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Henrik Alm,¹ Birger Scholz,¹ Celia Fischer,² Kim Kultima,¹ Henrik Viberg,² Per Eriksson,² Lennart Dencker,¹ and Michael Stigson¹

¹Department of Pharmaceutical Biosciences, Division of Toxicology, and ²Department of Environmental Toxicology, Uppsala University, Sweden

Abstract
Exposure to the brominated flame retardant 2,2´,4,4´,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to maleNMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) , we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., -enolase ; -enolase ; ATP synthase, H⁺ transporting, mitochondrial F₁ complex, β subunit (Atp5b) ; and -synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds. Key words: 2D-GE, brain development, brain growth spurt, MALDI-ToF-MS, neonatal, neurodegeneration, PBDE-99, PKC, proteomics. Environ Health Perspect 114:254-259 (2006) . doi:10.1289/ehp.8419 available via http://dx.doi.org/ [Online 6 October 2005]

Address correspondence to H. Alm, Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Box 594, SE-751 24 Uppsala, Sweden. Telephone: 46 18 471 42 65. Fax: 46 18 471 42 53. E-mail: Henrik.Alm@farmbio.uu.se

The authors acknowledge the help provided by the WCN Expression Proteomics Facility, Uppsala University, which is funded by the Wallenberg Consortium North (WCN) , and E. Malmport, GE Healthcare, Uppsala.

This work was supported by grants from AstraZeneca (M.S.) , the Foundation for Strategic Environmental Research (P.E., H.V.) and the Swedish Environmental Protection Agency (H.A., B.S., K.K., and L.D.) .

M.S. received funding from AstraZeneca. All other authors declare they have no competing financial interests.

Received 22 June 2005 ; accepted 6 October 2005.