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Disposition of β-N-methylamino-L-alanine (L-BMAA), a Neurotoxin, in Rodents Following a Single or Repeated Oral Exposure

Suramya Waidyanatha, Kristen Ryan, J. Michael Sanders, Jacob D. McDonald, Christopher J. Wegerski, Melanie Doyle-Eisle, C. Edwin Garner
Toxicology and Applied Pharmacology (2018). DOI: https://doi.org/10.1016/j.taap.2017.12.008 PMID: 29248465

Publication

Abstract

β-N-methylamino-l-alanine (L-BMAA) is produced by cyanobacteria (blue-green algae). Human exposure to L-BMAA occurs via consumption of L-BMAA-contaminated water and food. It is speculated that exposure to L-BMAA, and subsequent brain accumulation, may contribute to an increased incidence of neurodegenerative diseases indicating the need to evaluate risk of L-BMAA exposure to humans. As an initial step in this process, we have evaluated disposition following a single or repeated gavage administration of 1, 10 or 100mg/kg [14C]L-BMAA in rats and mice. L-BMAA was well absorbed following a single gavage administration with minimal dose, species, or sex-related effect. In both species, the main excretion route was as exhaled CO2 (46-61%) with 7-13% and 1.4-8% of the administered dose excreted in the urine and feces, respectively. L-BMAA was distributed to all tissues examined; the total radioactivity in tissues increased with the dose and was significant in both species (8-20%). In male rats, L-BMAA was slowly eliminated from blood and tissues (half-lives ≥48h). Following 1, 5 and 10days of dosing in male rats, levels in tissues increased with the number of doses demonstrating potential for accumulation of BMAA-derived equivalents. There was no greater affinity for accumulation in the brain compared to other organs and tissues. Following repeated exposure in rats, amino acid mass shifts associated with L-BMAA were detected in brain peptides. However, the low frequency of occurrence suggests that the substitution of an amino acid with L-BMAA is not significant relative to substitutions and/or modifications by other L-BMAA-derived equivalents.

Figures

Figure 1. Structure of β-N-methylamino-l-alanine (L-BMAA).

Positions of radiolabel in [14C]L-BMAA are indicated by asterisks.

Figure 2. Cumulative excretion of [14C]L-BMAA A) in urine and B) as CO2 24 h.

Cumulative excretion of [14C]L-BMAA A) in urine and B) as CO2 24 h following a single gavage administration of 1, 10, and 100 mg/kg in male Harlan Sprague Dawley rats.

Figure 3. Radioactivity in selected tissues.

Radioactivity in selected tissues 24 h following 1, 5, and 10 daily gavage doses of 1 mg/kg [14C]L-BMAA in male Harlan Sprague Dawley rats.

Figure 4. Total radioactivity vs. time profiles of blood and brain.

Total radioactivity vs. time profiles of blood and brain following a single gavage administration of 10 mg/kg [14C]L-BMAA in male Harlan Sprague Dawley rats.

Figure 5. Cumulative excretion of [14C]L-BMAA A) in urine and B) as CO2 24 h.

Cumulative excretion of [14C]L-BMAA A) in urine and B) as CO2 24 h following a single gavage administration of 1, 10, and 100 mg/kg in male B6C3F1/N mice.

Figure 6. Total radioactivity and comparison.

A) Total radioactivity in brain (open square) and associated with brain proteins (open circle) B) Comparison of percent extractable and protein-associated radioactivity following 1, 5, and 10 daily gavage doses of 1 mg/kg [14C]L-BMAA and sacrificed 24 h following last dose administration in male Harlan Sprague Dawley rats.

Figure 7. Scatter plot of numbers of mass shifts at specific amino acids found in plasma proteins.

Scatter plot of numbers of mass shifts at specific amino acids found in plasma proteins from control rats versus rats exposed rats to 5 consecutive doses of 100 mg/kg L-BMAA. Modifications with a p-value of > 0.1 were considered non-candidates (diamonds), 0.1–0.05 were considered low probability candidates (circles) and 0.05–0.01 were ranked medium (triangles).

Figure 8. Scatter plot of numbers of mass shifts at specific amino acids found in brain proteins.

Scatter plot of numbers of mass shifts at specific amino acids found in brain proteins from control rats versus rats exposed rats to 5 consecutive doses of 100 mg/kg L-BMAA. Modifications with a p-value of > 0.1 were considered non-candidates (diamonds), 0.1–0.05 were considered low probability candidates (circles), 0.05–0.01 were ranked medium (triangles), and 0.01 and less were ranked high (squares).

Tables

Table 1. Gavage and intravenous administration ADME study design.

Gavage and intravenous administration ADME study design of [14C]L-BMAA in Harlan Sprague Dawley rats and B6C3F1/N mice.
a Study duration after the last dose is shown.
b Intravenous groups.

Table 2. Disposition of [14C]L-BMAA in male and female Harlan Sprague Dawley rats.

Disposition of [14C]L-BMAA in male and female Harlan Sprague Dawley rats 24 h following a single gavage or intravenous administration.
a Mean ± SD for 5 animals.
b Includes cage rinse and urine present in the urinary bladder at study termination.

Table 3. Elimination half-livesa of L-BMAA in blood and tissues.

Elimination half-livesa of L-BMAA in blood and tissues following gavage administration of 10 mg/kg [14C]L-BMAA in male Harlan Sprague Dawley rats.
a Data given are based on total radioactivity.
b Half-lives were estimated as 0.693/k, where k, elimination rate constant, is the slope of log linear curves of total radioactive equivalents vs. time.

Table 4. Disposition of [14C]L-BMAA in male and female B6C3F1/N mice 24 h.

Disposition of [14C]L-BMAA in male and female B6C3F1/N mice 24 h following a single gavage or intravenous administration.
a Mean ± SD for 5 animals.
b Includes cage rinse and urine present in the urinary bladder at study termination.

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Supplemental Data