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Dose-Dependent Adult Neurodegeneration in a Rat Model After Neonatal Exposure to β-N-Methylamino-l-Alanine

  • Laura Scott
  • Timothy DowningEmail author
Original Article
  • 22 Downloads

Abstract

The link between neonatal BMAA exposure and neurodegeneration has recently been demonstrated in rodents. We therefore investigated the behavioral and histopathological dose response to BMAA administered as a single dose. We report here that exposure to a BMAA dose as low as 50 mg/kg on PND 3 caused mild short-term behavioral alterations as well as beta-amyloid deposition together with neuronal loss in the hippocampus of adult rats. Additionally, all histopathological abnormalities and behavioral deficits that had been observed in a previous study in the brain and spinal cord tissue of rats exposed to 400 mg/kg BMAA on PND 3 were also observed here in the brain and spinal cord tissue of male and female rats exposed to 100 mg/kg BMAA at the same age, although the proteinopathy burdens and volume losses were lower. Both behavioral deficits and histopathology increased with increasing dose, and a single neonatal BMAA exposure at a dose of 100 mg/kg was the lowest dose able to cause clinical signs of toxicity, behavioral deficits, and neuropathology that are typically observed in AD, PD, and/or ALS patients.

Keywords

β-N-methylamino-l-alanine BMAA Rats Behavior Neurodegeneration Dose response 

Notes

Funding

This study was partly funded by the National Research Foundation of South Africa.

Compliance with Ethical Standards

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. And all procedures performed here involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Al-Sammak MA, Hoagland KD, Cassada D, Snow DD (2014) Co-occurrence of the cyanotoxins BMAA, DABA and anatoxin-a in Nebraska reservoirs, fish and aquatic plants. Toxins (Basel) 6(2):488–508CrossRefGoogle Scholar
  2. Altman J, Bayer SA (1995) Atlas of prenatal rat brain development. CRC, Boca RatonGoogle Scholar
  3. Andersson M, Karlsson O, Bergstrom U, Brittebo E, Brandt I (2013) Maternal transfer of the cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) via milk to suckling offspring. PlOs One.  https://doi.org/10.1371/journal.pone.0078133
  4. Bailey KR, Crawley JN (2009) Anxiety-related disorders in mice. CRC Press/Taylor & Francis, Boca RatonGoogle Scholar
  5. Banack SA, Metcalf JS, Spáčil Z, Downing TG, Downing S, Long A, Nunn PB, Cox PA (2011) Distinguishing the cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) from other diamino acids. Toxicon 57(5):730–738CrossRefGoogle Scholar
  6. Berg DA, Belnoue L, Song H, Simon A (2013) Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain. Development 140:2548–2561CrossRefGoogle Scholar
  7. Björklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30(5):194–202CrossRefGoogle Scholar
  8. Brand LE (2009) Human exposure to cyanobacteria and BMAA. Amyotroph Lateral Scler 10:85–95CrossRefGoogle Scholar
  9. Brand LE, Pablo J, Compton A, Hammerschlag N, Mash DC (2010) Cyanobacterial blooms and the occurrence of the neurotoxin, β-N-methylamino-L-alanine (BMAA), in South Florida aquatic food webs. Harmful Algae 9(6):620–635CrossRefGoogle Scholar
  10. Carmichael O, Xie J, Fletcher E, Singh B, DeCarli C (2012) The Alzheimer’s disease neuroimaging initiative. Localized hippocampus measures are associated with Alzheimer pathology and cognition independent of total hippocampal volume. Neurobiol Aging 33(6):1124, e31–1124.  https://doi.org/10.1016/j.neurobiolaging CrossRefPubMedGoogle Scholar
  11. Conn PM (1993) Paradigms for the study of behaviour. Methods in neuroscience. Academic Press, Inc, CaliforniaGoogle Scholar
  12. Contardo-Jara V, Schwanemann T, Pflugmacher S (2014) Uptake of a cyanotoxin β-N-methylamino-L-alanine (BMAA), by wheat (Triticum aestivum). Ecotoxicol Environ Saf 104:127–131CrossRefGoogle Scholar
  13. Cruz-Aguado R, Winkler D, Shaw CA (2006) Lack of behavioural and neuropathological effects of dietary β-methylamino-L-alanine (BMAA) in mice. Pharmacol Biochem Behav 84:294–299CrossRefGoogle Scholar
  14. Dawson R Jr, Marschall EG, Chan KC, Millard WJ, Eppler B, Patterson TA (1998) Neurochemical and neurobehavioural effects of neonatal administration of b-methylamino-L-alanine and 3,3′iminodipropionitrile. Neurotoxicol Teratol 20:181–192CrossRefGoogle Scholar
  15. Deng R, Chow TJ (2010) Hypolipidemic, antioxidant, and antiinflammatory activities of microalgae Spirulina. Cardiovasc Ther 28(4):33–45CrossRefGoogle Scholar
  16. Dietrich DR, Fischer A, Michel C, Hoeger SJ (2008) Toxin mixture in cyanobacterial bloom – a critical comparison of reality with current procedures employed in human health risk assessment. Cyanobacterial harmful algal blooms: state of the science and research needs. Adv Exp Med Biol 619:885–912CrossRefGoogle Scholar
  17. Dobbing J, Sands J (1989) Comparative aspects of the brain growth spurt. Early Hum Dev 3(1):79–83CrossRefGoogle Scholar
  18. Duncan MW, Villacreses NE, Pearson PG, Wyatt L, Rapoport SI, Kopin IJ, Markey SP, Smith QR (1991) 2-Amino-3-(methylamino)-propanoic acid (BMAA) pharmacokinetics and blood–brain barrier permeability in the rat. J Pharmacol Exp Ther 258:27–35PubMedGoogle Scholar
  19. Duncan MW, Markey SP, Weick BG, Pearson PG, Ziffer H, Hu Y, Kopin IJ (1992) 2-Amino-3-(methylamino)propanoic acid (BMAA) bioavailability in the primate. Neurobiol Aging 13(2):333–337CrossRefGoogle Scholar
  20. Esterhuizen M, Pflugmacher S, Downing TG (2011) β-N-methylamino-L-alanine (BMAA) uptake by the aquatic macrophyte Ceratophyllum demersum. Ecotoxicol Environ Saf 74(1):74–77CrossRefGoogle Scholar
  21. Fanselow MS, Gale GD (2003) The amygdala, fear and memory. Ann N Y Acad Sci 985:125–134CrossRefGoogle Scholar
  22. Glazova NY, Merchieva SA, Volodina MA, Sebentsova EA, Manchenko DM, Kudrun VS, Levitskaya NG (2014) Effects of neonatal fluvoxamine administration on the physical development and activity of the serotoninergic system in white rats. Acta Nat 6(3):98–105Google Scholar
  23. Huang H, Liu CM, Sun J, Hao T, Xu CM, Wang D, Wu YQ (2016) Ketamine affects the neurogenesis of the hippocampal dentate gyrus in 7-day-old rats. Neurotox Res 30(2):185–198.  https://doi.org/10.1007/s12640-016-9615-7 CrossRefPubMedGoogle Scholar
  24. Jacob FD, Habas P, Kim K, Corbett-Detig J, Xu D, Studholme C, Glenn OA (2011) Fetal hippocampal development: analysis by magnetic resonance imaging volumetry. Pediatr Res 69(5):425–429CrossRefGoogle Scholar
  25. Jiang L, Kiselova N, Rosen J, Ilag LL (2014) Quantification of neurotoxin BMAA (β-N-methylamino-L-alanine) in seafood from Swedish markets. Sci Rep 4:6931CrossRefGoogle Scholar
  26. Jonasson S, Eriksson J, Berntzon L, Spáčil Z, Ilag LL, Ronnevi L-O, Rasmussen U, Bergman B (2010) Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure. Proc Natl Acad Sci U S A 107(20):9252–9257CrossRefGoogle Scholar
  27. Kapoor R, Mehta U (1993) Effect of supplementation of blue green alga (Spirulina) on outcome of pregnancy in rats. Plant Foods Hum Nutr 43(1):29–35CrossRefGoogle Scholar
  28. Karamyan VT, Speth RC (2008) Animal models of BMAA neurotoxicity: a critical review. Life Sci 82(5–6):233–246CrossRefGoogle Scholar
  29. Karlsson O, Roman E, Brittebo EB (2009a) Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-alanine. Toxicol Sci 112(1):185–195CrossRefGoogle Scholar
  30. Karlsson O, Lindquist NG, Brittebo EB, Roman E (2009b) Selective brain uptake and Behavioural effects of the cyanobacterial toxin BMAA (b-N-methylamino-L-alanine) following neonatal administration to rodents. Toxicol Sci 109(2):286–295CrossRefGoogle Scholar
  31. Karlsson O, Roman E, Berg AL, Brittebo EB (2011) Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period. Behav Brain Res 219(2):310–320CrossRefGoogle Scholar
  32. Karlsson O, Berg A-L, Lindstrom A-K, Arnerup G, Roman E, Bergquist J, Hanrieder J, Lindquist NG, Brittebo EB, Andersson M (2012) Neonatal exposure to the cyanobacterial toxin BMAA induces changes in protein expression, and neurodegeneration in adult hippocampus. Toxicol Sci 130(2):391–404CrossRefGoogle Scholar
  33. Karlsson O, Jiang L, Errson L, Malmstrom T, Ilag LL, Brittebo EB. (2015) Environmental neurotoxin interaction with proteins: dose-dependent increase of free and protein-associated BMAA in neonatal rat brain. Sci Rep 5, Article number 15570Google Scholar
  34. Kulisevsky J, Garcia-Sanchez C, Berthier ML, Barbanoj M, Pascual-Sedano B, Gironell A, Estevevez-Gonzalez A (2000) Chronic effects of dopaminergic replacement on cognitive function in Parkinson’s disease: a two-year follow-up study of previously untreated patients. Mov Disord 15(4):613–626CrossRefGoogle Scholar
  35. Kurland LT, Mulder DW (1954) Epidemiologic investigations of amyotrophic lateral sclerosis. 1. Preliminary report on geographic distribution, with special reference to the Mariana Islands, including clinical and pathological observations. Neurology 4:355–378CrossRefGoogle Scholar
  36. Lamprea MR, Cardenas FP, Setem J, Morato S (2008) Thigmotactic responses in an open field. Braz J Med Biol Res 41:135–140CrossRefGoogle Scholar
  37. Meyerson BJ (1985) Influence of early beta-endorphin treatment on the behaviour and reaction to beta-endorphin in the adult male rat. Psychoneuroendocrinology 10:135–147CrossRefGoogle Scholar
  38. Mondo L, Hammerschlag N, Basile M, Pablo J, Banack SA, Mash DC (2012) Cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) in shark fins. Food Chem Toxicol 10(2):509–520Google Scholar
  39. Mondo K, Glover BW, Murch SJ, Liu G, Cai Y, Davis DA, Mash DC (2014) Environmental neurotoxins β-N-methylamino-L-alanine (BMAA) and mercury in shark cartilage dietary supplements. Food Chem Toxicol 70:26–32CrossRefGoogle Scholar
  40. Murch SJ, Cox PA, Banack SA (2004) A mechanism for slow release of biomagnified cyanobacterial toxins and neurodegenerative disease in Guam. Proc Natl Acad Sci 101:12228–12231CrossRefGoogle Scholar
  41. Perry TL, Bergeron C, Biro AJ, Hansen S (1989) Chronic oral administration of b-N-methylamino-L-alanine is not neurotoxic to mice. J Neurol Sci 94:173–180CrossRefGoogle Scholar
  42. Plato CC, Garruto RM, Galasko D, Craig UK, Plato M, Gamst A, Torres JM, Wiederholt W (2003) Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 157(2):149–157CrossRefGoogle Scholar
  43. Reveillon D, Abadie E, Sechet V, Masseret E, Hess P, Amzil Z (2015) β-N-methylamino-L-alanine (BMAA) and isomers: distribution on different food web compartments of Thau lagoon, French Mediterranean Sea. Mar Environ Res 110:8–18CrossRefGoogle Scholar
  44. Reveillon D, Sechet V, Hess P, Amzil Z (2016) Systemic detection of BMAA (β-N-methylamino-L-alanine) and DAB (2,4-diaminobutyric acid) in mollusks collected in shellfish production areas along the French coasts. Toxicon 110:35–46CrossRefGoogle Scholar
  45. Salomonsson ML, Fredriksson E, Alfjorden A, Hedeland M, Bondesson U (2015) Seafood sold in Sweden contains BMAA: a study of free and total concentrations with UHPLC-MS/MS and dansyl chloride derivatization, Toxicol. Reports 2:1473–1481Google Scholar
  46. Santiago M, Matarredona ER, Machado A, Cano J (2006) Acute perfusion of BMAA in the rat’s striatum by in vivo microdialysis. Toxicol Lett 167(1):34–39CrossRefGoogle Scholar
  47. Scott LL, Downing TG (2018a) A single neonatal exposure to BMAA in a rat model produces neuropathology consistent with neurodegenerative diseases. Toxins 10(1):22.  https://doi.org/10.3390/toxins10010022 CrossRefGoogle Scholar
  48. Scott LL, Downing TG (2018b) β-N-methylamino-L-alanine (BMAA) toxicity is gender and exposure-age dependent in rats. Toxins 10(1):16CrossRefGoogle Scholar
  49. Scott LL, Downing S, Downing TG (2017) The evaluation of BMAA inhalation as a potential exposure route using a rat model. Neurotox Res 33:6–14.  https://doi.org/10.1007/s12640-017-9742-9 CrossRefPubMedGoogle Scholar
  50. Scott LL, Downing S, Downing TG (2018) Potential for dietary exposure to β-N-methylamino-L-alanine and microcystin from a freshwater system. Toxicon 150:261–266CrossRefGoogle Scholar
  51. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein L (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106-107:1–16CrossRefGoogle Scholar
  52. Shanks N, Greek R, Greek J (2009) Are animal models predictive for humans? PEHM 4:2.  https://doi.org/10.1186/1747-5341-4-2. CrossRefPubMedGoogle Scholar
  53. Steffen J, Krohn M, Paarmann K, Schwitlick C, Bruning T, Marreiros R, Muller-Schiffmann A, Korth C, Braun K, Pahnke J (2016) Revisiting rodent models: Octodon degus as Alzheimer’s disease model? Acta Neuropathol Commun 4(1):91CrossRefGoogle Scholar
  54. Voorn P, Kalsbeck A, Jorritsma-Byham B, Groenewegen HJ (1988) The pre- and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat. Neuroscience 25:857–887CrossRefGoogle Scholar
  55. Waidyanatha S, Ryan K, Sanders JM, McDonald JD, Wegerski CJ, Doyle-Eisle M, Garner CE (2018) Disposition of B-N-methylamino-L-alanine (BMAA), a neurotoxin, in rodents following a single or repeated oral exposure. Toxicol Appl Pharmacol 15(339):151–160CrossRefGoogle Scholar
  56. Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behaviour in rodents. Nat Protoc 2(2):322–328CrossRefGoogle Scholar
  57. Winner B, Geyer M, Couillard S et al (2006) Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb. Exp Neurol 197(1):113–121CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biochemistry and MicrobiologyNelson Mandela UniversityPort ElizabethSouth Africa

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