Boutros Paul C, Yan Rui, Moffat Ivy D, Pohjanvirta Raimo, Okey Allan B
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
BMC Genomics. 2008 Sep 16;9:419. doi: 10.1186/1471-2164-9-419.
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).
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.
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.
小鼠和大鼠模型是药理学、毒理学及药物研发的主要支柱——但品系间和物种间的差异使数据解读及应用于人类健康变得复杂。二噁英类多卤代芳烃是一类对环境和经济有重要影响的主要毒物。在哺乳动物中，二噁英暴露会导致广泛的不良反应，包括不同程度的肝毒性。多项研究表明，二噁英会广泛改变肝脏mRNA水平。然而，令人惊讶的是，对转录组有限部分的分析显示，大鼠和小鼠的反应差异很大（Boverhof等人，《毒理学科学》94:398 - 416，2006年）。
我们使用寡核苷酸阵列比较了8125个大鼠和小鼠直系同源基因的反应。我们证实二噁英反应基因的种间重叠有限。大鼠特异性和小鼠特异性基因在物种间不同的特定功能组中富集，这可能解释了肝脏组织病理学中的物种特异性。虽然未发现拷贝数变异参与的证据，但在转录调控网络中发现了广泛的种间变异；Nr2f1和Fos分别成为解释物种特异性和非物种特异性反应的候选基因。
我们的结果表明，一小部分核心基因负责介导大鼠和小鼠中二噁英肝毒性的相似特征，但同时非重叠途径也在起作用，导致不同的组织病理学结果。小鼠和大鼠转录组反应的极端差异似乎反映了不同的转录调控网络。综上所述，这些数据表明大鼠和小鼠模型都应用于筛选药物和有毒化合物的急性肝毒性作用。
