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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):227-236; 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
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

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,*

1 Department of Pharmacology and Toxicology and
2 Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
3 Arkansas Children’s Nutrition Center, 1212 Marshall Street, Little Rock, AR 72205, USA

* To whom correspondence should be addressed. Tel: +1 501 364 2796; Fax: +1 501 364 3161; Email: ronismartinj{at}uams.edu

Estrogenic status is thought to influence the cancer risk in women and has been reported to affect 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 on postnatal day 50 and infused with E2 (5 µg/kg/day) or polyethylene glycol using osmotic pumps and 14 days later gavaged with DMBA (50 mg/kg) or sesame oil and killed 24 h 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 and sixteen genes were downregulated; whereas, 106 genes were upregulated 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 demonstrate that in animals cotreated with E2 and DMBA, there was enhanced recruitment of estrogen receptor-{alpha} to the regulatory regions of CYP1A1 and aryl hydrocarbon receptor (AhR) genes compared with that observed in animals treated with DMBA alone. E2 supplementation leads to increased DMBA-induced CYP1A1 transcription, while the AhR gene was upregulated in the presence of E2 +DMBA only. Our data suggest that estrogenic status is (i) important in AhR regulation and can influence the effects of xenobiotics and (ii) may be an important factor in DMBA-mediated carcinogenicity.

Abbreviations: AhR, aryl hydrocarbon receptor; BW, body weight; E2, estradiol; ER, estrogen receptor; cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; CYP, cytochrome P450; DMBA, 7,12-dimethylbenz(a)anthracene; Gstm, Glutathione S-transferase mu; mRNA, messenger RNA; Nqo1, reduced nicotinamide adenine dinucleotide phosphate quinone reductase-1; PAH, polycyclic aromatic hydrocarbon; PCR, polymerase chain reaction; QRTPCR, quantitative real-time PCR; TCDD, 2,4,7,8-tetracholorodibenzo-p-dioxin; XRE, xenobiotic response element

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


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