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Carcinogenesis Advance Access published online on February 1, 2007
Carcinogenesis, doi:10.1093/carcin/bgm013
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Increase of carcinogenic risk via enhancement of cyclooxygenase-2 expression and hydroxyestradiol accumulation in human lung cells as a result of interaction between BaP and 17-beta estradiol

Louis W. Chang, Yun-Ching Chang, Chia-Chi Ho, Ming-Hsien Tsai and Pinpin Lin*

Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC

* All correspondence should be addressed to Dr. Pinpin Lin, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC. Tel: (886) 37-246-166, ext. 36508, Fax: (886) 37-587-406, E-mail: pplin{at}nhri.org.tw

Animal studies demonstrated that females are more susceptible than males to benzo[a]pyrene-induced toxicities, including lung carcinogenesis. Elevation of cyclooxygenase-2 (COX-2) expression has been shown to increase the risk of cancer development. BaP induces COX-2 expression, and an interaction between BaP and estrogen in relation to COX-2 expression is suspected. In the present study, 10 µM BaP alone only slightly increased COX-2 mRNA expression and 10 nM 17-beta estradiol (E2) alone slightly increased prostaglandin E2 (PGE2) secretion in human bronchial epithelial cells. However, co-treatment with BaP and E2 potentiated COX-2 mRNA expression and significantly elevated PGE2 secretion. Utilizing specific inhibitors and reporter assays, we further investigated the potentiation mechanisms of E2 on BaP-induced COX-2 expression. First, E2 activated estrogen receptor to increase PGE2 secretion, which directly increased COX-2 expression. Second, E2 potentiated BaP-induced NF-{kappa}B activation, which regulates COX-2 expression. Third, although the aryl hydrocarbon receptor (AhR) did not play a role in BaP-induced COX-2 expression, the potentiation effect of E2 itself was AhR dependent. We further demonstrated that BaP induced the production of genotoxic E2 metabolites (2- and 4-hydroxyestradiols) via AhR-upregulated cytochromes P4501A1 and 1B1. These metabolites could directly activate NF-{kappa}B to further promote COX-2 mRNA expression in human lung epithelial cells. These findings were further supported by increased PGE2 secretion in rat lung slice cultures. Our findings that the BaP/E2 interaction enhanced COX-2 expression and hydroxyestradiol accumulation in the media of cultivated lung cells and tissues provide the needed scientific basis for higher risk of BaP-associated lung cancer in females.

Key Words: benzo[a]pyrene • 17 beta estradiol • cyclooxygenase-2 • hydroxyestradiol • lung


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C.-C. Ho, Y.-C. Ling, L. W. Chang, H.-T. Tsai, M.-H. Tsai, and P. Lin
17-Beta Estradiol and Hydroxyestradiols Interact via the NF-Kappa B Pathway to Elevate Cyclooxygenase 2 Expression and Prostaglandin E2 Secretion in Human Bronchial Epithelial Cells
Toxicol. Sci., August 1, 2008; 104(2): 294 - 302.
[Abstract] [Full Text] [PDF]


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