title: Endogenous estrogen status, but not genistein supplementation, modulates 7,12-dimethylbenz[a]anthracene-induced mutation in the liver cII gene of transgenic big blue rats.
abstract: A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may safely alleviate the symptoms of menopause. One of these isoflavones, genistein, is commonly used by postmenopausal women as an alternative to hormone replacement therapy. Although sex hormones have been implicated as an important risk factor for the development of hepatocellular carcinoma, there are limited data on the potential effects of the estrogens, including phytoestrogens, on chemical mutagenesis in liver. Because of the association between mutation induction and the carcinogenesis process, we investigated whether endogenous estrogen and supplemental genistein affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in rat liver. Intact and ovariectomized female Big Blue rats were treated with 80 mg DMBA/kg body weight. Some of the rats also received a supplement of 1,000 ppm genistein. Sixteen weeks after the carcinogen treatment, the rats were sacrificed, their livers were removed, and mutant frequencies (MFs) and types of mutations were determined in the liver cII gene. DMBA significantly increased the MFs in liver for both the intact and ovariectomized rats. While there was no significant difference in MF between the ovariectomized and intact control animals, the mutation induction by DMBA in the ovariectomized groups was significantly higher than that in the intact groups. Dietary genistein did not alter these responses. Molecular analysis of the mutants showed that DMBA induced chemical-specific types of mutations in the liver cII gene. These results suggest that endogenous ovarian hormones have an inhibitory effect on liver mutagenesis by DMBA, whereas dietary genistein does not modulate spontaneous or DMBA-induced mutagenesis in either intact or ovariectomized rats.
authors.affiliation: Division of Genetic and Reproductive Toxicology, Food and Drug Administration/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. tchen@nctr.fda.gov
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hutts
authors.forename: Nan
authors.initials: N
authors.lastname: Mei
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bishop
authors.forename: Sharon
authors.initials: S
authors.lastname: Shelton
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: Anane
authors.initials: A
authors.lastname: Aidoo
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D009154:Mutation / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D011913:Rats, Inbred BB; D017422:Sequence Analysis, DNA
chemical_list: D000596:Amino Acids; D001551:Benz(a)Anthracenes; D017931:DNA Primers; D004967:Estrogens; C046810:7,12-dihydroxymethylbenz(a)anthracene; D019833:Genistein