Risk Assessment of Tetrabromobisphenol a on Cyclooxygenase-2 Expression Via Map Kinase/NF-kappa B/AP-1 Signaling Pathways in Murine Macrophages

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-1 beta. Transfection of a human COX-2 promoter construct demonstrated that TBBPA induced COX-2 promoter activity. Furthermore, transfection with pNF-kappa B-Luc and pAP-1-Luc plasmid revealed that TBBPA activated the NF-kappa B 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-kappa B/AP-1 pathways.