title: Genomic analysis of murine pulmonary tissue following carbonyl chloride inhalation.
abstract: Carbonyl chloride (phosgene) is a toxic industrial compound widely used in industry for the production of synthetic products, such as polyfoam rubber, plastics, and dyes. Exposure to phosgene results in a latent (1-24 h), potentially life-threatening pulmonary edema and irreversible acute lung injury. A genomic approach was utilized to investigate the molecular mechanism of phosgene-induced lung injury. CD-1 male mice were exposed whole body to either air or a concentration x time amount of 32 mg/m3 (8 ppm) phosgene for 20 min (640 mg x min/m3). Lung tissue was collected from air- or phosgene-exposed mice at 0.5, 1, 4, 8, 12, 24, 48, and 72 h postexposure. RNA was extracted from the lung and used as starting material for the probing of oligonucleotide microarrays to determine changes in gene expression following phosgene exposure. The data were analyzed using principal component analysis to determine the greatest sources of data variability. A three-way analysis of variance based on exposure, time, and sample was performed to identify the genes most significantly changed as a result of phosgene exposure. These genes were rank ordered by p values and categorized based on molecular function and biological process. Some of the most significant changes in gene expression reflect changes in glutathione synthesis and redox regulation of the cell, including upregulation of glutathione S-transferase alpha-2, glutathione peroxidase 2, and glutamate-cysteine ligase, catalytic subunit (also known as gamma-glutamyl cysteine synthetase). This is in agreement with previous observations describing changes in redox enzyme activity after phosgene exposure. We are also investigating other pathways that are responsive to phosgene exposure to identify mechanisms of toxicity and potential therapeutic targets.
authors.affiliation: Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5400, USA. alfred.mario.sciuto@us.army.mil
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Phillips
authors.forename: Linda D
authors.initials: LD
authors.lastname: Orzolek
authors.forename: Alison I
authors.initials: AI
authors.lastname: Hege
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Moran
authors.forename: James F
authors.initials: JF
authors.lastname: Dillman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D010705:Phosgene / Q000008:administration & dosage / Q000633:toxicity*; D016133:Polymerase Chain Reaction
chemical_list: D010705:Phosgene; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione