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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm288
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Estrogenic status modulates aryl hydrocarbon receptor - mediated hepatic gene expression and carcinogenicity

Rohit Singhal1, Kartik Shankar1,3, Thomas M Badger2,3 and Martin J Ronis1,3,4

1 Departments of Pharmacology and Toxicology
2 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR
3 Arkansas Children's Nutrition Center, Little Rock, AR, USA

4 Address all correspondence and reprint requests to: Martin J. Ronis, Ph.D., Arkansas Children's Nutrition Center, Slot 512-20B, 1212 Marshall Street, Little Rock, AR 72202. Phone (501) 364-2796; Fax: (501) 364-3161; Email: RonisMartinJ{at}uams.edu

Estrogenic status is thought to influence the cancer risk in women and has been reported to effect toxicity of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in animals. The objective of this study was to examine the influence of estradiol (E2) on hepatic gene expression changes-mediated by 7,12-dimethylbenz(a)anthracene (DMBA), a potent PAH. Sprague-Dawley rats were ovariectomized at PND50 and infused with E2 (5µg/kg/day) or polyethylene glycol using osmotic pumps and fourteen days later gavaged with DMBA (50mg/kg) or sesame oil and sacrificed 24h thereafter. To understand the mechanism of DMBA-mediated hepatocarcinogenicity in the presence of E2, microarray analysis (Rat 230-2.0 Affymetrix-GeneChip) was performed. Two hundred sixteen genes were down-regulated while 106 genes were up-regulated significantly (± 1.5 fold, P<0.05) by DMBA treatment. Hierarchical clustering revealed that the expression profile of 39 genes, regulated by DMBA, was significantly modified by E2 supplementation. Interestingly, 71 genes were uniquely modulated in the combined treatment of DMBA and E2, but not by either treatment alone. Results from chromatin-immunoprecipitation assay demonstrates that in animals co-treated with E2 and DMBA there was enhanced recruitment of estrogen receptor-{alpha} to the regulatory regions of CYP1A1 and AhR genes compared to that observed in animals treated with DMBA alone. E2 supplementation leads to increased DMBA-induced CYP1A1 transcription, while the AhR gene was up-regulated in the presence of both E2 and DMBA only. Our data suggest that estrogenic status is: 1) important in AhR regulation and can influence the effects of xenobiotics; and 2) may be an important factor in DMBA-mediated carcinogenicity.

Received January 21, 2007; revised November 15, 2007; accepted December 8, 2007.


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