Comparison of 7,12-dimethylbenz[a]anthracene metabolism and DNA binding in mammary epithelial cells from three rat strains with differing susceptibilities to mammary carcinogenesis

Abstract

The capacity of polycyclic aromatic hydrocarbons such as 7,12-dimethylbenz[a]anthracene (DMBA) to induce mammary carcinomas has been studied in three rat strains. Wistar/Furth (WF) rats are highly susceptible to DMBA-induced mammary carcinogenesis, Copenhagen (Cop) rats are completely resistant, and Fischer 344 (F344) rats have an intermediate susceptibility. We have previously shown that WF rats possess 'enhancer genes', which enhance susceptibility to induced mammary cancer. Cop rats, however, possess a single 'suppressor' gene which confers complete resistance to mammary cancer. Both gene types are apparently absent in F344 rats. In order to determine possible mechanisms of action of these enhancer and suppressor genes, we have examined DMBA metabolism and DNA binding in mammary epithelial cells isolated from each rat strain. Quantitative analyses of both metabolism and DNA binding indicate no significant differences among the strains. In addition, HPLC analyses of DMBA metabolites and DMBA-DNA adducts were essentially identical. These data suggest that the genes controlling susceptibility and resistance to mammary carcinogenesis in these rat strains are likely to be active at later stages of the carcinogenic process.

An evaluation of evidence for the carcinogenic activity of bisphenol A

“…Of note, the F1 hybrid mice that were utilized involved the C57BL/6 genetic background, which has been shown to be resistant to transgene-induced mammary carcinogenesis [7;8] and the promotion of chemically-induced skin tumors [9]. In contrast, the Fischer rats that were used in this study have varying susceptibility to diverse tumors that is dependent upon both the inducing agent and tumor site [10][11][12][13]. Given the variations in tumor susceptibility observed among different strains of rodents, use of multiple strains of mice and rats may be more reflective of the genetic variability observed in humans.…”

Comparison of the types of mutations induced by 7,12-dimethylbenz[a]anthracene in thelacI andhprt genes of Big Blue® rats

“…DMBA 1994]. The potential usefulness of these systems is sug-is a potent mammary gland carcinogen in the rat when gested by results with the rat model that demonstrate administered in a single gavage [Huggins et al, 1961; increased mutant frequencies in the livers of animals Isaacs, 1985;Moore et al, 1988]. We previously used treated with tamoxifen [Davies et al, 1996 and this DMBA treatment regimen to induce 6-thioguanineaflatoxin B 1 [Dycaico et al, 1996], and in splenic lympho-resistant (TG r ) lymphocyte mutants in Sprague-Dawley cytes from rats treated with 7,12-dimethylbenz [a]anthra-rats and found that the profile of hprt mutations was concene (DMBA) [Manjanatha et al, 1997].…”

Mammary cancer resistance and precocious mammary differentiation in the WKY rat: Identification of 2 quantitative trait loci

“…[14][15][16][17][18] The resistance or susceptibility phenotype is tissue specific and cell autonomous, at least in the contrasting strains COP and WF 19 and is not due to differences in carcinogen metabolism. 20 The susceptibility of the rat mammary gland to chemically induced tumours is highest when the inducing carcinogen agent is administered to young virgin females (45 to 60 day-old), when the mammary epithelium proliferation is characterized by a high proliferation rate. 6 The mammary glands contain a multitude of lactiferous ducts composed of 2 main cell types forming the epithelial and myoepithelial layers.…”