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ToxSci Advance Access published online on September 29, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh298
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 15, 2004
Accepted September 26, 2004

Environmental Toxicology

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

Trine Reistad 1*, Espen Mariussen 2, and Frode Fonnum 1

1 Norwegian Defence Research Establishment, Division for Protection, P. O. Box 25, N-2027 Kjeller, Norway
2 Norwegian institute for Air Research, P. O. Box 100, N-2027 Kjeller, Norway

* To whom correspondence should be addressed. E-mail: Trine.Reistad{at}ffi.no.


  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.

Keywords: Brominated flame-retardants (BFR); Tetrabromobisphenol-A; neutrophil granulocytes; reactive oxygen species (ROS); MAP kinase pathway; calcium; extracellular signal-regulated kinase (ERK).
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