ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn021
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Genistein is an efficient estrogen in the whole body throughout mouse development
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* 3rd Laboratory/Biotechnology (D.D.L., C.M., M.P., M.J.) Civic Hospital of Brescia, 25123 Brescia, Italy
+ Institute of Chemistry, (G.B.) University of Brescia , 25123 Brescia, Italy
± Department of Public Health and Cell Biology, Section of Histology and Embryology University of Rome Tor Vergata, (L.S.G., D.F.M.) Rome, Italy
Centre of Excellence on Neurodegenerative Diseases (P.C., A.M.), University of Milan, 20133 Milan, Italy
¶ Shared senior authorship
Corresponding author: Diego Di Lorenzo, 3rd Laboratory/Biotechnology, Civic Hospital of Brescia, 25123 Brescia, Italy, Tel. 0039 030 399 6805, FAX 0039 030 307 251, e-mail: dilorenzodiego{at}yahoo.it
Received November 15, 2007; revision received December 30, 2007; accepted January 2, 2008
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Abstract |
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The widespread use of diets containing estrogenic compounds raises questions on how relevant the presence of phytoestrogens may be, in order to allow a correct development of the reproductive ability and sexual maturity in humans and animals. The isoflavone genistein is the most estrogenically active molecule present in soy.
Here we show that genistein, through an estrogen receptor-mediated action, modulates gene expression in the whole body of male mice in a dose and time-dependent manner, at all ages.
By luciferase bioassays, we show that genistein-induced ER activation is present in reproductive and non-reproductive organs of the transgenic mice ERE-tK-LUC, although to an extent that is lower than what observed with the administration of estradiol. Peak activity was registered at genistein doses of 500-5000 µg/kg, at 12 hours from the administration by gavage. In the liver, ER
and ERβ mRNAs and two target genes, CYP17 and the progesterone receptor (PR), were modulated by genistein. CYP17 and PR time-dependent induction was similar to that of luciferase. ER protein level followed an opposite regulation by genistein and estradiol. Genistein passed from the lactating mother to the suckling offspring at levels sufficient to activate gene expression in reproductive and non-reproductive tissues of the pups, with maximal upregulation at 16-24 hours. We also followed responsiveness to genistein in the testis, from early development to adult age. Testis are well responsive to genistein as well as to estradiol already at day 14.5 of foetal development, as determined by exposing organotypic cultures from mouse fetus testis. Ovaries were not responsive under the same conditions. Activation of luciferase correlates with an activation of cell proliferation in testis, but not in the ovaries. Prolonged exposure (15 days) to genistein also decreases prostate weight like estradiol. In conclusion, our results show that genistein affects reproductive and non reproductive organs of male mice in a dose and time dependent manner, at all developmental ages.
Key Words: phytoestrogens; estrogen receptors; estrogen responsive elements; reporter mice; reproduction.