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Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
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.
2017 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed) Published
Abstract [en]

β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 320, p. 40-50
Keywords [en]
BMAA, Cellular transport, Amino acid transporters, Breast milk, Neurodegeneration
National Category
Cell Biology Developmental Biology
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-265857DOI: 10.1016/j.taap.2017.02.004ISI: 000396798200006PubMedID: 28174119OAI: oai:DiVA.org:uu-265857DiVA, id: diva2:866693
Funder
Swedish Research Council FormasAvailable from: 2015-11-03 Created: 2015-11-03 Last updated: 2019-12-19Bibliographically 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
2. β-N-methylamino-L-alanine (BMAA)-induced neurotoxicity: Studies in vitro and in vivo
Open this publication in new window or tab >>β-N-methylamino-L-alanine (BMAA)-induced neurotoxicity: Studies in vitro and in vivo
2020 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

β-N-methylamino-L-alanine (BMAA) is a neurotoxic non-proteinogenic amino acid produced naturally by cyanobacteria, diatoms and dinoflagellates and it has been detected in samples from fresh and marine water from all over the world. It can bioaccumulate in fish and shellfish, and has a potential to biomagnify in a terrestrial food chain. BMAA was first discovered in the search for a neurotoxin related to the amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC) found among the Chamorro people in Guam. This non-proteinogenic amino acid has also been suggested to contribute to sporadic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). BMAA can induce neurotoxicity via multiple mechanisms. It can act as an excitotoxin by activating glutamate receptors and to induce oxidative stress. It has also been suggested to be misincorporated into proteins leading to misfolded protein aggregates. Previous studies have demonstrated a specific damage in the hippocampus, including intracellular fibril formation, in adult rats following neonatal exposure to BMAA. In this thesis both in vitro and in vivo models were used to characterize the uptake, transport and effects of BMAA in cultured cell lines and in neonatal rodent brain tissue. The uptake of radiolabeled BMAA, as well as the effects of various amino acids and transporter antagonists on the uptake were studied in human mammary epithelial cells, intestinal epithelial cells, glioblastoma and neuroblastoma cells. Based on the obtained results a potential human mother-to-infant transfer of BMAA was suggested. BMAA-induced metabolic changes in a differentiated human neuroblastoma cell line were also characterized. The results revealed a plentitude of altered metabolites, many of them involved in amino acid metabolism and the TCA cycle. Of special interest were the perturbations in alanine, aspartate and glutamate metabolism as this pathway is involved in neurotransmission. The results revealed that BMAA can interfere with fundamental metabolic and neurotransmission pathways. Finally, the levels of free and protein-associated BMAA in the brain and peripheral tissues in neonatal rats exposed to BMAA were analysed. The results revealed high levels of free BMAA in some brain regions, thus demonstrating that the neonatal brain is not protected from BMAA by the blood-brain barrier. The results also revealed a protein-association of BMAA in the neonatal hypothalamus and hippocampus. Although the total amount of BMAA in the hippocampus was not high compared to other brain regions, the percentage of protein-associated BMAA was significantly higher. The results suggest that the protein-association of BMAA may play a role in the long-term effects in the hippocampus following neonatal exposure to BMAA. The studies in this thesis have demonstrated 1) a potential transfer of BMAA via breast milk to the brain of the nursing infant, 2) BMAA-induced metabolic alterations related to neurotransmission in human neuroblastoma cells and 3) that both free and protein-associated BMAA can be detected in the neonatal rat brain.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2020
Series
Licentiate theses / Faculty of Pharmacy, Uppsala University, ISSN 1400-6200
Keywords
BMAA, neurotoxin, neurodegeneration, cellular transport, metabolic profiling, protein-association
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-400222 (URN)
Presentation
2020-01-08, B7:101a, BMC Husargatan 3, Uppsala, 10:43 (English)
Supervisors
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2022-10-26Bibliographically approved

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Andersson, MarieErsson, LisaBrandt, IngvarBergström, Ulrika

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