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Title: Uterine physiological responses and global gene expression in ovariectomized (ovx) rats treated with soy protein isolate (spi) or 17Beta-estradiol

Author
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item GOMEZ-ACEVEDO, HORATIO - Arkansas Children'S Nutrition Research Center (ACNC)
item SINGHAL, ROHIT - University Arkansas For Medical Sciences (UAMS)
item DUNN, SHANNON - University Arkansas For Medical Sciences (UAMS)
item VANTREASE, JAMIE - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2011
Publication Date: 4/1/2012
Citation: Ronis, M.J., Blackburn, M., Shankar, K., Gomez-Acevedo, H., Singhal, R., Dunn, S., Vantrease, J., Badger, T.M. 2012. Uterine physiological responses and global gene expression in ovariectomized (ovx) rats treated with soy protein isolate (spi) or 17Beta-estradiol. The Federation of American Societies for Biology Conference Journal. 26(Meeting Abstracts):243.2.

Interpretive Summary: There is significant debate among both the general public and professionals with regards to the potential health benefits and risks associated with consumption of soy products. In large part this is due to the unique presence of phytochemicals in soy which have estrogenic properties. The major compounds are the isoflavones genistein and daidzein which remain associated with the protein on production of infant formula and processed foods in addition to traditional products such as miso, tofu and tempe.. One aspect of this debate is the possibility that soy consumption would increase the risk of estrogen-dependent cancers such as breast cancer and uterine cancer. Complicating the picture, soy products are foodstuffs containing a complex mixture of proteins, peptides and over 100 phytochemicals in addition to the isoflavones. It is possible that this complex mixture has completely different biological properties then the purified isoflavones which have been used for safety studies. The current study examined the effects of feeding soy protein isolate (SPI) which contains isoflavones and is the sole protein source used in infant formulas consumed by > 1 million US infants each year, with that of the pure female estrogen estradiol (E2). We used ovariectomized (OVX) female rats which have the ovaries removed to remove endogenous estrogens and which should be the most sensitive to estrogen-like actions on the uterus. A major estrogenic biomarker is increased uterine weight in OVX animals. As expected E2 increased uterine weight relative to OVX controls. However, SPI had no effect on uterine weight and when given together with E2 did not modify E2 effects. Analysis of the tissue at a molecular level by RNA-seq analysis demonstrated that only 5% of gene regulated by E2 were also regulated by SPI feeding and some of these were regulated in the opposite direction. Combined E2 + SPI treatment reduced the number of regulated genes compared to E2 alone suggesting some anti-estrogenic actions of SPI. These genes included a tissue proliferation marker Ki67 associated with uterine cancer. These data suggest SPI feeding does not produce uterine weight gain and actually inhibits the proliferative effects of E2 on the uterus.

Technical Abstract: Concerns regarding increased endometrial cancer risk have been raised in women who consume soy products as the result of the estrogenicity of phytochemical components such as the isoflavones genistein and daidzein. Female Sprague-Dawley rats (N = 20/group) were fed AIN-93G diets with casein or SPI as the protein source from PND30. On PND50, rats were OVX and 10/group infused s.c. with 5 micro g/kg/d 17beta-estradiol (E2) to restore physiological levels. On PND64, uteri were collected, weighed and mRNA isolated for massively parallel signature sequencing (RNA-seq) analysis of global gene expression profiles. Uterine wet weight was increased (P<0.05) after E2. However, SPI had no effects on uterus weight. E2 significantly regulated expression of 4,344 genes + >2-fold. In contrast, SPI feeding changed expression of only 457 genes, of which only 226 overlapped with E2. Many of these genes were regulated in opposite directions by E2 and SPI. 3,129 genes changed in response to E2 + SPI overlapped with E2 alone suggesting suppression of 25% of E2-regulated genes after SPI consumption. Ki67 mRNA, a marker of cell proliferation demonstrated this pattern of response when examined by real time RT-PCR. These data suggest SPI feeding does not produce uterine hyperplasia and actually inhibits the proliferative effects of E2 on the uterus.