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LONG-TERM MORPHOLOGICAL AND PROTEIN CHANGES IN THE BRAIN OF ADULT RATS NEONATALLY TREATED WITH THE ENVIRONMENTAL TOXIN β-N-METHYLAMINO-L-ALANINE (BMAA)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
AstraZeneca.
AstraZeneca.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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(English)Manuscript (preprint) (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-140784OAI: oai:DiVA.org:uu-140784DiVA: diva2:384378
Available from: 2011-01-09 Created: 2011-01-09 Last updated: 2011-03-21
In thesis
1. Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure
Open this publication in new window or tab >>Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many cyanobacteria are reported to produce the nonprotein amino acid β-N-methylamino-L-alanine (BMAA). Cyanobacteria are extensively distributed in terrestrial and aquatic environments and recently BMAA was detected in temperate aquatic ecosystems, e.g. the Baltic Sea. Little is known about developmental effects of the mixed glutamate receptor agonist BMAA. Brain development requires an optimal level of glutamate receptor activity as the glutamatergic system modulates many vital neurodevelopmental processes.

The aim of this thesis was to investigate the developmental neurotoxicity of BMAA, and its interaction with the pigment melanin. Autoradiography was utilized to determine the tissue distribution of 3H-labelled BMAA in experimental animals. Behavioral studies and histological techniques were used to study short and long-term changes in the brain following neonatal exposure to BMAA. Long-term changes in protein expression in the brain was also investigated using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS).

A notable targeting of 3H-BMAA to discrete brain regions e.g. hippocampus and striatum in mouse fetuses and neonates was determined by autoradiography. BMAA treatment of neonatal rats on postnatal days 9–10 induced acute but transient ataxia and hyperactivity. Postnatal exposure to BMAA also gave rise to reduced spatial learning and memory abilities in adulthood. Neonatal rat pups treated with BMAA at 600 mg/kg showed early neuronal cell death in the hippocampus, retrosplenial and cingulate cortices. In adulthood the CA1 region of the hippocampus displayed neuronal loss and astrogliosis. Lower doses of BMAA (50 and 200 mg/kg) caused impairments in learning and memory function without any acute or long-term morphological changes in the brain. The MALDI IMS studies, however, revealed changes in protein expression in the hippocampus and striatum suggesting more subtle effects on neurodevelopmental processes. The studies also showed that BMAA was bound and incorporated in melanin and neuromelanin, suggesting that pigmented tissues such as in the substantia nigra and eye may be sequestering BMAA.

In conclusion, the findings in this thesis show that BMAA is a developmental neurotoxin in rodents. The risks posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 134
Keyword
ALS/PDC, Guam, Developmental neurotoxicity, Brain growth spurt, Behavior, Nonprotein amino acid, Excitotoxic, Cyanobacteria, Apoptosis, BMAA, environmental toxin, Algal blooming, Algblomning, algtoxin, alggift, hjärnutveckling
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-140785 (URN)978-91-554-7984-8 (ISBN)
Public defence
2011-02-18, Sal C8:301 Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2011-01-28 Created: 2011-01-09 Last updated: 2011-03-11Bibliographically approved

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Bergquist, JonasAndersson, MalinBrittebo, Eva

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