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Title: Uterine responses to feeding soy protein isolate and treatment with 17B-estradiol differ in ovariectomized female rats

item RONIS, M - Arkansas Children'S Nutrition Research Center (ACNC)
item GOMEZ-ACEVEDO, H - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, M - Arkansas Children'S Nutrition Research Center (ACNC)
item CLEVES, M - Arkansas Children'S Nutrition Research Center (ACNC)
item SINGHAL, R - University Arkansas For Medical Sciences (UAMS)
item Badger, Thomas

Submitted to: Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/22/2016
Publication Date: 3/3/2016
Citation: Ronis, M.J., Gomez-Acevedo, H., Blackburn, M.L., Cleves, M.A., Singhal, R., Badger, T.M. 2016. Uterine responses to feeding soy protein isolate and treatment with 17B-estradiol differ in ovariectomized female rats. Toxicology and Applied Pharmacology. 297:68-80.

Interpretive Summary: Although there is published data in both animal models and in young women that eating diets rich in soy are not harmful, concerns persist on the potential risks of soy-isoflavone consumption on female reproductive health during early development and in post-menopause. In this study, female rats were ovariectomized to induce menopause, and then fed diets containing either casein protein, soy protein, and compared to ovariectomized rodents receiving estradiol supplementation. As expected, estradiol supplementation increased the size of the uterus in the rats, and up-regulated genes involved with the development of tumors. In contrast, rats receiving soy protein in their diets had no up-regulation of genes involved in tumor development. Combining the soy protein diet with estradiol supplementation in a group or ovariectomized rats showed that active components in soy protein are anti-estrogenic. These findings show that soy protein diets are potentially helpful in preventing uterine tumors in both pre- and post-menopausal women.

Technical Abstract: There are concerns regarding reproductive toxicity from consumption of soy foods, including an increased risk of endometriosis and endometrial cancer, as a result of phytoestrogen consumption. In this study, female rats were fed AIN-93G diets made with casein (CAS) or soy protein isolate (SPI) from postnatal day (PND) 30, ovariectomized on PND 50 and infused with 5mug/kg/d 17beta-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05). RNAseq analysis revealed that E2 significantly altered expression of 1991 uterine genes (P<0.05). SPI feeding had no effect on uterine weight and altered expression of far fewer genes than E2 at 152 genes (P<0.05). Overlap between E2 and SPI genes was limited to 67 genes. Functional annotation analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of estrogen receptor (ER) alpha to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were carcinogenesis and extracellular matrix organization, whereas SPI feeding up-regulated uterine peroxisome proliferator activated receptor (PPAR) signaling and fatty acid metabolism. The combination of E2 and SPI resulted in significant regulation of 504 fewer genes relative to E2 alone. The ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA) as measured by expression of PCNA and Ki67 mRNA was suppressed by feeding SPI (P<0.05). These data suggest that SPI is a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and is anti-estrogenic in the presence of endogenous estrogens.