Transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver: comparison of rat and mouse.
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.


CONCLUSIONS
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.
Boutros
Paul C
PC
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. Paul.Boutros@utoronto.ca
Yan
Rui
R
Moffat
Ivy D
ID
Pohjanvirta
Raimo
R
Okey
Allan B
AB
D000818:Animals; D051838:COUP Transcription Factor I / Q000378:metabolism; D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D016762:Genes, fos; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D013045:Species Specificity
D051838:COUP Transcription Factor I; D000072317:Polychlorinated Dibenzodioxins
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