10.6084/M9.FIGSHARE.12601315.V1
Tyler P. Nicholas
Anoria K. Haick
Tomomi W. Workman
William C. Griffith
James D. Nolin
Terrance J. Kavanagh
Elaine M. Faustman
William A. Altemeier
The effects of genotype × phenotype interactions on silver nanoparticle toxicity in organotypic cultures of murine tracheal epithelial cells
<p>Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no <i>in vitro</i> studies to date have used organotypic cultures as a high-content <i>in vitro</i> model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G × P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNPs with a gold core on barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes (‘Normal’ and ‘Type 2 [T2]-Skewed’), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 h, every other day, over 5 days [5 × 4 h]). We characterized the ‘T2-Skewed’ phenotype as an <i>in vitro</i> model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using <i>in vitro</i> and <i>in vivo</i> models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G × P effects when screening and prioritizing potential respiratory toxicants. Such <i>in vitro</i> studies can be used to inform regulatory policy aimed at special protections for all populations.</p>
Biochemistry
Medicine
Cell Biology
Genetics
59999 Environmental Sciences not elsewhere classified
69999 Biological Sciences not elsewhere classified
Cancer
Science Policy
110309 Infectious Diseases
Taylor & Francis
2020
2020-07-02
2020-09-12
Journal contribution
1635336 Bytes
10.1080/17435390.2020.1777475
10.6084/m9.figshare.12601315
CC BY 4.0