title: 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.
abstract: Animal studies demonstrated that females are more susceptible than males to benzo[a]pyrene (BaP)-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 muM BaP alone only slightly increased COX-2 mRNA expression and 10 nM 17-beta estradiol (E(2)) alone slightly increased prostaglandin E2 (PGE2) secretion in human bronchial epithelial cells. However, co-treatment with BaP and E(2) potentiated COX-2 mRNA expression and significantly elevated PGE2 secretion. Utilizing specific inhibitors and reporter assays, we further investigated the potentiation mechanisms of E(2) on BaP-induced COX-2 expression. First, E(2) activated estrogen receptor to increase PGE2 secretion, which directly increased COX-2 expression. Second, E(2) potentiated BaP-induced nuclear factor-kappaB (NF-kappaB) 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 E(2) itself was AhR dependent. We further demonstrated that BaP induced the production of genotoxic E(2) metabolites (2- and 4-hydroxyestradiols) via AhR-up-regulated cytochromes P450 1A1 and 1B1. These metabolites could directly activate NF-kappaB 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-E(2) 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.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chang
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ho
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001980:Bronchi / Q000166:cytology; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology / Q000633:toxicity*; D002393:Estrogens, Catechol; D000077267:Fulvestrant; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011959:Receptors, Estradiol / Q000037:antagonists & inhibitors; D015854:Up-Regulation
chemical_list: D000393:Air Pollutants; D002274:Carcinogens, Environmental; D002393:Estrogens, Catechol; D008565:Membrane Proteins; D016328:NF-kappa B; D011959:Receptors, Estradiol; D000077267:Fulvestrant; D001564:Benzo(a)pyrene; D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone