Gene expression profiling to recognize specific features of (non-) genotoxic carcinogens

The current test strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Non-genotoxic carcinogens (NGTXC) are negative for genotoxicity and go undetected. Therefore, alternative tests to detect these chemicals are urgently needed. NGTXC act through different modes of action, which complicates the development of such assays. We have demon­strated recently in primary mouse hepatocytes that some, but certainly not all, NGTXC can be categorized according to their mode of action based on feature detection at a gene expression level (Schaap et al. 2012, PMID22710402). Identification of a wider range of chemicals probably requires multiple in vitro systems. In the current study we describe the added value of using mouse embryonic stem cells. In this study the focus is on NGTXC, but we also included genotoxic carcinogens and non-carcinogens. This approach enables us to assess the robustness of this method and to evaluate the system for recognizing features of chemicals in general, which is important for application in future risk assessment. This serie consists of the gene expression data of the mouse embryonic stem cells. The expression data of the primary mouse hepatocytes cells is submitted separately under accession number GSE44088. Primary mouse hepatocytes and mouse embryonic stem cells were exposed to 26 chemicals ((non-) genotoxic carcinogens and non-carcinogens) representing diverse modes of action. Upon profiling, an unsupervised comparison approach was applied to recognize similar features at the transcriptomic level.

当前致癌性检测策略通常基于体外（in vitro）与体内（in vivo）遗传毒性试验。非遗传毒性致癌物（Non-genotoxic Carcinogens, NGTXC）在遗传毒性检测中呈阴性，因此无法被现有策略检出。故而，亟需开发可检测此类化学物的替代检测方法。非遗传毒性致癌物通过多种不同的作用模式发挥毒性，这使得此类检测方法的开发更为复杂。我们近期在原代小鼠肝细胞（primary mouse hepatocytes）中证实，部分（但并非全部）非遗传毒性致癌物可基于基因表达水平的特征检测结果，按照其作用模式进行分类（Schaap等，2012年，PMID22710402）。若要识别更广谱的化学物，可能需要采用多种体外检测系统。在本研究中，我们阐述了采用小鼠胚胎干细胞（mouse embryonic stem cells）的附加应用价值。本研究以非遗传毒性致癌物为核心研究对象，但同时纳入了遗传毒性致癌物与非致癌物。该研究方案可帮助我们评估该方法的稳健性，并从整体上评价该系统识别化学物特征的能力，这对于未来风险评估的应用具有重要意义。本数据集包含小鼠胚胎干细胞的基因表达数据。原代小鼠肝细胞的基因表达数据已以登录号GSE44088单独提交。本研究将原代小鼠肝细胞与小鼠胚胎干细胞暴露于26种代表不同作用模式的化学物，涵盖（非）遗传毒性致癌物与非致癌物。完成基因表达谱分析后，采用无监督比较方法以识别转录组水平上的相似特征。