Genistein is an Efficient Estrogen in the Whole-Body throughout Mouse Development

Abstract

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 microg/kg, at 12 h from the administration by gavage. In the liver, ER-alpha and ER-beta 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-alpha 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.

In Vivo Imaging Reveals Selective Peroxisome Proliferator Activated Receptor Modulator Activity of the Synthetic Ligand 3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)

“…These kinetics of nuclear receptor activity in response to treatment are in line with previous studies on the ERE-Luc reporter mouse by ours (Ciana et al, 2001;Ciana et al, 2003;Maggi et al, 2004) as well as other groups (Lemmen et al, 2004) and are supported by the analysis of the hormonal treatment of endogenous genes (Montani et al, 2008). It is important to underline that the use of firefly luciferase, a protein with a turnover rate of 2 to 3 h, was instrumental to show the cessation of drug action; this would have not been possible with the use of more stable reporters that would have maintained their activity after cessation of receptor activation.…”

Oilseeds ameliorate metabolic parameters in male mice, while contained lignans inhibit 3T3-L1 adipocyte differentiation in vitro

“…), and most of their health-related effects have been attributed to their activity as antioxidants [29,30]. A certain amount of data are now becoming available on the activity of these compounds at doses lower than those required to exert antioxidant activities, but sufficient to activate fundamental cell pathway-regulating metabolic functions [18,19,22,65,66]. Thus, the understanding of the possible health effect of lignans on the pathophysiological model of MetS has to go through the comprehension of their action as regulators of key factors that are central to metabolic pathway-regulating fat biosynthesis, fat storage and accumulation, glucose homeostasis, insulin biosynthesis and secretion, insulin sensitivity, cholesterol biosynthesis and secretion, and low chronic inflammation, which is the underlying contributor to the worsening of adipose metabolism and function [67,68].…”

Dietary sources of lignans and isoflavones modulate responses to estradiol in estrogen reporter mice

“…2). GENinduced estrogen reporter gene activity in liver has been documented before [18], but estrogenicity of GEN in the pituitary gland in vivo has not been described.…”

“…In vitro, GEN transactivates both ERs with preference for ERb, induces expression of estrogen-responsive genes, and promotes proliferation of estrogen-dependent cell lines [15 -17]. Accordingly, GEN induces estrogen reporter gene expression in various tissues in reporter mice in vivo [18]. However, in contrast to ENL and flaxseed, GEN and soy promote uterine weight in rodents [19 -21] and support the growth of estrogendependent tumors in experimental mammary carcinoma models [17, 22 -24].…”