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

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.