Effects of daidzein, genistein, and 17beta-estradiol on 7,12-dimethylbenz[a]anthracene-induced mutagenicity and uterine dysplasia in ovariectomized rats

Phytoestrogens, primarily isoflavones daidzein (DZ) and genistein (GE), are increasingly used by postmenopausal women as an alternative to hormone replacement therapy due to reports that estrogen therapy increases the risk of breast and endometrial cancers. These compounds, as estrogen receptor agonists, may influence chemical carcinogenesis in estrogen-responsive tissues such as the uterus. We utilized ovariectomized (OVX) rats to model menopause and assessed the effects of dietary DZ, GE, or 17beta-estradiol (E2) on carcinogen-induced mutagenesis and carcinogenesis in the rat uterus. Big Blue transgenic rats (derived from Fischer 344 strain) were exposed to 7,12-dimethylbenz[a]anthracene (DMBA) in the presence or absence of the supplements. At 16- or 20-wk sacrifice, the uteri were removed and processed to determine mutant frequencies (MFs) and immunohistochemical or histopathological parameters, respectively. In rats treated with DMBA alone, a significant increase in lacI MFs (P < 0.01) in both OVX and intact (INT) rats was observed. The DMBA-induced MFs were not significantly altered by dietary DZ, GE, or E2 in both OVX and INT rats. Although dysplasia was not induced in the uterus of OVX and INT rats treated with DMBA alone, it was detected in 55% of OVX rats fed E2 alone and in 100% of OVX rats fed E2 along with DMBA exposure. Cell proliferation also was significantly higher in OVX rats fed E2 and treated with DMBA. In rats fed the isoflavones and treated with DMBA, the incidence of dysplasia was either reduced or virtually absent in both OVX and INT groups. These results indicate that a high incidence of dysplasia was associated with E2 feeding with or without DMBA treatment in the OVX rats, whereas the incidence was low in rats fed DZ or GE and treated with DMBA, suggesting a weak estrogen receptor agonist of DZ or GE in the rat uterus. The absence of dysplasia in OVX rats exposed to DMBA alone also suggests, in part, a promotional mechanism via estrogen- or isoflavone-driven cell proliferation.