Previously, we proposed 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log2 data using the "R Project for Statistical Computing". GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3-24 h and 4-29 days, assessed with Welch's t-test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey's test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs.

中文翻译：

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在大鼠毒理基因组学公共数据中评估12种小鼠标记基因，公开TG-GATEs：区分非遗传毒性肝癌的遗传毒性。

以前，我们提出了12个标记基因（Aen，Bax，Btg2，Ccnf，Ccng1，Cdkn1a，Gdf15，Lrp1，Mbd1，Phlda3，Plk2和Tubb4b）来区分小鼠遗传毒性肝癌致癌物（GTHC）与非遗传毒性肝癌致癌物。这是通过qPCR和主成分分析（PCA）确定的，目的是在体内短期筛选遗传毒性肝致癌物。在本文中，我们对12种小鼠标记基因在大鼠数据Open TG-GATEs（公共数据）中的应用进行了研究。我们分析了五种典型的大鼠GTHC（2-乙酰氨基芴，黄曲霉毒素B1、2-硝基芴，N-亚硝基二乙胺和N-亚硝基吗啉），不仅分析了七种典型的大鼠NGTHC（氯贝特，乙醇，非诺贝特，吉非贝齐，六氯苯，苯巴比妥和WY-14643） ），但还有11种非遗传毒性非肝致癌物（NGTNHC；烯丙醇，阿司匹林，咖啡因，氯苯那敏，氯丙酰胺，地塞米松，地西epa，吲哚美辛，苯丁,、茶碱和甲苯磺丁酰胺）。在单次给药后3、6、9和24小时以及重复给药后4、8、15和29天进行分析。我们使用“统计计算R项目”将Open TG-GATEs DNA微阵列数据转换为log2数据。观察到GTHC特异性剂量依赖性基因表达变化，并用威廉姆斯检验评估其显着性。用Welch's t检验评估了3-24小时和4-29天的相似显着变化，但NGTHC或NGTNHC除外。根据Tukey检验，在11天的基因中，GTHC和NGTHC在11个基因（除Tubb4b除外）之间以及在12天的所有12个基因的GTHC和NGTNHC与在29天的10个基因（Ccnf和Mbd1除外）之间均观察到基因表达的显着差异。PCA在24小时和29天成功将GTHC与NGTHC和NGTNHC区别开来。结果表明，先前提出的12个小鼠标记基因可用于从NGTHC区分大鼠GTHC，从Open TG-GATE区分NGTNHC。