The Effect of a Brominated Flame Retardant, Tetrabromobisphenol-A, on Free Radical Formation in Human Neutrophil Granulocytes: The Involvement of the MAP Kinase Pathway and Protein Kinase C

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Abstract
This study investigates the effects of one of the most frequently used brominated flame-retardants (BFR), tetrabromobisphenol-A (TBBPA), on formation of reactive oxygen species (ROS) and calcium levels in human neutrophil granulocytes. TBBPA enhanced ROS production in a concentration-depended manner (1–12 μM), measured as 2,7-dichlorofluorescein diacetate amplified (DCF) fluorescence. The results on ROS production by TBBPA was confirmed by lucigenin-amplified chemiluminescence. The TBBPA induced formation of ROS was due to activation of respiratory burst, as shown by the NADPH oxidase inhibitor DPI (10 μM). TBBPA induced activation of respiratory burst was also inhibited by the MEK 1/2 inhibitor U0126 (10 μM), the PKC inhibitor BIM (0.25 μM), and the tyrosine kinase inhibitor erbstatin-A (25 μM). We also found a small reduction in ROS formation in the absence of extracellular calcium and when verapamil was added. The phosphorylation of ERK 1/2 was confirmed by Western blotting. TBBPA also induced a concentration dependent increase in intracellular free calcium measured with Fura-2/AM. We suggest that exposure of human neutrophil granulocytes to the brominated flame retardant TBBPA leads to an activation of the NADPH oxidase primarily by an ERK 1/2 stimulated pathway. The data also show that PKC, calcium, and tyrosine kinases may be involved in the activation

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