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.