Location: Arkansas Children's Nutrition CenterTitle: Soy protein isolate and estradiol differ in their effects on the mammary gland of weanling male and female rats Author
Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 2/19/2014
Publication Date: 4/15/2014
Citation: Ronis, M.J., Miousse, I.R., Gomez-Acevedo, H., Hennings, L., Shankar, K., Cleves, M., Badger, T.M. 2014. Soy protein isolate and estradiol differ in their effects on the mammary gland of weanling male and female rats. The FASEB Journal. 28(1 Supplement):818.1. Interpretive Summary: There is controversy over the potential for either beneficial or harmful effects of eating soy products, including soy infant formulas. One such controversy is do soy products protect against breast cancer or does soy consumption increase breast cancer risk. Much of the research in this area has focused on a class of chemicals found bound to soy proteins called isoflavones. These chemicals (genisetin, daidzein) have structures related to the female hormone estradiol, and it has been suggested that health effects of soy are associated with estrogenic signaling via the isoflavones. The current study was designed to ask the question, "Is soy estrogenic in breast tissue from male and females before puberty." Male and female rats were fed diets containing a cow's milk protein (casesin) or soy protein isolate (the form of soy found in infant formula and processed foods) from when they were weaned off their mothers onto solid food until puberty and compared to animals fed casein but treated with estradiol. Estradiol treatment changed the structure of male breast tissue and increased cell proliferation (a marker of increased risk of breast cancer) but eating soy did not. No effects of either treatment were seen in female breast tissue at this age. When gene expression profiles were probed, estradiol changed expression of hundreds of genes in the breast tissue of both sexes; in contrast, very few genes were affected by feeding soy. Moreover, although there was a small amount of overlap in soy-regulated and estrogen-regulated genes in the male breast and estrogen receptors were activated by both estradiol and soy, there was no correlation between estrogen receptor binding to promoters and gene expression after soy feeding. These results suggest that in children prior to puberty, when sex steroids are normally very low, soy feeding can activate estrogen receptors, but the receptors appear to be in the wrong shape to recruit functional transcriptional complexes to most estrogen responsive genes and so soy does not act like a weak estrogen at all in breast tissue but appears to modify only a very small sub-set of estrogen regulated genes and appears not to change breast structure or increase breast cancer risk.
Technical Abstract: 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, we fed weanling male and female Sprague-Dawley rats a casein diet from PND21 to PND33, the same diet substituting soy protein isolate (SPI) for casein, or the casein diet supplemented with estradiol (E2) at 10 µg/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 changed =2-fold in the SPI group versus 509 changed significantly by E2, and 8 versus 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 SPI in males. SPI and E2 both down-regulated the expression of ER alpha (Esr1) in males and females, and ER beta (Esr2) only in males. Chromatin immunoprecipitation (ChIP) revealed an increased binding of ER alpha to the promoter of the progesterone receptor (Pgr) and Esr1 in both SPI and E2 treated males compared to the casein group but differential recruitment of ERß. 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.