Quantitative analysis of liver GST-P foci promoted by a chemical mixture of hexachlorobenzene and PCB 126: implication of size-dependent cellular growth kinetics

• Published in: Archives of toxicology 2008-02, Vol.82 (2), p.103-116
• Main Authors: Lu, Yasong, Lohitnavy, Manupat, Reddy, Micaela, Lohitnavy, Ornrat, Eickman, Elizabeth, Ashley, Amanda, Gerjevic, Lisa, Xu, Yihua, Conolly, Rory B., Yang, Raymond S. H.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Assay; Biomedical and Life Sciences; Biomedicine; Carcinogenicity Tests; Carcinogens - administration & dosage; Carcinogens - toxicity; Cells; Chemicals; Computer Simulation; Dose-Response Relationship, Drug; Environmental Health; Environmental Pollutants - administration & dosage; Environmental Pollutants - toxicity; Genotoxicity and Carcinogenicity; Glutathione S-Transferase pi - drug effects; Glutathione S-Transferase pi - metabolism; Hexachlorobenzene - administration & dosage; Hexachlorobenzene - toxicity; Kinetics; Liver; Liver - drug effects; Liver - pathology; Male; Medical sciences; Models, Biological; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Polychlorinated Biphenyls - administration & dosage; Polychlorinated Biphenyls - toxicity; Rats; Rats, Inbred F344; Studies; Toxicology
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-007-0238-x

The objectives of this study were twofold: (1) evaluating the carcinogenic potential of the mixture of two persistent environmental pollutants, hexachlorobenzene (HCB) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), in an initiation-promotion bioassay involving the development of π glutathione S-transferase (GST-P) liver foci, and (2) analyzing the GST-P foci data using a biologically-based computer model (i.e., clonal growth model) with an emphasis on the effect of focal size on the growth kinetics of initiated cells. The 8-week bioassay involved a series of treatments of initiator, two-thirds partial hepatectomy, and daily oral gavage of the mixture of two doses in male F344 rats. The mixture treatment significantly increased liver GST-P foci development, indicating carcinogenic potential of this mixture. Our clonal growth model was developed to simulate the appearance and development of initiated GST-P cells in the liver over time. In the model, the initiated cells were partitioned into two subpopulations with the same division rate but different death rates. Each subpopulation was further categorized into single cells, mini- (2–11 cells), medium- (12–399 cells), and large-foci (>399 cells) with different growth kinetics. Our modeling suggested that the growth of GST-P foci is size-dependent; in general, the larger the foci, the higher the rate constants of division and death. In addition, the modeling implied that the two doses promoted foci development in different manners even though the experimental foci data appeared to be similar between the two doses. This study further illustrated how clonal growth modeling may facilitate our understanding in chemical carcinogenic process.