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• W3080802355 abstract "Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants generated from the incomplete combustion of organic material. PAHs have been studied as genotoxicants, but some also act via non-genotoxic mechanisms in estrogen-dependent malignancies, such as breast cancer. PAHs require metabolic activation to electrophilic metabolites to exert their genotoxicity but non-genotoxic properties may also contribute to their carcinogenicity. The role of PAHs in endometrial cancer, a cancer associated with unopposed estrogen action is unknown. We assessed the metabolism of the representative PAH, benzo[ a ]pyrene (B[ a ]P), to estrogenic compounds in Ishikawa human endometrial cells in the presence and absence of cytochrome P450 induction. Using stable-isotope dilution high-performance liquid chromatography and APCI tandem mass spectrometry in the selected reaction monitoring mode, we analyzed B[ a ]P metabolism in Ishikawa cells. Estrogenic activity of B[ a ]P metabolites was determined by the endogenous estrogen inducible alkaline phosphatase reporter gene and an exogenous estrogen response element (ERE) luciferase reporter gene construct. We also assessed whether PAHs can induce a proliferative phenotype via estrogen receptor (ER)- and non-ER-regulated pathways. We demonstrate that B[ a ]P can be metabolized in human endometrial cells into 3-OH-B[ a ]P and B[ a ]P-7,8-dione in sufficient amounts to activate ERs. We also show that only B[ a ]P-7,8-dione induces endometrial cell proliferation at concentrations lower than required to activate the ER; instead non-genomic signaling by the EGF receptor (EGFR) and activation of the mitogen-activated protein kinase (MAPK) pathway was responsible. This work indicates that human endometrial cells can metabolize PAHs into estrogenic metabolites, which may induce cell proliferation through non-ER-regulated pathways." @default.
• W3080802355 created "2020-09-01" @default.
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• W3080802355 date "2020-11-01" @default.
• W3080802355 modified "2023-09-27" @default.
• W3080802355 title "Estrogen receptor-dependent and independent roles of benzo[a]pyrene in Ishikawa cells" @default.
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• W3080802355 doi "https://doi.org/10.1530/joe-19-0579" @default.
• W3080802355 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7534831" @default.
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• W3080802355 hasPublicationYear "2020" @default.
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