ToxSci Advance Access originally published online on March 16, 2005
Toxicological Sciences 2005 85(2):952-962; doi:10.1093/toxsci/kfi147
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Differential Effects of Commercial Polybrominated Diphenyl Ether and Polychlorinated Biphenyl Mixtures on Intracellular Signaling in Rat Brain in Vitro
Cellular and Molecular Toxicology Branch, Neurotoxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received February 17, 2005; accepted March 4, 2005
Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants and have been detected in human blood, adipose tissue, and breast milk. Developmental and long-term exposures to these contaminants may pose a human health risk, especially to children. Previously, we demonstrated that polychlorinated biphenyls (PCBs), which are neurotoxic and structurally similar to PBDEs, perturbed intracellular signaling events, including calcium homeostasis and subsequent events such as protein kinase C (PKC), which are critical for the normal function and development of the nervous system. The objective of the present study was to test whether commercial PBDE mixtures (DE-71, a pentabrominated dipheyl ether mixture, and DE-79, a mostly octabromodiphenyl ether mixture) affected intracellular signaling mechanisms in a similar way to that of PCBs and other organohalogens, as an attempt to understand the common mode of action for these persistent chemicals. PKC translocation was studied by determining 3H-phorbol ester (3H-PDBu) binding in rat cerebellar granule cells, and calcium buffering was determined by measuring 45Ca2+ uptake by microsomes and mitochondria isolated from adult male rat brain (frontal cortex, cerebellum, and hippocampus). As seen with PCBs, DE-71 increased PKC translocation and inhibited 45Ca2+ uptake by both microsomes and mitochondria in a concentration-dependent manner. The effect of DE-71 on 45Ca2+ uptake seems to be similar in all three brain regions. Between the two organelles, DE-71 inhibited mitochondrial 45Ca2+ uptake to a greater extent than microsomal 45Ca2+ uptake. DE-79 had no effects on either neurochemical event even at 30 µg/ml. Aroclor 1254 altered both events to a greater extent compared to DE-71 on a weight basis. When the results were compared on a molar basis, Aroclor 1254 altered PKC translocation and microsomal 45CaP2+ uptake to a greater extent than DE-71, however, Aroclor 1254 and DE-71 equally affected mitochondrial 45Ca2+ uptake. These results indicate that PBDEs perturbed intracellular signaling mechanisms in rat brain as do other organohalogen compounds and the efficacy between the commercial PCB and PBDE mixtures seem to vary with different endpoints.
Key Words: polychlorinated biphenyls (PCBs); polybrominated diphenyl ethers (PBDEs); neurotoxicity; intracellular signaling; cytotoxicity; protein kinase C; calcium signaling.
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