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Characterizing early molecular biomarkers of zinc-induced adaptive and adverseoxidative stress responses in human bronchial epithelial cells
Citation:
Currier, J., W. Cheng, R. Conolly, AND B. Chorley. Characterizing early molecular biomarkers of zinc-induced adaptive and adverseoxidative stress responses in human bronchial epithelial cells. EMGS, New Orleans, LA, September 26 - 30, 2015.
Impact/Purpose:
To be presented at the EMGS conference in New Orleans, LA on Sept 26-30 2015.
Description:
Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure. A pharmacokinetic model for normal human bronchial epithelial (BEAS-2B) cells exposed to Zn2+ and pyrithione, an ionophore facilitating cellular uptake, was developed to predict the saturation of intracellular Zn2+ sequestration necessary for mediating adverse oxidative effects leading to apoptosis. Computational simulations predicted that 2–10 µM Zn2+/pyrithione would increase free intracellular Zn2+. BEAS-2B cells treated with 2–10 µM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and apoptotic Zn2+ exposure conditions were determined by assessment of NRF2 nuclear translocation and apoptotic protein markers. Differences in global gene expression under these conditions were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicated that the apoptotic p53 pathway was more significantly enriched under apoptotic exposure conditions with –log(p values) between 9.0 and 5.4. After 4 h, 236 genes were differentially expressed (p<0.01) between the adaptive and apoptotic Zn2+ concentrations. Assessment of gene expression and ChiP-seq databases revealed 62 potential p53-target transcriptomic biomarkers. These data suggest that the switch between adaptation and apoptosis in our model begins to occur at exposures of approximately 3 µM Zn2+ and as early as 4 h after exposure. Future work will determine the genomic response that mediates this switch. This abstract does not necessarily reflect the policy of the US EPA.