Conserved Transcriptional Response of Rodent Liver to TCDD: Rat
ABSTRACT: 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. 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.
INSTRUMENT(S): [RAE230A] Affymetrix Rat Expression 230A Array