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- Karlsson, Oskar, 1980-
(författare)
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Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA) : Brain changes and behavioral impairments following developmental exposure
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Tofighi, Roshan, et al.
(författare)
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Non-dioxin like polychlorinated biphenyls interfere with neuronal differentiation of embryonic neural stem cells
- 2011
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Ingår i: Toxicological Sciences. - : Oxford Journals. - 1096-6080 .- 1096-0929. ; 124:1, s. 192-201
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Tidskriftsartikel (refereegranskat)abstract
- Developmental exposure to food contaminants, such as polychlorinated biphenyls (PCBs), has been considered as a possible cause of neurodevelopmental disorders. We have investigated the effects of non-cytotoxic concentrations of PCB 153 and 180 on spontaneous differentiation of rat embryonic neural stem cells (NSCs). Upon removal of basic fibroblast growth factor to induce spontaneous differentiation, cells were exposed to 100 nM of the selected PCBs for 48 h and analyzed after 5 days. Both PCB 153 and 180 induced a significant increase in the number of neurite-bearing Tuj1 positive cells with a concomitant decrease in proliferating cells, as detected by Fucci-transfection and EdU-staining. Measurements of spontaneous Ca(2+) oscillations showed a decreased number of cells with Ca(2+) activity after PCB exposure, further confirming the increase in neuronal cells. Conversely, exposure to methylmercury (MeHg), which we evaluated in parallel, led to an increased number of cells with Ca(2+) activity, in agreement with the previously observed inhibition of neuronal differentiation. Analysis with q-PCR of the Notch pathway revealed that PCBs has a repressive action on Notch signaling, whereas MeHg activates it. All together, the data indicate that nM concentrations of the selected non-dioxin like PCBs and MeHg interfere in opposite directions with neuronal spontaneous differentiation of NSCs through Notch signaling. Combined exposures to PCBs and MeHg resulted in an induction of apoptosis and an antagonistic interaction on spontaneous neuronal differentiation. NSCs are further proven to be a valuable in vitro model to identify potential developmental neurotoxicants.
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