Genomic Analysis of Murine Pulmonary Tissue Following Carbonyl Chloride Inhalation

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 × time amount of 32 mg/m3 (8 ppm) phosgene for 20 min (640 mg ×
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 α-2, glutathione peroxidase 2, and glutamate-cysteine
ligase, catalytic subunit (also known as γ-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.