Abstract：
The development of a rapid and accurate model for determining the genotoxicity and carcinogenicity of chemicals is crucial for effective cancer risk assessment. This study aims to develop a 1-day, single-dose model for identifying genotoxic hepatocarcinogens (GHCs) in rats. Microarray gene expression data from the livers of rats administered a single dose of 58 compounds, including 5 GHCs, was obtained from the Open TG-GATEs database and used for the identification of marker genes and the construction of a predictive classifier to identify GHCs in rats. We identified 10 gene markers commonly responsive to all 5 GHCs and used them to construct a support vector machine-based predictive classifier. In the silico validation using the expression data of the Open TG-GATEs database indicates that this classifier distinguishes GHCs from other compounds with high accuracy. To further assess the model\'s effectiveness and reliability, we conducted multi-institutional 1-day single oral administration studies on rats. These studies examined 64 compounds, including 23 GHCs, with gene expression data of the marker genes obtained via quantitative PCR 24 h after a single oral administration. Our results demonstrate that qPCR analysis is an effective alternative to microarray analysis. The GHC predictive model showed high accuracy and reliability, achieving a sensitivity of 91% (21/23) and a specificity of 93% (38/41) across multiple validation studies in three institutions. In conclusion, the present 1-day single oral administration model proves to be a reliable and highly sensitive tool for identifying GHCs and is anticipated to be a valuable tool in identifying and screening potential GHCs.
摘要：
开发快速准确的模型来确定化学物质的遗传毒性和致癌性对于有效的癌症风险评估至关重要。这项研究旨在开发一个为期1天的，用于鉴定大鼠基因毒性肝癌（GHCs）的单剂量模型。微阵列基因表达数据从大鼠的肝脏施用单剂量的58种化合物，包括5个GHCs，从OpenTG-GATEs数据库中获得，并用于标记基因的鉴定和预测分类器的构建以鉴定大鼠中的GHCs。我们确定了10个基因标记通常响应于所有5个GHC，并使用它们来构建基于支持向量机的预测分类器。在使用OpenTG-GATEs数据库的表达数据的计算机验证中,表明该分类器以高准确度将GHC与其他化合物区分开。为了进一步评估模型的有效性和可靠性，我们对大鼠进行了多机构1日单次口服给药研究.这些研究检查了64种化合物，包括23个GHCs，在单次口服给药后24小时通过定量PCR获得标记基因的基因表达数据。我们的结果表明qPCR分析是微阵列分析的有效替代方法。GHC预测模型具有较高的准确性和可靠性,在三个机构的多个验证研究中，灵敏度达到91％（21/23），特异性达到93％（38/41）。总之,目前的1天单次口服给药模型被证明是鉴定GHCs的可靠且高度敏感的工具,并有望成为鉴定和筛查潜在GHCs的有价值的工具.
