Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver:: A quantitative analysis of experimental data using a stochastic model
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver:: A quantitative analysis of experimental data using a stochastic model
复制标题
DOI：
10.1006/taap.2000.8980
复制
发表时间：
2000-08-15
影响因子：
3.8
通讯作者：
Schwarz, M
中科院分区：
文献类型：
--
作者：
Luebeck, EG;Buchmann, A;Schwarz, M
我们使用一个随机模型描述的启动和克隆生长的改变细胞分析数据，从启动-促进肝癌发生实验在雌性Wistar大鼠。从7周龄开始，用起始剂二乙基亚硝胺（DEN，10 mg/kg体重/天）处理动物10天。在10周的休息期后，动物通过每两周一次皮下注射1.4 μ g/g体重的溶解在玉米油中的TCDD，用玉米油或2，3，7，8-四氯二苯并-对-二恶英（TCDD）进行治疗。在TCDD/玉米油治疗开始后3、17、31、73和115天，每组4或5只动物被安乐死。分析的数据包括不同时间点GST-P阳性局灶性横断的数量和大小。通过拟合模型的数据，我们估计了在实验的不同时间段的起始，细胞分裂和细胞死亡的速率，细胞动力学参数的模型估计与直接进行的细胞分裂和细胞死亡的实验观察是一致的。该模型预测，DEN诱导的GST-P阳性细胞的启动在对照组和TCDD治疗的动物中都是高度延长的。我们还发现，TCDD干扰细胞（DEN造成的）DNA损伤转化为表达GST-P阳性表型的细胞的正常速率，这表明TCDD介导的“加速”从头GST-P阳性启动细胞从受损的前体细胞的外观。此外，该模型预测在TCDD治疗的前4至5周内，以及TCDD治疗10周后，凋亡率显著降低，但在这之间没有。(C)北京大学出版社.
We use a stochastic model describing initiation and clonal growth of altered cells to analyze data from an initiation-promotion hepatocarcinogenesis experiment in female Wistar rats. Starting at 7 weeks of age, the animals were treated for 10 days with the initiating agent diethylnitrosamine (DEN, 10 mg/kg body wt per day). After a 10-week resting period, the animals were treated either with corn oil or with 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) via biweekly sc injections of 1.4 mu g/g body wt of TCDD dissolved in corn oil. Groups of four or five animals were euthanized 3, 17, 31, 73, and 115 days after start of TCDD/corn oil treatment. The data analyzed consist of the number and sizes of GST-P-positive focal transections at various time points. By fitting the model to the data, we estimate the rates of initiation, cell division, and cell death during different time periods of the experiment,The model estimates of cell kinetic parameters are consistent with directly made experimental observations of cell division and cell death. The model predicts that DEN-induced initiation of GST-P-positive cells is highly protracted in controls and TCDD-treated animals alike. We also find that TCDD interferes with the normal rate at which cells with (DEN-inflicted) DNA damage are converted into cells expressing the GST-P-positive phenotype, suggesting a TCDD-mediated "acceleration" of the appearance of de novo GST-P-positive initiated cells from damaged precursor cells. Furthermore, the model predicts a significant reduction in the rate of apoptosis within the first 4 to 5 weeks of TCDD treatment, and after 10 weeks of TCDD treatment, but not in between. (C) 2000 Academic Press.