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ToxSci Advance Access originally published online on June 15, 2005
Toxicological Sciences 2005 87(1):57-65; doi:10.1093/toxsci/kfi222
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

A Commercial Mixture of the Brominated Flame Retardant Pentabrominated Diphenyl Ether (DE-71) Induces Respiratory Burst in Human Neutrophil Granulocytes In Vitro

Trine Reistad*,1 and Espen Mariussen{dagger}

* Norwegian Defence Research Establishment, Division for Protection, P. O. Box 25, N-2027 Kjeller, Norway, and {dagger} Norwegian Institute for Air Research, P. O. Box 100, N-2027 Kjeller, Norway

Received March 15, 2005; accepted June 2, 2005

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants (BFRs), which have become ubiquitous in the environment. This study investigates the effects of the pentabrominated diphenyl ether mixture, DE-71, on human neutrophil granulocytes in vitro. DE-71 enhanced production of reactive oxygen species (ROS) in a concentration-dependent manner measured as lucigenin-amplified chemiluminescence. Octabrominated diphenyl ether (OBDE), decabrominated diphenyl ether (DBDE), and the non-brominated diphenyl ether did not induce ROS formation at the concentrations tested. DPI (4 µM), an inhibitor of the NADPH oxidase completely inhibited DE-71 induced ROS formation, highlighting a role for NADPH oxidase activation. The protein kinase C inhibitor BIM (0.25 µM) and the selective chelator of intracellular calcium, BAPTA-AM (5 µM), also inhibited NADPH oxidase activation, indicating a calcium-dependent activation of PKC. ROS formation was also inhibited by the tyrosine kinase inhibitor tyrphostin (1 µM), the phospholipase C inhibitor ET-18-OCH3 (5 µM), and the phosphatidylinositol-3 kinase inhibitor LY294002 (25 µM). Alterations in intracellular calcium were measured using fura-2/AM, and a significant increase was measured after exposure to DE-71 both with and without extracellular calcium. The tetra brominated compound BDE-47 also enhanced ROS formation in a concentration dependent manner. The combination of DE-71 with the bacteria-derived N-formyl peptide fMLP and PCB153 induced an additive effect in the lucigenin assay. We suggest that tyrosine kinase mediated activation of PI3K could result in enhanced activation of calcium-dependent PKC by enhanced PLC activity, followed by intracellular calcium release leading to ROS formation in neutrophil granulocytes.

Key Words: brominated flame retardants (BFR); pentabrominated diphenyl ethers (PeBDE); reactive oxygen species (ROS); lucigenin; calcium; intracellular signaling pathways.


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