Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells

Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on...

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Bibliographic Details
Published in:	PloS one 2016-05, Vol.11 (5), p.e0155875
Main Authors:	Currier, Jenna M, Cheng, Wan-Yun, Menendez, Daniel, Conolly, Rory, Chorley, Brian N
Format:	Article
Language:	eng
Subjects:	21st century Activation Apoptosis Biocompatibility Biology and Life Sciences Biomarkers Biomarkers - metabolism Bronchi - cytology Cell Line Cell Survival Cellular stress response Cytotoxicity DNA damage Environmental effects Environmental protection Epithelial cells Epithelial Cells - metabolism Exposure Gene expression Gene Expression Profiling Gene Expression Regulation Genes Genetic aspects Genetic Markers Genomes Glutathione - metabolism High-throughput screening Homeostasis Human behavior Humans Immunoassay In vivo methods and tests Information processing Laboratories Molecular modelling NF-E2-Related Factor 2 - metabolism Oligonucleotide Array Sequence Analysis Oxidative Stress p53 Protein Physical Sciences Physiological aspects Principal Component Analysis Respiratory tract Risk Assessment Signal Transduction Signaling Target recognition Toxicity testing Transcription factors Tumor Suppressor Protein p53 - metabolism Zinc Zinc - chemistry
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Summary:	Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2-10 μM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the importance of characterizing molecular mechanisms around the tipping point of adverse responses to better inform HTS paradigms.
ISSN:	1932-6203 1932-6203