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

Abstract

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 μg/kg 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.