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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
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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.

Place, publisher, year, edition, pages
2014. Vol. 226, no 1, p. 1-5
Keywords [en]
ALS/PDC, Cyanobacteria, Autoradiography, Mass spectrometry, Misincorporation, N-(2-aminoethyl) glycine
National Category
Medical and Health Sciences Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-222718DOI: 10.1016/j.toxlet.2014.01.027ISI: 000332409000001PubMedID: 24472610OAI: oai:DiVA.org:uu-222718DiVA, id: diva2:713048
Funder
Swedish Research Council FormasAvailable from: 2014-04-17 Created: 2014-04-14 Last updated: 2017-06-30Bibliographically approved
In thesis
1. Cellular transport and secretion of the cyanobacterial neurotoxin BMAA into milk and egg: Implications for developmental neurotoxicity
Open this publication in new window or tab >>Cellular transport and secretion of the cyanobacterial neurotoxin BMAA into milk and egg: Implications for developmental neurotoxicity
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA) is a neurotoxin implicated in the etiology of neurodegenerative diseases. Cyanobacteria are cosmopolitan organisms present in various environments. BMAA can cause long-term neurodegenerative alterations in rats exposed during the neonatal period, a period that corresponds to the last trimester and the first few years of life in humans. As BMAA has been reported to be bioaccumulated in the aquatic food chain and detected in mussels, crayfish and fish used for human consumption, the main aim of this thesis has been to investigate the final step in the mammalian food-chain, i.e. the transfer of BMAA into breast milk.

Autoradiographic imaging and mass spectrometry analysis showed an enantiomer-selective uptake of BMAA and that the neurotoxin was transferred from lactating mice and rat, via the milk, to the brain of the nursed pups. The results show that transport of BMAA may be disproportional to dose. In addition, BMAA was found present both as free amino acid and tightly associated to proteins in rat brains. Surprisingly, however, no association to milk proteins was found. In vitro studies of murine (HC11) and human (MCF7) mammary epithelial cells suggest that BMAA can pass the human mammary epithelium into milk. Additional transport studies on human intestinal, glioblastoma and neuroblastoma cells showed that L-BMAA was consistently favored over D-BMAA and that the transport was mediated by several amino acid transporters. We also demonstrated that egg-laying quail transfer BMAA to its offspring by deposition in the eggs, particularly in the yolk but also in the albumen. Furthermore, comparative analysis of carboxyl- and methyl-labeled [14C]-BMAA suggested that BMAA was not metabolized to a large degree.

Altogether, the results indicate that BMAA can be transferred from mothers, via the milk, to the brain of nursed human infants. Determinations of BMAA in mothers’ milk and cows’ milk are therefore warranted. We also propose that birds’ eggs could be an additional source of BMAA exposure in humans. It might therefore be of concern that mussels are increasingly used as feed in commercial egg production.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 72
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1316
Keywords
BMAA, beta-N-methylamino-L-alanine, milk, secretion, amino acid transporter, autoradiography, metabolism
National Category
Developmental Biology Cell Biology
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-265865 (URN)978-91-554-9408-7 (ISBN)
Public defence
2015-12-18, Friessalen, EBC, Norbyvägen 14, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2015-11-26 Created: 2015-11-03 Last updated: 2016-01-13

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Karlsson, OskarAndersson, MarieBrittebo, Eva B.

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