Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells
Publication Date
May 19, 2016
Journal
PLOS ONE
Authors
Jenna M. Currier, Wan Yun Cheng, Daniel Menendez, Rory Conolly, et al
Volume
11
Issue
5
Pages
e0155875
DOI
https://dx.plos.org/10.1371/journal.pone.0155875
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0155875
Scopus
84973639343
Mendeley
http://www.mendeley.com/research/developing-gene-biomarker-tipping-point-adaptive-adverse-responses-human-bronchial-epithelial-cells
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Mendeley | Further Information

{"title"=>"Developing a gene biomarker at the tipping point of adaptive and adverse responses in human bronchial epithelial cells", "type"=>"journal", "authors"=>[{"first_name"=>"Jenna M.", "last_name"=>"Currier", "scopus_author_id"=>"49862897500"}, {"first_name"=>"Wan Yun", "last_name"=>"Cheng", "scopus_author_id"=>"35214449500"}, {"first_name"=>"Daniel", "last_name"=>"Menendez", "scopus_author_id"=>"8973393200"}, {"first_name"=>"Rory", "last_name"=>"Conolly", "scopus_author_id"=>"7007060637"}, {"first_name"=>"Brian N.", "last_name"=>"Chorley", "scopus_author_id"=>"8710359400"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"610471101", "sgr"=>"84973639343", "issn"=>"19326203", "pmid"=>"27195669", "scopus"=>"2-s2.0-84973639343", "doi"=>"10.1371/journal.pone.0155875"}, "id"=>"34d8d9eb-df36-3118-a10c-76426d67cb45", "abstract"=>"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.", "link"=>"http://www.mendeley.com/research/developing-gene-biomarker-tipping-point-adaptive-adverse-responses-human-bronchial-epithelial-cells", "reader_count"=>11, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>3}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}}, "reader_count_by_country"=>{"Brazil"=>1}, "group_count"=>0}

Scopus | Further Information

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