ReviewDietary exposure and neurotoxicity of the environmental free and bound toxin β-N-methylamino-l-alanine
Graphical abstract
Introduction
Rapid proliferation of microscopic algae in aquatic environments, the so-called harmful algal blooms (HABs), is recognized as a growing problem worldwide. Even when the exact causes of HABs are not yet clear, human impacts combined with climate changes are thought to contribute to the recent increase in the incidence of these episodes (Paerl & Paul, 2012). Although being commonly referred as toxic algae, the microorganisms causing blooms belong to different kingdoms of life: eukaryotic microalgae and prokaryotic cyanobacteria, also known as blue-green algae. Many of the microorganisms responsible for the HABs are known to produce toxins that have a variety of adverse effects, such as skin irritation, diarrhea, hepatotoxicity and neurotoxicity in humans and animals (Dittmann, Fewer, & Neilan, 2013). Consumption of water and food exposed to HABs represents a major route of exposure to these toxins, which may result in serious or even fatal consequences. Particularly, filter-feeders, such as bivalve mollusks may consume HABs organisms and accumulate significant amounts of toxins (Regueiro et al., 2011, Regueiro et al., 2011).
Among the different classes of HAB toxins identified so far, β-N-methylamino-l-alanine (BMAA) has recently triggered an emerging interest because of the increasing evidence that links the exposure to this toxin to progressive neurodegenerative diseases, such as the amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) (Banack and Cox, 2003, Cox et al., 2016, Spencer et al., 1987). This compound belongs to the family of non-proteinogenic amino acids, an extremely diversified group accounting for > 1000 different chemical species (Rodgers, 2014).
It is already known that a number of chemicals may induce or accelerate the development of certain neurodegenerative diseases (Cannon & Greenamyre, 2011). For instance, exposure of humans to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a syndrome that mimics the core neurological symptoms and relatively selective dopaminergic neurodegeneration of Parkinson's disease (PD) (Dauer & Przedborski, 2003). PD has also been linked to exposure to rotenone and paraquat in agricultural workers (Tanner et al., 2011), whereas exposure to lead, mercury, and pesticides have been reported as potential risk factors for ALS (Johnson & Atchison, 2009). However, the role of naturally occurring toxins, such as BMAA, in progressive neurodegenerative diseases has not been extensively studied.
Here, we present an overview on the recent literature examining the neurotoxicity of BMAA, the main sources of this toxin in nature, as well as the available data regarding its occurrence in food and human exposure through the diet. We will not review analytical methodologies for extraction and detection of BMAA in different sample matrices, as they have been recently summarized by Cohen (2012) and Porojan, Mitrovic, Yeo, and Furey (2016). However, some critical points affecting the accuracy of the reported concentration levels are discussed. Finally, this paper highlights some potential implications of the dietary exposure to BMAA and difficulties faced in its prevention.
Section snippets
Sources of BMAA
BMAA was first identified in the seeds of the gymnosperm Cycas circinalis, currently known as Cycas micronesica Hill, a palm-like tree widespread on the tropical island of Guam in the Western Pacific Ocean (Hill, 1994, Vega and Bell, 1967). In 2003, Cox, Banack, and Murch (2003) found that BMAA was produced by nitrogen-fixing cyanobacteria of the genus Nostoc living symbiotically within the coralloid roots of the cycad trees. This finding prompted the search for BMAA in other cyanobacteria,
Chemical identity of BMAA
Structurally, BMAA, also known as l-α-amino-β-methylaminopropionic acid, is an amino acid consisting of a carboxyl group, a primary amine attached to the α-carbon and a methylamine moiety as a part of the side chain (Fig. 1). Therefore, this molecule presents three ionizable groups with estimated pKa values of 1.96, 6.61 and 9.86, respectively, which means that BMAA will be negatively charged in basic media, positively charged in acidic media and as zwitterion around neutral pH.
BMAA is a
Mechanisms of BMAA neurotoxicity
BMAA has been associated with some progressive neurological diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease and Alzheimer's dementia (AD) (Banack et al., 2010, Bradley and Mash, 2009, Pablo et al., 2009). However, several authors highlight the lack of enough scientific evidence to establish a direct link. A special issue on BMAA neurotoxicity is currently being published in Neurotoxicity Research (Cox, Kostrzewa, & Guillemin, 2017).
First animal studies investigating
Dietary exposure to BMAA
Human exposure to BMAA may occur in a variety of ways including consumption of contaminated food and water, recreational water use or even inhalation of contaminated aerosols (Cox et al., 2009, Downing et al., 2014, Jiang et al., 2014). However, dietary intake is recognized as the major exposure pathway to this compound, especially through the consumption of aquatic organisms such as filter-feeding bivalve mollusks (Jiang et al., 2014, Jonasson et al., 2010, Reveillon et al., 2015). The recent
Challenges faced in BMAA research
The findings of this review indicate that even though significant research effort has been devoted in recent times to this topic, further research is still required to address several important gaps in the actual state of knowledge.
Thus, the metabolic fate and biotransformation products of BMAA in different organisms remain largely unknown. Downing, Esterhuizen-Londt, and Grant Downing (2015) studied the metabolism of BMAA in the aquatic plant Ceratophyllum demersum using stable isotopically
Conclusions
The present work provides a detailed overview of the principal sources for human exposure to BMAA and their contribution to the overall exposure to this neurotoxin. Although other routes are possible, dietary intake of BMAA-contaminated food has been identified as the major contributor. To date, most of available data refer to contaminated fish and shelfish, particurlay fillter-feeding bivalve molusks. Therefore, more investigations are necessary to assess the ocurrence of BMAA in other
Acknowledgments
N. Negreira acknowledges the Ministry of Culture, Education and University Planning of the Xunta de Galicia for her postdoctoral contract. J. Regueiro would also like to thank the Spanish Ministry of Economy, Industry and Competitiveness for his Ramón y Cajal contract.
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