Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2007
Publication Date: 3/15/2008
Citation: Singhal, R., Shankar, K., Badger, T.M., Ronis, M.J. 2008. Estrogenic status modulates aryl hydrocarbon receptor - mediated hepatic gene expression and carcinogenicity. Carcinogenesis. 29(2):227-236.
Interpretive Summary: A large percentage of cancer is thought to be caused by environmental chemicals that find their way into our bodies. Some come from over-cooked food, especially char-broiled meats. Polycyclic aromatic hydrocarbons (PAHs) are one of these chemicals. Some PAHs are not carcinogens, but are termed procarcinogens, because they are converted (metabolized) to carcinogens by enzymes in the body; one such enzyme is CYP1A1. The rates of cancer differ between men and women, and one major factor in these sex differences is the level and type of estrogens in the body. In this study we examined the effects of estrogens on metabolism. We found that many genes were changed by the interaction between E2 and DMBA (a PAH frequently used in cancer research) including gene encoding CYP1A1. We found that procarcinogens are metabolized (converted) to carcinogens differently in the presence or absence of estrogens. We speculate that there is an increased carcinogenesis by exposure to PAHs in the presence of estrogens (like in case of pre-menopausal women) compared with exposure to PAHs in the absence of estrogens (like in case of post-menopausal women and males).
Technical Abstract: 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 at PND50 and infused with E2 (5 micro g/kg/day) or polyethylene glycol using osmotic pumps and 14 days later gavaged with DMBA (50mg/kg) or sesame oil and sacrificed 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 sixteen genes were down-regulated, while 106 genes were up-regulated significantly (Plus and/or equal to 1.5 fold, P less than 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.