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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 μM 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-κB (NF-κB) 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-κB 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.

carcinogenesis

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