Induction of cell proliferation, micronuclei and hyperdiploidy/polyploidy in the mammary cells of DDT- and DMBA-treated pubertal rats

• Published in: Environmental and molecular mutagenesis 2005-07, Vol.46 (1), p.43-52
• Main Authors: Uppala, Padma T., Roy, Shambhu K., Tousson, Albert, Barnes, Stephen, Uppala, Gurunatha R., Eastmond, David A.
• Format: Article
• Language: English
• Subjects: 12-dimethylbenz[a]anthracene; 7,12‐dimethylbenz[a]anthracene; 9,10-Dimethyl-1,2-benzanthracene - toxicity; Animals; Biological and medical sciences; cancer; Carcinogens - toxicity; cell proliferation; Cell Proliferation - drug effects; DDT - toxicity; dichlorodiphenyltrichloroethane; Drug Synergism; Female; fluorescence in situ hybridization; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genistein - toxicity; hyperdiploidy; In Situ Hybridization, Fluorescence; mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - growth & development; Medical sciences; Micronuclei, Chromosome-Defective - chemically induced; Micronucleus Tests; Polyploidy; Rats; Rats, Sprague-Dawley; Toxicology
• ISSN: 0893-6692; 1098-2280
• DOI: 10.1002/em.20131

The environmental estrogen, dichlorodiphenyltrichloroethane (DDT), and its metabolites have been implicated in the development of breast cancer through mechanisms that remain to be elucidated. It has been hypothesized that exposure to DDT and its metabolites, during critical periods of development, can contribute to an elevated risk for breast cancer in adults. In the present study, we have investigated the effect of o,p′‐DDT on mammary gland cell proliferation and chromosomal alterations, in a rat mammary cancer model (commonly used to study human cancer), to gain insights into its potential role in the development of breast cancer. Twenty‐one‐day‐old female Sprague‐Dawley (SD) rats were administered o,p′‐DDT, 7,12‐dimethylbenz[a]anthracene (DMBA), genistein, DDT+DMBA, or DDT+DMBA+genistein, over a 14‐day period. To determine changes in chromosome number and structure, we used the micronucleus assay as well as multicolor fluorescence in situ hybridization (FISH) region‐specific DNA probes for rat chromosomes 4 and 19. Cell proliferation was evaluated using 5‐bromo‐2′‐deoxyuridine (BrdU). Significant increases in BrdU‐incorporated cells were seen in the rats treated with DDT+DMBA. Although micronucleus frequencies were somewhat elevated in several of the treatment groups, significant increases were not seen in any of them. Significant increases in numerical chromosomal aberrations were detected in all of the DDT‐ and DMBA‐treated groups. Genistein significantly reduced BrdU incorporation and polyploidy in the DDT+DMBA‐treated rats. These initial studies indicate that DDT and DMBA can induce cellular and chromosomal alterations in the rat mammary gland, which is consistent with the hypothesis that these agents can induce early events in mammary carcinogenesis. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.