Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/29/2008
Publication Date: 1/15/2009
Citation: Singhal, R., Badger, T.M., Ronis, M.J. 2009. Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA). Journal of Toxicology and Applied Pharmacology. 234(1):89-97.
Interpretive Summary: Consumption of soy foods has been shown to reduce the incidence of certain diseases, such as cardiovascular disease and breast cancer. However, there has been a controversy over whether isoflavones in the soy bean act as estrogens, in which case they would might actually pose a cancer risk. In this study, we used one of the most widely employed animal models of breast cancer (the DMBA model) to determine the relative actions of estrogens and soy protein isolate (SPI) on gene expression. We found interactions among SPI, DMBA and estrogens resulted in unique gene expression profiles. These data suggest that soy does not act as an estrogen, but rather acts differently in the presence of estrogens. Animals fed soy-containing food had different gene profiles in response to DMBA when estrogen were present than when estrogen was either absent or very low. These results suggest that the biological effects of consuming soy foods will differ in premenopausal women (who have higher estrogen levels) than in postmenopausal women (who have lower estrogen levels).
Technical Abstract: We examined the influence of estradiol (E2) status and soy protein isolate (SPI) intake on the hepatic responses altered by 7,12-dimethylbenz(a)anthracene (DMBA, a polycyclic aromatic hydrocarbon [PAH]). Sprague–Dawley rats were ovariectomized (OVX) at PND50 and infused with E2 or vehicle for 14 d and gavaged with 50 mg/kg DMBA or vehicle 24 h before sacrifice at PND64. Rats were fed an AIN-93G diet made with SPI or casein as sole protein source throughout the study. Basal AhR protein levels were reduced (P less than 0.05) by SPI feeding irrespective of the E2 status. However, DMBA increased (P less than 0.05) AhR-induced CYP1A1 gene expression in OVX, SPI-fed rats, but reduced (P less than 0.05) CYP1A1 in OVX + E2, SPI-fed rats. Chromatin-immunoprecipitation demonstrated lower (P less than 0.05) DMBA-mediated recruitment of estrogen receptor alpha to the CYP1A1 promoter by SPI feeding in the presence of E2, suggesting an estrogen-like action of SPI on DMBA-mediated signaling in the absence of E2. Further, microarray analysis (Rat 230-2.0 Affymetrix-GeneChip TM) revealed 231 genes common to SPI + DMBA and SPI + E2 + DMBA (normalized to E2) treatments. AhR-activated genes (CYP1A1, CYP1A2, and NQO1) were down-regulated by SPI + E2 + DMBA compared to SPI + DMBA. Unique interactions among SPI, DMBA and E2 altered the expression profile of 316 genes, not observed by either treatment alone. Our data suggest that although E2 status does not effect soy-mediated AhR degradation, it modulates the effects of soy on many genes, including CYP1A1.