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Klint, H., Lejonklou, M. H., Karimullina, E., Rönn, M., Lind, L., Lind, P. M. & Brittebo, E. (2017). Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue. Upsala Journal of Medical Sciences, 122(1), 20-27
Open this publication in new window or tab >>Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 20-27Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.

MATERIALS: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10(4) nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.

RESULTS: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10(4) nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.

CONCLUSIONS: . Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.

Keywords
Angiogenesis, bisphenol A, cardiomyocytes, cardiovascular disease, endocrine disruption, fructose, heart, vascular tone
National Category
Pharmacology and Toxicology General Practice
Identifiers
urn:nbn:se:uu:diva-311874 (URN)10.1080/03009734.2016.1225870 (DOI)000396476600003 ()27622962 (PubMedID)
Funder
Swedish Research Council Formas, 216-2009-972
Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2018-01-13Bibliographically approved
Engskog, M. K., Karlsson, O., Haglöf, J., Elmsjö, A., Brittebo, E., Arvidsson, T. & Pettersson, C. (2017). The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats. Amino Acids, 49(5), 905-919, Article ID 10.1007/s00726-017-2391-8.
Open this publication in new window or tab >>The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats
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2017 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, no 5, p. 905-919, article id 10.1007/s00726-017-2391-8Article in journal (Refereed) Published
Abstract [en]

The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.

Keywords
β-N-methylamino-L-alanine, cyanobacteria, energy metabolism, neurotoxin, metabolomics, NMR
National Category
Analytical Chemistry Pharmaceutical Sciences
Research subject
Analytical Pharmaceutical Chemistry; Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-205735 (URN)10.1016/j.tox.2013.07.010 (DOI)000327005300002 ()23886855 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2013-08-22 Created: 2013-08-22 Last updated: 2018-01-11
Engskog, M. K. R., Ersson, L., Haglöf, J., Arvidsson, T., Pettersson, C. & Brittebo, E. (2017). β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling. Amino Acids, 49(5), 905-919
Open this publication in new window or tab >>β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling
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2017 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, no 5, p. 905-919Article in journal (Refereed) Published
Abstract [en]

β-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that induces long-term cognitive deficits, as well as an increased neurodegeneration and intracellular fibril formation in the hippocampus of adult rodents following short-time neonatal exposure and in vervet monkey brain following long-term exposure. It has also been proposed to be involved in the etiology of neurodegenerative disease in humans. The aim of this study was to identify metabolic effects not related to excitotoxicity or oxidative stress in human neuroblastoma SH-SY5Y cells. The effects of BMAA (50, 250, 1000 µM) for 24 h on cells differentiated with retinoic acid were studied. Samples were analyzed using LC-MS and NMR spectroscopy to detect altered intracellular polar metabolites. The analysis performed, followed by multivariate pattern recognition techniques, revealed significant perturbations in protein biosynthesis, amino acid metabolism pathways and citrate cycle. Of specific interest were the BMAA-induced alterations in alanine, aspartate and glutamate metabolism and as well as alterations in various neurotransmitters/neuromodulators such as GABA and taurine. The results indicate that BMAA can interfere with metabolic pathways involved in neurotransmission in human neuroblastoma cells.

Keywords
BMAA, Global metabolite profiling, MS, Metabolism, NMR, Neurotoxin
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-322142 (URN)10.1007/s00726-017-2391-8 (DOI)000399176200006 ()28161796 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2018-01-13Bibliographically approved
Andersson, M., Karlsson, O., Bergström, U., Brittebo, E. B. & Brandt, I. (2015). Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring. PLoS ONE, 8(10), Article ID e78133.
Open this publication in new window or tab >>Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, article id e78133Article in journal (Refereed) Published
National Category
Cell Biology Developmental Biology
Identifiers
urn:nbn:se:uu:diva-265863 (URN)10.1371/journal.pone.0133110 (DOI)000358194900136 ()26172384 (PubMedID)
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-12-01Bibliographically approved
Karlsson, O., Jiang, L., Ersson, L., Malmstrom, T., Ilag, L. L. & Brittebo, E. B. (2015). Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (beta-N-methylamino-L-alanine) in neonatal rat brain. Scientific Reports, 5, Article ID 15570.
Open this publication in new window or tab >>Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (beta-N-methylamino-L-alanine) in neonatal rat brain
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15570Article in journal (Refereed) Published
Abstract [en]

beta-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-267198 (URN)10.1038/srep15570 (DOI)000363397500001 ()26498001 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2015-11-19 Created: 2015-11-19 Last updated: 2018-01-10Bibliographically approved
Karlsson, O., Berg, A.-L., Hanrieder, J., Arnerup, G., Lindström, A.-K. & Brittebo, E. B. (2015). Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA. Archives of Toxicology, 89(3), 423-436
Open this publication in new window or tab >>Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA
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2015 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 89, no 3, p. 423-436Article in journal (Refereed) Published
Abstract [en]

The environmental neurotoxin β-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease, and recent studies indicate that BMAA can be misincorporated into proteins. BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal CA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9-10) with BMAA (460 mg/kg) using immunohistochemistry (IHC), transmission electron microscopy, and laser capture microdissection followed by LC-MS/MS for proteomic analysis. The histological examination demonstrated progressive neurodegenerative changes, astrogliosis, microglial activation, and calcification in the hippocampal CA1 3-6 months after exposure. The IHC showed an increased staining for α-synuclein and ubiquitin in the area. The ultrastructural examination revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons, and astrocytes of the CA1. Proteomic analysis of the affected site demonstrated an enrichment of chaperones (e.g., clusterin, GRP-78), cytoskeletal and intermediate filament proteins, and proteins involved in the antioxidant defense system. Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. In addition, TDP-43 and the negative regulator of autophagy, GLIPR-2, were exclusively detected. The present study demonstrates that neonatal exposure to BMAA may offer a novel model for the study of hippocampal fibril formation in vivo.

National Category
Pharmacology and Toxicology Neurosciences
Identifiers
urn:nbn:se:uu:diva-225453 (URN)10.1007/s00204-014-1262-2 (DOI)000350030200011 ()24798087 (PubMedID)
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2018-01-11Bibliographically approved
Hanrieder, J., Gerber, L., Persson Sandelius, A., Brittebo, E. B., Ewing, A. G. & Karlsson, O. (2014). High resolution metabolite imaging in the hippocampus following neonatal exposure to the environmental toxin BMAA using ToF-SIMS. ACS Chemical Neuroscience, 5(7), 568-575
Open this publication in new window or tab >>High resolution metabolite imaging in the hippocampus following neonatal exposure to the environmental toxin BMAA using ToF-SIMS
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2014 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 5, no 7, p. 568-575Article in journal (Refereed) Published
Abstract [en]

The environmental neurotoxin β-N-methylamino-l-alanine (BMAA) is suggested to be linked with neurodegenerative disease. In a rat model, neonatal exposure to BMAA induced selective uptake in the hippocampus and caused cell loss, mineralization and astrogliosis as well as learning and memory impairments in adulthood. Moreover, neonatal exposure resulted in increased protein ubiquitination in the cornus ammonis 1 (CA1) region of the adult hippocampus indicating that BMAA may induce protein aggregation. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) based imaging is a powerful technology for spatial profiling of small molecular weight compounds in biological tissues with high chemical specificity and high spatial resolution. The aim of this study was to characterize neurochemical changes in the hippocampus of six month-old rats treated neonatally (postnatal days 9-10) with BMAA. Multivariate data analysis of whole section ToF-SIMS scans was performed to delineate anatomical regions of interest based on their chemical distribution pattern. Further analysis of spectral data obtained from the outlined anatomical regions, including CA1 and dentate gyrus (DG) revealed BMAA-induced long-term changes. Increased levels of phospholipids and protein fragments in the histopathologically altered CA1 region as well as phosphate depletion in the DG were observed. Moreover, high resolution SIMS imaging revealed a specific localization of phosphatidylcholine lipids, protein signals and potassium in the histopathologically altered CA1. These findings demonstrate that ToF-SIMS based imaging is a powerful approach for probing biochemical changes in situ and might serve as promising technique for investigating neurotoxin-induced brain pathology.

National Category
Neurosciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-225455 (URN)10.1021/cn500039b (DOI)000339226100013 ()24779349 (PubMedID)
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2018-01-11Bibliographically approved
Fransson, M., Piras, E., Wang, H., Burman, J., Duprez, I., Harris, R. A., . . . Loskog, A. S. (2014). Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis. Immunology, 142(3), 431-441
Open this publication in new window or tab >>Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis
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2014 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 142, no 3, p. 431-441Article in journal (Refereed) Published
Abstract [en]

Treatment with mesenchymal stromal cells (MSC) is currently of interest for a number of diseases including multiple sclerosis (MS). MSCs is well known to target inflamed tissues however, in a therapeutic scenery, systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal (i.n) administration and persist in CNS tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein (MOG)-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon i.n. cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). The mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSC did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model.

National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-223631 (URN)10.1111/imm.12275 (DOI)000337600500012 ()24588452 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2018-05-18Bibliographically approved
Hanrieder, J., Karlsson, O., Brittebo, E. B., Malmberg, P. & Ewing, A. G. (2014). Probing the lipid chemistry of neurotoxin-induced hippocampal lesions using multimodal imaging mass spectrometry. Paper presented at 19th International Conference on Secondary Ion Mass Spectrometry (SIMS), SEP 29-OCT 04, 2013, Jeju, SOUTH KOREA. Surface and Interface Analysis, 46(1), 375-378
Open this publication in new window or tab >>Probing the lipid chemistry of neurotoxin-induced hippocampal lesions using multimodal imaging mass spectrometry
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2014 (English)In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 46, no 1, p. 375-378Article in journal (Refereed) Published
Abstract [en]

The environmental toxin -N-methylamino-l-alanine (BMAA) has been causatively linked to neurodegenerative disease pathology. In a rat model, neonatal BMAA resulted in selective uptake in the hippocampal formation and caused learning and memory impairments in adult animals. Moreover, high dose neonatal BMAA exposure resulted in formation of histopathological lesions in the CA1 region of the adult hippocampus; however, the mechanism underlying BMAA induced neuropathology remains elusive. Imaging mass spectrometry (IMS) is a powerful method for spatial interrogation of biochemical distribution in biological tissue with high chemical specificity. The aim of this study was to therefore characterize the lipid microenvironment of BMAA-induced hippocampal lesions in adult rats using matrix-assisted laser desorption/ionization (MALDI) and time-of-flight SIMS (ToF-SIMS imaging). Multimodal imaging was carried out by ToF-SIMS scans of the hippocampal formation followed by whole tissue scans using MALDI imaging. Multivariate analysis was performed on the SIMS data in order to delineate the spatial biochemistry surrounding the lesions. The data show lesion-specific localization of phosphatidylcholine fragments, suggesting neuroinflammatory glial cell activation. Complementary MALDI imaging data showed increased levels of phosphoethanolamines colocalizing with the proteopathic lesions pointing to macroautophagic mechanisms associated with neurotoxin-induced protein accumulation. Multimodal IMS by means of ToF-SIMS and MALDI mass spectrometry proved to be a powerful technique for neurotoxicological research. 

Keywords
imaging mass spectrometry (IMS), beta-N-methylamino-l-alanine (BMAA), ALS, PD-Complex, matrix-assisted laser desorption, ionization (MALDI), time-of-flight secondary ion mass spectrometry (ToF-SIMS)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-240448 (URN)10.1002/sia.5418 (DOI)000345696200094 ()
Conference
19th International Conference on Secondary Ion Mass Spectrometry (SIMS), SEP 29-OCT 04, 2013, Jeju, SOUTH KOREA
Available from: 2015-01-08 Created: 2015-01-07 Last updated: 2018-01-11Bibliographically approved
Karlsson, O., Jiang, L., Andersson, M., Ilag, L. L. & Brittebo, E. B. (2014). Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats. Toxicology Letters, 226(1), 1-5
Open this publication in new window or tab >>Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats
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2014 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed) Published
Abstract [en]

The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

Keywords
ALS/PDC, Cyanobacteria, Autoradiography, Mass spectrometry, Misincorporation, N-(2-aminoethyl) glycine
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-222718 (URN)10.1016/j.toxlet.2014.01.027 (DOI)000332409000001 ()24472610 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2014-04-17 Created: 2014-04-14 Last updated: 2017-06-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7644-1967

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