ToxSci Advance Access originally published online on February 14, 2008
Toxicological Sciences 2008 103(1):57-67; 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 Civic Hospital of Brescia
Institute of Chemistry, University of Brescia, 25123 Brescia, Italy
Department of Public Health and Cell Biology, Section of Histology and Embryology University of Rome Tor Vergata, Rome, Italy
Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
2 To whom correspondence should be addressed at 3rd Laboratory/Biotechnology, Civic Hospital of Brescia, 25123 Brescia, Italy. Fax: +39-030-307-251. E-mail: dilorenzodiego{at}yahoo.it.
Received November 15, 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 (ER)–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 nonreproductive organs of the transgenic mice Estrogen Responsive Element (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 h from the administration by gavage. In the liver, ER-
and ER-β messenger RNAs and two target genes, CYP17 and the progesterone receptor, 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 nonreproductive tissues of the pups, with maximal upregulation at 16–24 h. 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 fetal 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 nonreproductive 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.
1 Shared senior authorship.