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., α-enolase; γ-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, β subunit (Atp5b); and α-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.

Prenatal Transfer of Polybrominated Diphenyl Ethers (PBDEs) Results in Developmental Neurotoxicity in Zebrafish Larvae

“…In mice, the increased expression of GAP-43 protein (1.25-fold) was found in developing mouse brains after 24 h exposure to BDE-99 (12 mg/kg body weight). 42 Following neonatal exposure to BDE-209 (20.1 mg/ kg body) in mice, GAP-43 was significantly increased in the hippocampus after 7 days. 43 However, neonatal exposure to BDE-203 and -206 (21 μmol/kg) for 24 h in mice during rapid brain growth and development did not affect GAP-43.…”

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…A decrease of CaMKII, in addition to decreases in the levels of brain derived neurotrophic factor (BDNF) and of Gap-43 (neuromodulin) were also found on PND 10 in mice exposed to BDE-209 on PND 3 (Viberg et al 2007b). A proteomic analysis of hippocampus and striatum of mice 24 h after the administration of BDE-99 (12 mg/ kg on PND 10) revealed changes in the levels of a number of proteins (Alm et al 2006). Among these, Gap-43, which was increased in the striatum, and stathmin, which was decreased.…”

“…Both are substrates of protein kinase C (PKC), which has been shown to be affected by PBDEs in vitro (Madia et al 2004;. Various enolases, as well as alpha synuclein were also increased in the hippocampus (Alm et al 2006). In a study in rats, prenatal exposure to BDE-99 was shown to increase the activity of the glutamate -nitric oxide-cGMP pathway, as assessed by microdialysis (Llansola et al 2007).…”

Proteomic Analysis of Near-Isogenic Sunflower Varieties Differing in Seed Oil Traits

“…Although there have been numerous statistical analyses performed with DIGE investigations, there is presently no consensus strategy for identifying differential proteins. 31,34,35 We present here an alternative that is simple yet robust for minimizing false-positives.…”

“…FDR is used extensively in microarray transcript profiling experimentation and has also been used by a few groups to characterize proteome data sets. 9,31,34,35 In this paper, we applied FDR for selection of deferentially expressed spots. FDR is a statistical procedure that is effective in correcting for multiple simultaneous hypothesis tests.…”