Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets
Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets
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DOI：
10.2131/jts.41.281
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发表时间：
2016-04-01
影响因子：
2
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
--
作者：
Kanki, Masayuki;Gi, Min;Wanibuchi, Hideki
几项研究已成功地检测到大鼠肝癌的基因表达数据的基础上。然而，预测肝癌与某些作用机制（MOAs），如酶诱导剂和过氧化物酶体增殖物激活受体α（PPAR α）激动剂，可以证明是困难的，使用一个单一的模型，需要一个高毒性的剂量。在这里，我们建立了一个模型，用于检测非遗传毒性（NGTX）肝癌的物质，并预测其MOA在大鼠。保存在开放毒理基因组学项目-基因组学辅助毒性评价系统（TG-GATEs）中的基因表达数据用于研究基因标记集。采用主成分分析（PCA）对不同MOA进行判别，并采用支持向量机算法构建预测模型。该方法确定了106个探针集作为PCA的基因标记集，并能够构建预测模型。在PCA中，NGTX肝癌物质根据其MOA分类如下：细胞毒性物质、PPARa激动剂或酶诱导剂。在14天和28天重复给药研究中，预测模型检测到肝癌的准确性超过90%。此外，能够预测NGTX肝致癌性的剂量接近大鼠致癌性试验所需的剂量。总之，我们的PCA和预测模型，使用基因标记集将有助于评估人类肝癌的风险的基础上MOA和减少两年啮齿动物生物测定的数量。
Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets. Principal component analysis (PCA) was applied to discriminate different MOAs, and a support vector machine algorithm was applied to construct the prediction model. This approach identified 106 probe sets as gene marker sets for PCA and enabled the prediction model to be constructed. In PCA, NGTX hepatocarcinogens were classified as follows based on their MOAs: cytotoxicants, PPARa agonists, or enzyme inducers. The prediction model detected hepatocarcinogenicity with an accuracy of more than 90% in 14- and 28-day repeated-dose studies. In addition, the doses capable of predicting NGTX hepatocarcinogenicity were close to those required in rat carcinogenicity assays. In conclusion, our PCA and prediction model using gene marker sets will help assess the risk of hepatocarcinogenicity in humans based on MOAs and reduce the number of two-year rodent bioassays.