title: Proteomic evaluation of neonatal exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether.
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 male NMRI 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., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-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.
authors.affiliation: Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Sweden. Henrik.Alm@farmbio.uu.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Alm
authors.forename: Birger
authors.initials: B
authors.lastname: Scholz
authors.forename: Celia
authors.initials: C
authors.lastname: Fischer
authors.forename: Kim
authors.initials: K
authors.lastname: Kultima
authors.forename: Henrik
authors.initials: H
authors.lastname: Viberg
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Lennart
authors.initials: L
authors.lastname: Dencker
authors.forename: Michael
authors.initials: M
authors.lastname: Stigson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000737:chemistry*; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D006624:Hippocampus / Q000737:chemistry*; D008297:Male; D051379:Mice; D010647:Phenyl Ethers / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; C086401:pentabromodiphenyl ether; D011493:Protein Kinase C