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| Status |
Public on Sep 19, 2008 |
| Title |
Conserved Transcriptional Response of Rodent Liver to TCDD: Rat |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
|
| Summary |
Background
Mouse and rat models are mainstays in pharmacology, toxicology and drug development – but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398–416, 2006).
Results
We employed oligonucleotide arrays to compare the response of 8,125 rat and mouse orthologs. We confirmed that there is limited inter-species overlap in dioxin-responsive genes. Rat-specific and mouse-specific genes are enriched for specific functional groups which differ between species, conceivably accounting for species-specificities in liver histopathology. While no evidence for the involvement of copy-number variation was found, extensive inter-species variation in the transcriptional-regulatory network was identified; Nr2f1 and Fos emerged as candidates to explain species-specific and species-independent responses, respectively.
Conclusion
Our results suggest that a small core of genes is responsible for mediating the similar features of dioxin hepatotoxicity in rats and mice but non-overlapping pathways are simultaneously at play to result in distinctive histopathological outcomes. The extreme divergence between mouse and rat transcriptomic responses appears to reflect divergent transcriptional-regulatory networks. Taken together, these data suggest that both rat and mouse models should be used to screen the acute hepatotoxic effects of drugs and toxic compounds.
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| Overall design |
Wild-type Long-Evans(Kuopio) rats were treated with 100 ug/kg TCDD (n=4) or with cornoil vehicle as control (n=4) for 19 hours. Their livers were then excised, RNA extracted, and the resulting samples hybridized to Affymetrix RAE230A arrays to survey changes in the transcriptome profile.
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| Contributor(s) |
Boutros PC, Pohjanvirta R, Okey AB |
| Citation(s) |
18796159 |
| Submission date |
Mar 09, 2008 |
| Last update date |
Mar 03, 2017 |
| Contact name |
Paul C Boutros |
| E-mail(s) |
Paul.Boutros@utoronto.ca
|
| Organization name |
Ontario Institute for Cancer Research
|
| Street address |
101 College Street, Suite 800
|
| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G 0A3 |
| Country |
Canada |
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| Platforms (1) |
| GPL341 |
[RAE230A] Affymetrix Rat Expression 230A Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA107443 |
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