Evaluation of species difference in extrapolation of animal toxicogenomic data to human

2006年，我们获得了暴露于三氯乙烯（TCE）的人肝细胞的转录组。因此，我们对人、小鼠和大鼠的转录组进行了种间比较。根据贝叶斯定理，我们在过滤了标记在每组四个样本中至少三个显示存在或边缘的探针后，提取了显著变化的探针（p<0.01）。通过MAPPFinder或GSEA （Gene Set Enrichment Analysis）等公开软件进行分析。MAPPFinder功能分析显示，仅在5mM TCE处理24小时的小鼠中β -氧化相关基因上调。用GSEA分析了转录组的相似性。发现TCE暴露中下调的基因与大鼠相似。三氯乙酸和三氯乙醇是人体的代谢物。从新陈代谢的角度来看，人类与小鼠相似。三氯乙酸和三氯乙醇被认为是重要的过氧化物酶体增殖，下游的β氧化。考虑到β氧化是致癌的开始，MAPPFinder的功能分析结果很有趣。啮齿类动物对过氧化物酶体增殖剂的敏感性高于人类，在啮齿类动物中，小鼠高于大鼠。小鼠β -氧化相关基因的上调与致癌性试验结果一致，TCE在小鼠中优先引起肝癌。DNA微阵列可在一次实验中研究多种途径，被认为可用于评估化学品对人类健康的风险以及阐明动物的毒理学机制。

In 2006, we obtained the transcriptome of human hepatocytes exposed to trichloroethylene (TCE). Thus, we made inter-species comparison of human, mouse and rat transcriptome. With the Bayes' theorem, we extracted significantly changed probes(p<0.01) after filtering probes whose flag showed present or marginal in at least three out of four samples in each group. Analysis was conducted by the publicly available software such as MAPPFinder or GSEA (Gene Set Enrichment Analysis). The functional analysis by MAPPFinder revealed up-regulation of beta oxidation related genes only in mice treated 5mM TCE for 24 hours. The analogy of transcriptome was studied by GSEA. Down-regulated genes in TCE exposure were found to be similar to those of rats. Trichloroacetic acid and trichloroethanol are metabolites in human. Human is similar to mice in the view point of metabolism. Trichloroacetic acid and trichloroethanol are thought to be important for peroxisome proliferation, of which downstream beta oxidation lies. Given that beta oxidation is the beginning of carcinogenesis, the result of the functional analysis by MAPPFinder is interesting. Rodents are higher than humans in the sensitivity to peroxisome proliferators, and mice are higher than rats among rodents. Up-regulation of beta oxidation related genes in mice is in accordance with the results of carcinogenicity test, where TCE causes liver cancer preferentially in mice. DNA microarray, which is feasible to study numerous pathways in one experiment, was thought to be useful to evaluate human health risk of chemicals along with elucidation of toxicological mechanism by animals.