstream transcriptomic assessment in healthy and vulnerable individuals with a disease-compromised respiratory system is the subject of this study. 3D human bronchial epithelial cells cultured at an air−liquid interface that mimics relevant inhalatory exposure[20] were exposed to aerosols of pristine (nCuO) and carboxylated (nCuOCOOH)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
