17 Beta-estradiol and not genistein modulates lacI mutant frequency and types of mutation induced in the heart of ovariectomized big blue rats treated with 7, 12-dimethylbenz[a]anthracene.
In industrialized countries, heart disease rates are higher among women after menopause. Recent studies indicate that consumption of phytoestorogens, e.g., isoflavones such as genistein (GE), may have potential cardiovascular health benefits; however, no studies have evaluated the effect of these agents on toxicant-induced damage in the heart. Since estrogen receptors are found in the heart, and GE mimics estrogenic effects, we have examined whether or not dietary GE or 17 beta-estradiol (E2) modulates the lacI mutant frequency (MF) in the heart of ovariectomized (OVX) Big Blue rats exposed to the model carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Groups of female rats were administered 80 mg/kg DMBA or vehicle by gavage and were chronically fed with diets containing 0, 250, or 1,000 microg/g GE or 5 microg/g E2. Sixteen weeks after carcinogen treatment, the animals were sacrificed and the hearts were removed and processed for determining the frequency and types of mutations in the heart tissue. GE and E2 supplementation alone resulted in nonsignificant increases in MF. The DMBA-induced lacI MF in the heart was sevenfold higher than the control (119.8 +/- 18.7 x 10(-6) vs. 17.4 +/- 3.2 x 10(-6); P < 0.001). GE in the diet had no significant effect on DMBA mutagenicity, while feeding E2 to DMBA-treated rats caused a significant reduction in the MF (119.8+/- 18.7 x 10(-6) vs. 61.4 +/- 13.5 x 10(-6); P < 0.017). DNA sequence analysis revealed that the majority of DMBA-induced mutations in rats fed control diet were A:T-->T:A (42%) and G:C-->T:A (19%) transversions, followed by G:C-->A:T (13%) and A:T-->G:C (8%) transitions. Feeding E2 altered the DMBA-induced mutational spectra by decreasing A:T-->T:A (23%) and G:C-->T:A (13%) transversions and increasing G:C-->A:T (24%) and A:T-->G:C (21%) transitions. Taken together, the results suggest that DMBA can induce gene mutations in heart tissue of OVX rats, and while dietary GE had little or no effect on DMBA-induced mutation, dietary E2 reduced the mutagenicity of DMBA.
Manjanatha
Mugimane G
MG
Division of Genetic and Reproductive Toxicology, Food and Drug Administration/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. mmanjanatha@nctr.fda.gov
Shelton
Sharon D
SD
Rhodes
Bobbie S
BS
Bishop
Michelle E
ME
Lyn-Cook
Lascelles E
LE
Aidoo
Aname
A
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D007763:Lac Operon; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010052:Ovariectomy; D051381:Rats
D009153:Mutagens; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D019833:Genistein