No 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.

No abstract

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it.

The goal of this systematic review performed under a contract with EFSA was the evaluation of information on assessment methods in the field of developmental neurotoxicity (DNT). Therefore, a systematic and comprehensive literature search and collection of scientific literature and all other relevant grey literature and website information (in English) from past 20 years until mid of April 2014 on the state of the art of in vivo DNT testing methods including novel and alternative non-mammalian models, in vitro test methods, in silico methods, read across and combination of testing methods in test batteries was performed. This systematic review identified a variety of methods covering early and later stages of neurodevelopment that have the ability to predict DNT of chemicals. Few in vivo models alternative to OECD TG 426 were identified. In general, the available published in vivo data is scattered and heterogeneous, making comparisons across exposure paradigms and compounds very difficult. Thus, to make more useful evaluations, publications with more consistent experimental designs are needed, and more focused in vivo-in vitro comparisons are needed to establish useful effect biomarkers and testing models. From the alternative methods, a testing strategy covering early and later neurodevelopmental stages (from stem cell to zebrafish larvae motor behaviour) can be assembled. For gaining regulatory acceptance, definition of biological application domains of alternative methods by performing e.g. in vitro -in vivo validation is needed. Moreover, protocols for cell-based and zebrafish assays need international standardization. With such standardized protocols, the test battery needs to be tested for its sensitivity and specificity by testing concentration-responses of known DNT positive and negative compounds across the different assays. Such data might then be used either for regulatory decision-making or compound prioritization in favour of a reduction of rodent guideline in vivo testing.