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Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis
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. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, SE-17176 Stockholm, Sweden.
Inst Ethnomed, POB 3464, Jackson, WY 83001 USA.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
2016 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, 108-114 p.Article in journal (Refereed) Published
Abstract [en]

The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
2016. Vol. 258, 108-114 p.
Keyword [en]
BMAA; Cyanobacterial neurotoxin, kinetics; Milk secretion; Developmental neurotoxicity; Mother-to-offspring transfer
National Category
Developmental Biology
URN: urn:nbn:se:uu:diva-265847DOI: 10.1016/j.toxlet.2016.06.015ISI: 000381648300012PubMedID: 27320960OAI: oai:DiVA.org:uu-265847DiVA: diva2:866692
Milk, secretion, BMAA, beta-N-methylamino-L-alanine, autoradiography, mass spectrometry
Swedish Research Council Formas
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2016-09-15Bibliographically 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. 72 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1316
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
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)
Available from: 2015-11-26 Created: 2015-11-03 Last updated: 2016-01-13

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