Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats

Abstract

Ronis MJJ. Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats. Physiol Genomics 45: 1072-1083. First published September 17, 2013 doi:10.1152/physiolgenomics.00096.2013.-Isoflavones are phytochemical components of soy diets that bind weakly to estrogen receptors (ERs). To study potential estrogen-like actions of soy in the mammary gland during early development, we fed weanling male and female Sprague-Dawley rats a semipurified diet with casein as the sole protein source from postnatal day 21 to 33, the same diet substituting soy protein isolate (SPI) for casein, or the casein diet supplemented with estradiol (E2) at 10 g/kg/day. In contrast to E2, the SPI diet induced no significant change in mammary morphology. In males, there were 34 genes for which expression was changed Ն2-fold in the SPI group vs. 509 changed significantly by E2, and 8 vs. 174 genes in females. Nearly half of SPI-responsive genes in males were also E2 responsive, including adipogenic genes. Serum insulin was found to be decreased by the SPI diet in males. SPI and E2 both downregulated the expression of ER␣ (Esr1) in males and females, and ER␤ (Esr2) only in males. Chromatin immunoprecipitation revealed an increased binding of ER␣ to the promoter of the progesterone receptor (Pgr) and Esr1 in both SPI-and E2-treated males compared with the casein group but differential recruitment of ER␤. ER promoter binding did not correlate with differences in Pgr mRNA expression. This suggests that SPI fails to recruit appropriate co-activators at E2-inducible genes. Our results indicate that SPI behaves like a selective estrogen receptor modulator rather than a weak estrogen in the developing mammary gland.

Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity

“…al. 2009, Ronis et al, 2011a) or in estrogen-sensitive reproductive tissues such as the mammary, uterus or testis (Ronis et al, 2012; Miousse et al, 2013; Ronis et al, 2014; Ronis et al, 2016). These data suggest that although studies on the effects of pure isoflavones on CYP expression and activity may be of importance in consumers of isoflavone supplements, they probably have limited relevance to soy consumers.…”

“…In studies in cultured pig granulosa cells genistein was reported to inhibit CYP11A1 activity (cholesterol side chain cleavage enzyme) which catalyzes the conversion of cholesterol to pregnanolone and reduced progesterone production (Piasecka-Srader et al 2014). Interestingly in this regard, Miousee et al (2013) reported that feeding SPI compared to casein diets reduced serum progesterone in weanling female but not male rats. In contrast, the reported effects of genistein on CYP19 (aromatase) expression and activity are inconsistent.…”

Soy protein isolate feeding does not result in reproductive toxicity in the pre-pubertal rat testis

“…1,2 Moreover, we have observed dramatically different gene expression profiles in liver, bone, mammary gland, and uterus of adult and pre-pubertal rats after feeding SPI relative to those elicited by 17β estradiol (E2). 21–25 These data suggest that the endocrine effects of purified isoflavones relative to feeding SPI are quite different. The current study was designed to determine if feeding SPI, the sole protein source in soy infant formula to pre-pubertal male rats has different effects than estrogens on male reproductive development during a developmental window corresponding to human neonatal and early childhood development.…”

Adverse Effects of Nutraceuticals and Dietary Supplements

“…The most intensively studied nutraceutical flavonoids are the soy derived isoflavones genistein and daidzein, and the daidzein metabolite equol. Unlike other flavonoids, the isoflavones in their purified form have been shown to possess estrogenic properties in vitro and in animal models, including the ability to produce uterine hypertrophy or reproductive tract malformations, reduce testis size, inhibit androgen production, reduce fertility, and stimulate estrogen-dependent tumor growth (36,37,45,48,49,51,52,56). Since evidence emerged demonstrating health risks following hormone replacement therapy in post-menopausal women, menopausal women have increasingly turned to use of dietary supplements to treat symptoms such as hot flashes, depression and bone loss.…”