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Catechol estrogens are considered critical intermediates in estrogen-induced carcinogenesis. We demonstrated previously that 17beta-estradiol (E(2)), estrone (E(1)) and four of their catechol estrogens, 2- and 4-hydroxyestradiols (2- and 4-OHE(2)), and 2- and 4-hydroxyestrones (2- and 4-OHE(1)) induce morphological transformation in Syrian hamster embryo (SHE) fibroblasts, and the transforming abilities vary as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) vertical line E(2), E(1). To examine the involvement of catechol estrogens in the initiation of hormonal carcinogenesis, we studied the ability of E(2), E(1) and their catechol estrogens to induce DNA adducts in SHE cells by using a (32)P-post-labeling assay. DNA adducts were detected in cells treated with each of all the catechol estrogens at concentrations of 10 microg/ml for 1 h and more. 2- or 4-OHE(2) formed a single DNA adduct, which was chromatographically distinct from each other. In contrast, 2- or 4-OHE(1) produced one major and one minor adduct, and the two adducts formed by each catechol estrogen exhibited identical mobilities on the chromatograms. Neither E(2) nor E(1) at concentrations up to 30 microg/ml induced DNA adducts. The abilities of the estrogens to induce DNA adducts were ranked as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) > > E(2), E(1), which corresponds well to the transforming and carcinogenic abilities of the estrogens. In addition, the level of DNA adducts induced by the catechol estrogens was markedly decreased by co-treatment of cells with the antioxidant L-ascorbic acid. The results indicate the possible involvement of oxidative metabolites of catechol estrogens of E(2) and E(1) in the initiation of endogenous estrogen-induced carcinogenesis.

For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of phytoestrogens, the abilities of 5 phytoestrogens, daidzein, genistein, biochanin A, prunetin, and coumestrol, to induce cell transformation and genetic effects were examined using the Syrian hamster embryo (SHE) cell model. Cellular growth was inhibited by all phytoestrogens in a concentration-related manner. The growth inhibitory effect of the compounds was ranked: genistein, prunetin > coumestrol > biochanin A > daidzein, which did not correspond to their apoptosis-inducing abilities. Key words: mammalian cells; transformation; phytoestrogensEpidemiological studies and animal or tumor cell studies suggest a protective effect of weak plant estrogens, termed phytoestrogens, against several cancers, including breast and prostate cancers. 1 On the other hand, there have been reports that suggest the carcinogenic effects of phytoestrogens. demonstrated that a maternal exposure of rats to genistein, a phytoestrogen, during pregnancy increases 7,12-dimethylbenz[a]-anthracene-induced mammary tumorigenesis in the offspring. Subcutaneous injection of genistein into rats during the perinatal period increases the multiplicity of N-methyl-N-nitrosourea-induced mammary carcinoma. 3 Genistein ingestion increases aberrant crypt foci that subsequently develop into adenomas and adenocarcinomas in rat distal colon. 4 Dietary genistein enhances azoxymethane-induced colon adenocarcinomas in rats. 5 Uterine adenocarcinomas are induced after neonatal exposure of mice to genistein. 6 There are several reports on genotoxicity tests performed with phytoestrogens. The isoflavone group of phytoestrogens, (daidzein, genistein and biochanin A), and the coumestan group of phytoestrogen, (coumestrol), are not mutagenic to Salmonella typhimurium TA1538, TA98 or TA100 with or without the addition of rat liver microsomal fraction. 7 Genistein and coumestrol induce DNA strand breaks, micronuclei containing acentric fragments and somatic mutations at the hprt locus in Chinese hamster V79 cells. 8 Genistein also induces micronuclei in cultured mouse splenocytes, 9 chromosome aberrations in cultured human lymphocytes 10 and DNA strand breaks in human colon tumor cells. 11 Coumestrol elicits mutations at the Thymidine Kinase locus in human lymphoblastoid cells. 12 Sister chromatid exchanges in bone marrow cells are elicited by intra-peritoneal treatment of mice with daidzein or genistein. 13 These findings indicate carcinogenic and mutagenic potentials of some phytoestrogens in the isoflavone and coumestan groups against mammalian cells. The mechanisms underlying tumor development and genetic damage by these compounds are not known.Genistein and daidzein are the major isoflavones found in soybean foods. 14 Coumestrol is the major representative of the coumestan group of phytoestrogens found in numerous plants including soybeans and alfalfa. 15 Therefore, human may be exposed to high levels of phytoestrogens through the consumption of a diet rich in plants and soyfood ...