| 1. |
- Alm, Henrik, et al.
(author)
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Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether
- 2006
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In: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 114:2, s. 254-259
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Journal article (peer-reviewed)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.
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| 2. |
- Alm, Elisabet, 1948-
(author)
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Sveconorwegian metallogenesis in Sweden
- 2000
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Doctoral thesis (other academic/artistic)abstract
- Two main ore types are found in the Sveconorwegian Orogen in southwestern Sweden (Southwest Scandinavian Domain). One of them comprises stratabound Cu mineralizations in the Dal group, located west of lake Vänern. The other comprises quartz veins with varying precious and base metal contents, distributed over 250 km between lake Mjøsa (southeastern Norway) and lake Vänern. In this thesis, both ore types are discussed, although the main emphasis is on Au-bearing quartz veins, particularly those in the Harnäs area near lake Vänern.The Dal group is a 2000 m thick sequence of clastic sediments and intercalated mafic volcanic rocks, metamorphosed under greenschist facies conditions. It records deposition mainly in a shallow marine basin, formed during a rift stage preceding the Sveconorwegian orogeny (c. 1.15-0.9 Ga). The volcanic rocks have been subject to various degrees of sodic and/or potassic alteration. Geochemical and Sm-Nd isotopic evidence indicate a continental setting of volcanism. Cu mineralizations (chalcopyrite and bornite) occur at two stratigraphic levels. An ore-genetic model involving synsedimentary (or syndiagenetic) deposition of sulphides from metal-bearing fluids is favoured.Among Au-bearing quartz veins in the Mjøsa-Vänern ore district, four paragenetic types have been distinguished: Cu-dominated veins with chalcopyrite and/or bornite; Pb-Cu-bearing veins with pyrite, galena and chalcopyrite; Zn-Pb-dominated veins with sphalerite, galena, pyrite and chalcopyrite; Mn-bearing vein(s) with galena, chalcopyrite and hausmannite. In addition, e.g. native gold, argyrodite, hessite, tellurobismuthite and altaite are recognized. The ore lead isotopic composition is complex and metals appear to be derived from a variety of source rocks.The orthogneisses, which constitute the host rocks to the Harnäs veins and the Brustad Au quartz veins (Eidsvoll, near lake Mjøsa), have been investigated with respect to geochemistry, U-Pb zircon age and feldspar lead isotopic composition. The obtained intrusion age of the Brustad augen gneiss is 1674 ± 10 Ma and this rock is considered to belong to the Transscandinavian Igneous Belt. The Harnäs gneiss yielded a protolith age of 1595 +24/-17 Ma and is considered to be a member of the Åmål granitoid suite. Both orthogneisses have undergone ductile deformation during the Sveconorwegian orogeny. A complete isotopic resetting of the feldspar lead through dynamic recrystallization in conjunction with this deformation, at c. 1.0 Ga, has been demonstrated.The steeply dipping Harnäs veins are hosted in a local left-lateral shear zone, which transects the fabric in the surrounding orthogneisses. The moderate wall rock alteration was mainly sericitic. Fluid inclusions show that the ore-bearing vein system at Harnäs developed essentially in three stages: a quartz stage, a pyrite-gold stage and finally a galena stage. The early ore fluid was CO2-bearing, of low salinity and with a temperature of c. 200 oC, while in the galena stage it was purely aqueous, with a slightly higher salinity and a slightly lower temperature. Oxygen and sulphur isotope results imply a predominantly metamorphic origin for the ore fluid and suggest that the fluid constituents were derived from the regional orthogneisses. Ore lead isotopic compositions indicate metal derivation from these orthogneisses shortly after the Sveconorwegian deformation and resetting of feldspar lead. Subordinate Au-anomalous quartz veins in the Harnäs area as well as the Brustad Au quartz veins show characteristics similar to the Harnäs veins. Despite recognized variations, e.g. in mineralogy, a common origin is envisaged for most veins in the Mjøsa-Vänern ore district. They are characterized as late Proterozoic orogenic type Au deposits, with modern analogues e.g. in the western Alps.
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| 3. |
- Alm Grundström, Henrik
(author)
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Developments in Topology Optimization in the ADDMAN Project
- 2018
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Reports (other academic/artistic)abstract
- This document gives an account of some of the work done so far on topology optimization (TO) in the ADDMAN project. As well as the mathematical formulations and implementations details, short discussions are presented on some of the nuances of the different formulations and how they should be used efficiently
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| 4. |
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| 5. |
- Alm, Henrik, et al.
(author)
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Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex
- 2008
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In: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 29:4, s. 628-637
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Journal article (peer-reviewed)abstract
- Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.
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| 6. |
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| 7. |
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| 8. |
- Alm, Henrik, et al.
(author)
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In Vitro Neurotoxicity of PBDE-99 : Immediate and Concentration-Dependent Effects on Protein Expression in Cerebral Cortex Cells
- 2010
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 9:3, s. 1226-1235
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Journal article (peer-reviewed)abstract
- Polybrominated diphenyl ethers (PBDEs) are commonly used flame retardants in various consumer products. Pre- and postnatal exposure to congeners of PBDEs disrupts normal brain development in rodents. Two-dimensional difference gel electrophoresis (2D-DIGE) was used to analyze concentration-dependent differences in protein expression in cultured cortical cells isolated from rat fetuses (GD 21) after 24 h exposure to PBDE-99 (3, 10, or 30 muM). Changes on a post-translational level were studied using a 1 h exposure to 30 muM PBDE-99. The effects of 24 h exposure to 3 and 30 muM PBDE-99 on mRNA levels were measured using oligonucleotide microarrays. A total of 62, 46, and 443 proteins were differentially expressed compared to controls after 24 h of exposure to 3, 10, and 30 muM PDBE-99, respectively. Of these, 48, 43, and 238 proteins were successfully identified, respectively. We propose that the biological effects of low-concentration PBDE-99 exposure are fundamentally different than effects of high-concentration exposure. Low-dose PBDE-99 exposure induced marked effects on cytoskeletal proteins, which was not correlated to cytotoxicity or major morphological effects, suggesting that other more regulatory aspects of cytoskeletal functions may be affected. Interestingly, 0.3 and 3 muM, but not 10 or 30 muM increased the expression of phosphorylated (active) Gap43, perhaps reflecting effects on neurite extension processes.
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| 9. |
- Alm, Henrik, 1974-
(author)
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Proteomic Characterization of Induced Developmental Neurotoxicity
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The developing brain goes through a number of developmental periods during which it displays an increased sensitivity to exogenous disturbances. On such period is the so called “Brain growth spurt” (BGS) which in humans takes place starting from the third trimester of pregnancy and throughout the first few years of life. The corresponding period in rats and mice is the first postnatal weeks. Exposure to relatively modest concentrations of the brominated flame retardant PBDE-99 during the second week of life in mice causes a more or less permanent impairment in the ability of the animals to adjust properly to environmental changes at adulthood. This “late response on early exposure” reflects the long-term consequences of disrupting the developing brain during a sensitive time period. The cellular mechanisms underlying the behavioral effects are far from clear. To address the initial damage occurring around the time of exposure, the approach used in this thesis is to use proteomics to analyze the effects of PBDE-99 on protein expression soon (24 hours) after exposure of the neonatal mouse on postnatal day (PND) 10.The thesis comprises the effects on the proteome in three distinct brain parts: cerebral cortex, striatum and the hippocampus. In addition, an in vitro model was developed and used to evaluate the PBDE-99 effects on cultured cerebral cortex cells from embryonic rat brains. Gel-based proteomics (2D-DIGE) coupled to MALDI- or ESI-MS has been used throughout for the proteomics experiments, but other techniques aimed at analyzing both proteins and mRNA have also been used to better characterize the effects. Even if the protein complements expressed by the different brain parts and separated with 2D-DIGE are seemingly similar, the effects are apparently specific for the different brain regions. In hippocampus, PBDE induces effects on proteins involved in metabolism and energy production, while the effects in striatum point towards effects on neuroplasticity. PBDE-99 changes the expression of cytoskeletal proteins in the cerebral cortex 24 hours after exposure. Interestingly, in vitro exposure of cerebral cortex cells to a PBDE-99 concentration in the same order of magnitude as in the in vivo neonatal brain also induces cytoskeletal effects, in the absence of cytotoxicity. This may suggest effects on regulatory aspects of cytoskeletal dynamics such as those involved in neurite sprouting. This thesis also addresses the problems involved in presenting proteomics data. Many of the available methods and approaches for presenting transcriptomics data are not suitable for isoform rich protein data. Modifications of existing methods and the development of a new approach (DEPPS) is also presented. Most importantly, the thesis presents the application and usefulness of proteomics as hypothesis generating techniques in neurotoxicology.
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| 10. |
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