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Phosgene exposure in the mouse lung

ABSTRACT: Carbonyl chloride (phosgene) is a toxic industrial compound (TIC) 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 hr), 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 (c x t) 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 hr post-exposure. 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 (PCA) to determine the greatest sources of data variability. A three-way analysis of variance (ANOVA) 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 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. Male CD-1 mice were exposed to air or 32 mg per cubic meter phosgene for 20 min and tissue collected at 30 min, 1 hr, 4 hr, 8 hr, 12 hr, 24 hr, 48 hr, or 72 hr before collection and analysis of lung tissue using oligonucleotide microarrays. Keyword=phosgene Keyword=mouse Keyword=lung Keyword=carbonyl chloride Keywords: ordered

ORGANISM(S): Mus musculus

PROVIDER: GSE2565 | GEO | 2005/08/31

SECONDARY ACCESSION(S): PRJNA91969

REPOSITORIES: GEO

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Project description:Carbonyl chloride (phosgene) is a toxic industrial compound (TIC) 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 hr), 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 (c x t) 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 hr post-exposure. 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 (PCA) to determine the greatest sources of data variability. A three-way analysis of variance (ANOVA) 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 ÃÂ³-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.,Male CD-1 mice were exposed to air or 32 mg per cubic meter phosgene for 20 min and tissue collected at 30 min, 1 hr, 4 hr, 8 hr, 12 hr, 24 hr, 48 hr, or 72 hr before collection and analysis of lung tissue using oligonucleotide microarrays.,Keyword=phosgene,Keyword=mouse,Keyword=lung,Keyword=carbonyl chloride

Project description:Background: Ozone (O3) is the predominant oxidant air pollutant associated with respiratory inflammation, lung dysfunction, and worsening preexisting airway diseases. We determined that TNFR signlaing pathway plays a key role in lung injury and inflammation caused by O3 in mice. However, downstream molecular mechanisms underlying TNFR pathway have not been investigated. Methods: To investigate the role of TNFR pathway in gene expression changes, Tnfr1/2-deficient (Tnfr-/-) and wild-type (Tnfr+/+, C57BL/6J) mice were exposed to air or 0.3-ppm O3. Total RNAs were isolated from lung homogenates and cDNA microarray analyses were performed to elucidate TNFR-directed transcriptomics in basal lungs (air-exposed) as well as in the lung exposed to time course of O3 (24, 48, and 72 hr). Results: O3 caused time-dependent changes in lung gene expressions with the greatest transcriptome changes at 48-72 hr of exposure in Tnfr+/+ mice. At early time of exposure (24 hr), acute phase and inflammatory responses gene as well as redox and lipid metabolism genes were increased by O3 while cell cycle and DNA damage repair genes were markedly increased by O3 at later time points (48-72 hr). Compared to Tnfr+/+ mice, Tnfr-/- mice had lowered expression of inflammatory response and vascular disorder-related genes at baseline (air). After O3 exposure, Tnfr-/- had enhanced expression of immune and inflammatory genes at 24 hr, indicating compensatory or adpative poentiation of immunity in Tnfr-/- mice. At 48 hr of O3 exposure, Tnfr-/- mice showed suppressed expression of genes involved in epithelial proliferation, inflammatory cell influxes and epithelial injury, compared to Tnfr+/+ mice. At 72 hr of O3 exposure, neurodegeneration and neurotransmitter transport genes were suppressed in Tnfr-/- than in Tnfr+/+. Conclusion: Overall, deficiency of TNFR-mediated signaling in mouse lungs altered transcriptomes to protect lungs from O3-induced inflammation, cell proliferation, oxidative stress, and neuronal disorders.

Project description:The effect, if any, of age on the pulmonary toxicity induced by Min-U-Sil 5 crystalline silica exposure was investigated in rats. As part of the study, the changes in global gene expression profiles in the blood and lungs of the animals were determined. To conduct these studies, to determine if age influences the pulmonary response to crystalline silica exposure, two different age groups of healthy, male F344 rats were used. In this study the old age group of rats (12 months old at the time of exposure) was exposed to either air or crystalline silica (Min-U-Sil 5) (15 mg/m3, 6 hours/day, 5 days) by whole body inhalation. The old age group of rats simulates a group of workers who would be 45 to 50 years old. At two crystalline silica post-exposure time periods (1-day and 6-months) animals were euthanized and pulmonary inflammatory, cytotoxic, and oxidant responses were determined. Analysis of bronchoalveolar lavage parameters of toxicity such as oxidant generation and inflammation revealed significant changes in pulmonary toxicity in the crystalline silica exposed rats compared with the time-matched, air exposed control rats. The blood gene expression profiles showed only minimal changes, at both the time points, in the crystalline silica exposed rats compared with the controls. Specifically, no genes were significantly differentially expressed (fold change >1.5 and FDR p<0.05) in the one-day post-exposure group and only 6 genes were significantly differentially expressed in the 6-month post-exposure group. However, the lung gene expression profiles showed substantial changes in the crystalline silica exposed animals at both one-day and 6-month post-exposure. Specifically, there were a total of 325 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) at the one-day post-exposure group and 3348 genes significantly differentially expressed at the 6-month post-exposure. The data obtained from the present study demonstrated that crystalline silica inhalation exposure, under the conditions employed in the present study, resulted in significant changes in lung toxicity parameters and lung gene expression profile in the rats at both 1-day and 6-month post-exposure.

Project description:The effect, if any, of age on the pulmonary toxicity induced by Min-U-Sil 5 crystalline silica exposure was investigated in rats. As part of the study, the changes in global gene expression profiles in the blood and lungs of the animals were determined. To conduct these studies, to determine if age influences the pulmonary response to crystalline silica exposure, two different age groups of healthy, male F344 rats were used. In this study the young age group of rats (6 months old at the time of exposure) was exposed to either air or crystalline silica (Min-U-Sil 5) (15 mg/m3, 6 hours/day, 5 days) by whole body inhalation. The young age group of rats simulates a group of workers who would be 18 to 20 years old. At two crystalline silica post-exposure time periods (1-day and 6-months) animals were euthanized and pulmonary inflammatory, cytotoxic, and oxidant responses were determined. Analysis of bronchoalveolar lavage parameters of toxicity such as oxidant generation and inflammation revealed significant changes in pulmonary toxicity in the crystalline silica exposed rats compared with the time-matched, air exposed control rats. The blood gene expression profiles showed only minimal changes, at both the time points, in the crystalline silica exposed rats compared with the controls. Specifically, there were a total of 5 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) in the one-day post-exposure group and no significantly differentially genes in the 6-month post-exposure group. However, the lung gene expression profiles showed substantial changes in the crystalline silica exposed animals at both one-day and 6-month post-exposure. Specifically, there were a total of 385 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) at the one-day post-exposure group and 317 genes significantly differentially expressed at the 6-month post-exposure. The data obtained from the present study demonstrated that crystalline silica inhalation exposure, under the conditions employed in the present study, resulted in significant changes in lung toxicity parameters and lung gene expression profile in the rats at both 1-day and 6-month post-exposure.

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Phosgene exposure in the mouse lung

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