Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents

Abstract

Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents. Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse brain. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg s.c.) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure

“…Both free and proteinassociated BMAA also have been found in several tissue types, including brain, muscle, skin, intestine, kidney, and fur, in flying foxes (Pteropus mariannus and P. tonganus) (42). CNS uptake and long-term and short-term neurotoxic effects of BMAA have been demonstrated in rodents after perinatal administration (13,43). The mechanisms of entry to the CNS of BMAA remain unclear, however.…”

“…BMAA was later shown to cause selective motor neuron loss in dissociated mixed spinal cord cultures at concentrations ≈30 μM (11), and also to potentiate neuronal injury induced by other insults at concentrations as low as 10 μM (12). Hippocampal neurons are among the most BMAA-sensitive neuronal populations in vitro (13). The hypothesis that BMAA acts as a possible pathogenic factor in human neurodegenerative disease is further supported by the observation of high BMAA levels in relevant central nervous system (CNS) areas in Alzheimer's disease and ALS patients in North America (14).…”

Detection of BMAA in the human central nervous system

“…Furthermore, free BMAA in the human CNS could potentially escape detection due to a short half-life, known to be less than one day in the CNS of rats (Duncan et al, 1991;Smith et al, 1992). The reported rapid binding of BMAA to specific regions of the brain in neonatal mice also implies that free BMAA perhaps reside in the CSF for only a short time span (Karlsson et al, 2009b). In addition, free BMAA in the plasma and brain of BMAA-injected mice steadily decreased (within days), while the protein-associated BMAA levels in the brain reached a plateau (within hours) and accounted for most of the BMAA detected one week later (Xie et al, 2013).…”

The neurotoxin BMAA in aquatic systems : analysis, occurrence and effects

“…Recent studies indeed indicate that BMAA can either associate with, or be incorporated into proteins [65,90,141,176], although this association might in some cases be superficial [91]. BMAA can be maternally transferred as shown for mice, either directly [177] or trough milk during lactation [178]. If BMAA can reside inside the body for a longer period of time and can be transferred to offspring, it is likely that BMAA exposure can have trans generational effects.…”

“…This means that BMAA was maternally transferred, and that in D. magna females, the internal BMAA concentration is lowered through reproduction. Similarly, in mice, the internal BMAA load in mothers is reduced when BMAA is transferred to their offspring via the placenta and lactation [177,178].…”