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Milou M.L. Dingemans,¹ Geert M.J. Ramakers,² Fabrizio Gardoni,³ Regina G.D.M. van Kleef,¹ Åke Bergman,⁴ Monica Di Luca,³ Martin van den Berg,¹ Remco H.S. Westerink,¹ and Henk P.M. Vijverberg¹

¹Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands; ²Rudolf Magnus Institute of Neuroscience, University Medical Centre, Department of Pharmacology and Anatomy, Utrecht, the Netherlands; ³Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy; ⁴Department of Environmental Chemistry, Wallenberg Laboratory, Stockholm University, Stockholm, Sweden

Abstract
Background: Increasing environmental levels of brominated flame retardants raise concern about possible adverse effects, particularly through early developmental exposure.

Objective: The objective of this research was to investigate neurodevelopmental mechanisms underlying previously observed behavioral impairments observed after neonatal exposure to polybrominated diphenyl ethers (PBDEs) .

Methods: C57Bl/6 mice received a single oral dose of 2,2´,4,4´-tetrabromodiphenyl ether (BDE-47) on postnatal day (PND) 10 (i.e., during the brain growth spurt) . On PND17–19, effects on synaptic plasticity, levels of postsynaptic proteins involved in long-term potentiation (LTP) , and vesicular release mechanisms were studied ex vivo. We investigated possible acute in vitro effects of BDE-47 on vesicular catecholamine release and intracellular Ca²⁺ in rat pheochromocytoma (PC12) cells.

Results: Field-excitatory postsynaptic potential (f-EPSP) recordings in the hippocampal CA1 area demonstrated reduced LTP after exposure to 6.8 mg (14 µmol) /kg body weight (bw) BDE-47, whereas paired-pulse facilitation was not affected. Western blotting of proteins in the postsynaptic, triton-insoluble fraction of hippocampal tissue revealed a reduction of glutamate receptor subunits NR2B and GluR1 and autophosphorylated-active Ca²⁺/calmodulin-dependent protein kinase II (αCaMKII) , whereas other proteins tested appeared unaffected. Amperometric recordings in chromaffin cells from mice exposed to 68 mg (140 µmol) /kg bw BDE-47 did not reveal changes in catecholamine release parameters. Modest effects on vesicular release and intracellular Ca²⁺ in PC12 cells were seen following acute exposure to 20 µM BDE-47. The combined results suggest a postsynaptic mechanism in vivo.

Conclusion: Early neonatal exposure to a single high dose of BDE-47 causes a reduction of LTP together with changes in postsynaptic proteins involved in synaptic plasticity in the mouse hippocampus.

Key words: αCaMKII, brain growth spurt, developmental neurotoxicity, field-EPSP recording, hippocampal synaptic plasticity, postsynaptic density. Environ Health Perspect 115: 865–870 (2007) . doi:10.1289/ehp.9860 available via http://dx.doi.org/ [Online 5 February 2007]

Address correspondence to M.M.L. Dingemans, Toxicology Division, Institute for Risk Assessment Sciences (IRAS) , Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, the Netherlands. Telephone: +31-30-2534387. Fax: +31-30-2535077. E-mail: M.Dingemans@iras.uu.nl

We thank A. de Groot for excellent technical assistance and L. van Halewijn for hippocampal Nissl staining.

This study was supported by the Faculty of Veterinary Medicine, Utrecht University.

The authors declare they have no competing financial interests.

Received 27 October 2006 ; accepted 5 February 2007.