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.
The major constituents of isoflavones daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary tissues. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E(2)) 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 E(2) and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E(2) supplementation alone resulted in the lac I 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 lac I MFs in the mammary tissues of both OVX and INT rats and Hprt MFs in spleen lymphocytes (P < 0.01). In general, feeding the isoflavones or E(2) did not cause any significant changes in DMBA-induced mutagenicity in the mammary tissues. However, feeding the isoflavone mixture (daidzein + genistein; DZG) resulted in a significant reduction in the DMBA-induced lac I 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.
Manjanatha
Mugimane
M
U.S. FDA National Center for Toxicological Research, Genetic Toxicology, Rockville, MD 20857, USA. mmanjanatha@nctr.fda.gov
Shelton
Sharon
S
Bishop
Michelle
M
Lyn-Cook
Lascelles
L
Aidoo
Anane
A
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight; D004032:Diet; D005260:Female; D019833:Genistein / Q000008:administration & dosage*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007529:Isoflavones / Q000008:administration & dosage*; D007763:Lac Operon; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control; D009154:Mutation; D009929:Organ Size; D010052:Ovariectomy; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011913:Rats, Inbred BB
D007529:Isoflavones; D018809:Proliferating Cell Nuclear Antigen; D015127:9,10-Dimethyl-1,2-benzanthracene; C004742:daidzein; D019833:Genistein; D007041:Hypoxanthine Phosphoribosyltransferase