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Tytuł:
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Toxic consequences and oxidative protein carbonylation from chloropicrin exposure in human corneal epithelial cells.
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Autorzy:
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Goswami DG; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Kant R; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Ammar DA; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Agarwal C; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Gomez J; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Agarwal R; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Saba LM; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Fritz KS; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
Tewari-Singh N; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824, USA. Electronic address: .
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Źródło:
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Toxicology letters [Toxicol Lett] 2020 Apr 01; Vol. 322, pp. 1-11. Date of Electronic Publication: 2019 Dec 26.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Amsterdam : Elsevier
Original Publication: Amsterdam, Elsevier/North Holland.
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MeSH Terms:
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Apoptosis/*drug effects
Epithelial Cells/*drug effects
Epithelium, Corneal/*drug effects
Hydrocarbons, Chlorinated/*toxicity
Oxidative Stress/*drug effects
Pesticides/*toxicity
Protein Carbonylation/*drug effects
Caspase 3/metabolism ; Cells, Cultured ; Cyclooxygenase 2/metabolism ; DNA Damage ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Epithelium, Corneal/metabolism ; Epithelium, Corneal/pathology ; Heme Oxygenase-1/metabolism ; Histones/metabolism ; Humans ; Inflammation Mediators/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipid Peroxidation ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism
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Grant Information:
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U01 EY023143 United States EY NEI NIH HHS
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Contributed Indexing:
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Keywords: Chloropicrin; Corneal injury; Oxidative stress; Pesticide; Protein carbonylation
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Substance Nomenclature:
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0 (H2AX protein, human)
0 (Histones)
0 (Hydrocarbons, Chlorinated)
0 (Inflammation Mediators)
0 (Pesticides)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
EC 1.14.14.18 (HMOX1 protein, human)
EC 1.14.14.18 (Heme Oxygenase-1)
EC 1.14.99.1 (Cyclooxygenase 2)
EC 1.14.99.1 (PTGS2 protein, human)
EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
EC 3.4.22.- (CASP3 protein, human)
EC 3.4.22.- (Caspase 3)
I4JTX7Z7U2 (chloropicrin)
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Entry Date(s):
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Date Created: 20191230 Date Completed: 20200217 Latest Revision: 20240411
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Update Code:
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20240411
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DOI:
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10.1016/j.toxlet.2019.12.023
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PMID:
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31884112
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Chloropicrin (CP), a warfare agent now majorly used as a soil pesticide, is a strong irritating and lacrimating compound with devastating toxic effects. To elucidate the mechanism of its ocular toxicity, toxic effects of CP (0-100 μM) were studied in primary human corneal epithelial (HCE) cells. CP exposure resulted in reduced HCE cell viability and increased apoptotic cell death with an up-regulation of cleaved caspase-3 and poly ADP ribose polymerase indicating their contribution in CP-induced apoptotic cell death. Following CP exposure, cells exhibited increased expression of heme oxygenase-1, and phosphorylation of H2A.X and p53 as well as 4-hydroxynonenal adduct formation, suggesting oxidative stress, DNA damage and lipid peroxidation. CP also caused increases in mitogen activated protein kinase-c-Jun N-terminal kinase and inflammatory mediator cyclooxygenase-2. Proteomic analysis revealed an increase in the carbonylation of 179 proteins and enrichment of pathways (including proteasome pathway and catabolic process) in HCE cells following CP exposure. CP-induced oxidative stress and lipid peroxidation can enhance protein carbonylation, prompting alterations in corneal epithelial proteins as well as perturbing signaling pathways resulting in toxic effects. Pathways and major processes identified following CP exposure could be lead-hit targets for further biochemical and molecular characterization as well as therapeutic intervention.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2019. Published by Elsevier B.V.)
