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Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
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2006 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, no 2, 254-259 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2006. Vol. 114, no 2, 254-259 p.
Keyword [en]
2D-GE, brain development, brain growth spurt, MALDI–ToF–MS, neonatal, neurodegeneration, PBDE-99, PKC, proteomics
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-95979DOI: 10.1289/ehp.8419PubMedID: 16451863OAI: oai:DiVA.org:uu-95979DiVA: diva2:170379
Available from: 2007-05-15 Created: 2007-05-15 Last updated: 2011-03-01Bibliographically approved
In thesis
1. Transcriptomics and Proteomics Applied to Developmental Toxicology
Open this publication in new window or tab >>Transcriptomics and Proteomics Applied to Developmental Toxicology
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Developmental toxicology is an important part of preclinical drug toxicology as well as environmental toxicology. Assessing reproductive and developmental toxicity is especially expensive and time demanding, since at least two generations of animals are needed in the tests. In light of this there is a great need for alternative test methods in many areas of developmental toxicity testing.

The complete set of RNA transcripts in any given organism is called the transcriptome. Proteomics refers to the study of the proteins in a given organism or cell population. The work of this thesis has focused on the use of high throughput screening methods in transcriptomics and proteomics to search for molecular markers of developmental toxicity.

We have studied the global gene expression effects of the developmentally toxic substance valproic acid (VPA) using microarray technology. Several genes were found that display the same gene expression pattern in vivo using mouse embryos as the pattern seen in vitro using the embryocarcinoma cell line P19. Based on these observations, the gene Gja1 was suggested as one potential molecular marker of VPA induced developmental toxicity and potential marker of histone deacetylase (HDAC) inhibition in vitro.

Using 2D-DIGE technology, which measures relative protein abundances, the effect of neonatal exposure to the flame retardant PBDE-99 was studied in mouse brain (cortex, hippocampus and striatum) 24 hr after exposure. Differentially expressed proteins in the cortex and the striatum indicate that PBDE-99 may alter neurite outgrowth.

Finally, we have suggested several improvements in the use of the 2D-DIGE technology. Novel methods for normalizing data were presented, with several advantages compared to existing methods. We have presented a method named DEPPS that makes use of all identified proteins in a dataset to make comprehensive remarks about biological processes affected.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 58
Toxicology, 2D-DIGE, Valproic acid, PBDE-99, Flame retardant, Neural tube defects, Microarray, In vivo, In vitro, Biomarker, Brain growth spurt, Normalization, Mouse embryo, Toxicogenomics, Toxikologi
urn:nbn:se:uu:diva-7921 (URN)978-91-554-6914-6 (ISBN)
Public defence
2007-06-08, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-05-15 Created: 2007-05-15Bibliographically approved

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