Abstract
Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 117-126 |
| Number of pages | 10 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 208 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 15 2005 |
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Keywords
- Gene array analysis
- NF-κB regulation of gene transcription
- Pentobarbital sleeping time
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Systemic responses to inhaled ozone in mice : Cachexia and down-regulation of liver xenobiotic metabolizing genes. / Last, Jerold A; Gohil, Kishorchandra; Mathrani, Vivek C.; Kenyon, Nicholas.
In: Toxicology and Applied Pharmacology, Vol. 208, No. 2, 15.10.2005, p. 117-126.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Systemic responses to inhaled ozone in mice
T2 - Cachexia and down-regulation of liver xenobiotic metabolizing genes
AU - Last, Jerold A
AU - Gohil, Kishorchandra
AU - Mathrani, Vivek C.
AU - Kenyon, Nicholas
PY - 2005/10/15
Y1 - 2005/10/15
N2 - Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.
AB - Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.
KW - Gene array analysis
KW - NF-κB regulation of gene transcription
KW - Pentobarbital sleeping time
UR - http://www.scopus.com/inward/record.url?scp=25444452139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=25444452139&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2005.02.001
DO - 10.1016/j.taap.2005.02.001
M3 - Article
C2 - 16183385
AN - SCOPUS:25444452139
VL - 208
SP - 117
EP - 126
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 2
ER -