Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA).
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<0.05) by SPI feeding irrespective of the E2 status. However, DMBA increased (P<0.05) AhR-induced CYP1A1 gene expression in OVX, SPI-fed rats, but reduced (P<0.05) CYP1A1 in OVX+E2, SPI-fed rats. Chromatin-immunoprecipitation demonstrated lower (P<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) 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.
Singhal
Rohit
R
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR-72205, USA.
Badger
Thomas M
TM
Ronis
Martin J
MJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002364:Caseins / Q000008:administration & dosage; D047369:Chromatin Immunoprecipitation; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000235:genetics; D004032:Diet; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D046228:Microarray Analysis; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects / Q000235:genetics; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D030262:Soybean Proteins / Q000008:administration & dosage* / Q000494:pharmacology
D002273:Carcinogens; D002364:Caseins; D047628:Estrogen Receptor alpha; D018336:Receptors, Aryl Hydrocarbon; D030262:Soybean Proteins; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human