title: Risk assessment of tetrabromobisphenol A on cyclooxygenase-2 expression via MAP kinase/NF-kappaB/AP-1 signaling pathways in murine macrophages.
abstract: Tetrabromobisphenol A [2,2-bis-(3,5-dibromo-4-hydroxyphenyl)propane; TBBPA] is used worldwide as a flame retardant in numerous products. In the present study, the effects of TBBPA were examined on the expression of cyclooxygenase-2 (COX-2), inflammation-related cytokines, transcription factors, and signaling pathways responsible for transcriptional activation of the COX-2 gene in murine RAW 264.7 macrophages. Exposure to TBBPA markedly enhanced the production of prostaglandin E(2), a major COX-2 metabolite, in macrophages. TBBPA concentration-dependently increased the levels of COX-2 protein and mRNA. In addition, TBBPA increased the secretion and mRNA levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Transfection of a human COX-2 promoter construct demonstrated that TBBPA induced COX-2 promoter activity. Furthermore, transfection with pNF-kappaB-Luc and pAP-1-Luc plasmid revealed that TBBPA activated the NF-kappaB and AP-1 sites. Phosphatidylinositol 3 (PI3) kinase, its downstream signaling molecule, Akt, and mitogen-activated protein kinases (MAPK) were also significantly activated by TBBPA. Our data demonstrate TBBPA-induced COX-2 and proinflammatory cytokine expression occurs through the PI3-kinase/Akt/MAP kinase/NF-kappaB/AP-1 pathways.
authors.affiliation: College of Pharmacy, Chosun University, Gwangju, South Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005411:Flame Retardants / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005411:Flame Retardants; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; D011075:Polybrominated Biphenyls; C000612141:REG3A protein, human; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases; C020806:tetrabromobisphenol A; D015232:Dinoprostone