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首页> 外文期刊>The Journal of toxicological sciences >Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats
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Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats

机译：在大鼠的两阶段肝癌发生研究中检测非遗传毒性致癌物的起始潜力

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摘要

We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or non-genotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a two-stage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg. MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with non-genotoxic TAA might have initiating potential in the liver.
机译：我们先前报道了基于肝癌的基于毒理基因组学的预测模型，其中重复剂量的遗传毒性或非遗传毒性化合物后的特征基因的表达模式相似。根据我们的预测模型的结果，我们假设重复剂量的非遗传毒性致癌物可能具有启动潜力。在这里，我们对暴露于引发剂亚硝基二乙胺（DEN）和肝毒性化合物硫代乙酰胺（TAA），甲萘丙啶（MP）和对乙酰氨基酚（APAP）的大鼠进行了为期两阶段的肝癌发生研究，然后进行了肝肿瘤启动子的研究苯巴比妥（PB）。初始治疗的持续时间是根据我们的预测模型得出的阳性结果确定的。联合治疗3或30 mg / kg的遗传毒性DEN和PB引起的肝细胞灶改变明显增加，并且谷胱甘肽S-转移酶-胎盘形式（GST-P）阳性灶的数目和面积随DEN剂量依赖性增加。在剂量为45 mg / kg的TAA处理的大鼠中也观察到少量肝细胞灶改变。剂量为100 mg / kg的MP诱发的病灶数量非常少，但APAP却没有。使用基因表达数据进行的层次聚类分析显示，TAA剂量为30 mg / kg的治疗2周和MP剂量为45 mg / kg的治疗2周诱导了DNA损伤相关基因的特异性表达，类似于DEN的1周治疗。剂量为30 mg / kg。这些结果表明，TAA和MP诱导DNA损伤，部分支持了我们的假设。尽管这项研究并未表明是否可以在该模型中评估对这些化合物的反应，但我们的研究结果表明，非遗传毒性TAA的累积治疗可能在肝脏中具有启动潜力。

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