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Carcinogenesis Advance Access published online on May 18, 2006
Carcinogenesis, doi:10.1093/carcin/bgl028
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Published by Oxford University Press 2006
Received January 10, 2006
Revised May 9, 2006
Accepted May 9, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue transgenic rats

Mugimane Manjanatha 1 *, Sharon Shelton 1, Michelle Bishop 1, Lascelles Lyn-Cook 1, and Anane Aidoo 1

1 U.S. FDA National Center for Toxicological Research, Genetic Toxicology

* To whom correspondence should be addressed.
Mugimane Manjanatha, E-mail: mmanjanatha{at}nctr.fda.gov; mugimane@yahoo.com


  Abstract

The major constituents of isoflavones, daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE, or 17-estradiol (E2) exposures on chemically-induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue transgenic rats. The rats were fed control diet containing the isoflavones and E2 and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND 50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E2 supplementation alone resulted in the lacI MFs that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lacI MFs in the mammary of both OVX and INT rats and Hprt MFs in spleen lymphocytes (p 0.01). In general, feeding the isoflavones or E2 did not cause any significant changes in DMBA-induced mutagenicity in the mammary. However, feeding the isoflavone mixture (DZG) resulted in a significant reduction in the DMBA-induced lacI MFs (p 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (p 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.

Keywords: DZ; intact; INT; ovariectomized; OVX.
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