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Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced gene expression profile in vivo using pathway-specific cDNA
Ahmet Zeytun1, Robert J McKallip, Michael Fisher
1Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23113, USA.
Abstract:
In the current study, we used pathway-specific cDNA arrays to detect the transcriptional signature induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo by studying simultaneously the expression profiles of 83 genes involved in apoptosis, cytokine production and angiogenesis. To this end, C57BL/6 mice were injected i.p. with 50 microg/kg body weight of TCDD and 1 or 3 days later, the thymus was analyzed for gene expression profiles. In the thymus, 23 out of 37 apoptotic genes screened were up-regulated by TCDD by a factor of two or more when compared to the vehicle-treated controls. In contrast, in the spleen, 20 out of 22 and in the liver, 16 out of 37 apoptotic genes were up-regulated. In the thymus, several genes encoding caspases, and members of the TNF family, including Fas ligand, were induced. Also, in the thymus, eight out of 23, and in the spleen, six out of 23 cytokine genes were up-regulated. In the liver and to a lesser extent in the thymus, certain angiogenesis genes were induced while others were repressed. When mice were injected with 0.1, 1, 10 or 50 microg/kg body weight of TCDD and the thymus was analyzed for apoptotic genes 1 day later, a dose-dependent response was not seen with most apoptotic genes. However, certain apoptotic genes were induced in the thymus even at low doses of 0.1 microg/kg body weight of TCDD. These data demonstrate that TCDD alters the expression of a large array of genes involved in apoptosis, cytokine production and angiogenesis. Thus, pathway-specific cDNA arrays may help in the identification of specific gene expression profiles induced by xenobiotics and to delineate the molecular mechanisms of toxicity.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly alters gene expression in mouse thymus, spleen, and liver, impacting apoptosis, cytokine production, and angiogenesis pathways. This xenobiotic exposure reveals complex molecular responses.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant.
- Understanding TCDD's molecular mechanisms of toxicity is crucial for risk assessment.
- Gene expression profiling offers insights into cellular responses to xenobiotics.
Purpose of the Study:
- To investigate the transcriptional signature induced by TCDD in vivo.
- To simultaneously analyze gene expression profiles of 83 genes involved in apoptosis, cytokine production, and angiogenesis.
- To delineate the molecular mechanisms of TCDD toxicity.
Main Methods:
- Pathway-specific cDNA arrays were employed to profile gene expression.
- C57BL/6 mice were injected with TCDD (50 microg/kg body weight).
- Thymus, spleen, and liver tissues were analyzed 1 and 3 days post-injection.
Main Results:
- TCDD significantly up-regulated apoptotic genes in the thymus (23/37), spleen (20/22), and liver (16/37).
- Key genes involved in apoptosis (caspases, Fas ligand) and cytokine production were induced.
- Angiogenesis genes showed mixed regulation (induction and repression) in the liver and thymus.
Conclusions:
- TCDD profoundly alters gene expression profiles related to apoptosis, cytokine production, and angiogenesis.
- Pathway-specific cDNA arrays are effective tools for identifying xenobiotic-induced gene expression patterns.
- These findings contribute to understanding the molecular basis of TCDD toxicity.