Invited critical reviewNodularins in poisoning☆
Introduction
Cyanobacteria, also known as blue-green algae, are the cause of intermittent but repeated cases of water poisoning in both animals and humans [1], [2]. As bacteria, they are aquatic, photosynthetic and often grow in visible colonies (algal bloom), which are commonly found in lakes, ponds, rivers, brackish and marine waters throughout the world. Cyanobacteria produce a wide range of cyanotoxins [3], among which are the nodularins, a group of hepatotoxic cyclic peptides that consist of five amino acids, including Mdhb (N-methyldehydrobutyric acid) and the unique β-amino acid Adda (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4(E),6(E)-dienoic acid).
Nodularins are mainly produced by Nodularia spumigena. Since first being described in 1988 [4], [5], approximately 10 variants have been discovered [6]. Compared with other frequently occurring and widespread cyanotoxin microcystins that have over 80 congeners [7], the number of fully characterized nodularin variants is low. However, detrimental effects from nodularins have been frequently reported in a number of countries, including Australia, Brazil, China, England, South Africa and the USA, over the past 30 years [8]. These toxins have been implicated in the deaths of wild and domestic animals as well as a potent cyanotoxin in humans. It is widely accepted that the toxicity of nodularins is due to the severe inhibition of the protein phosphatases 1 (PP-1), 2A (PP-2A) and 3 (PP-3), which leads to functional disturbance and structural disruption of the liver [9]. These toxins also act as liver tumor initiators and promoters [10]. Interestingly, no guidelines have been set for nodularins by the World Health Organization (WHO), and their toxicity can currently only be estimated from microcystins, which have been reported to have similar toxicity to nodularins [11]. Therefore, the aim of this article is to extensively discuss the toxicity and poisoning of nodularins. Because microcystins have been extensively reviewed [9], [12], the differences exhibited by nodularins receive focus here. In addition, due to the lack of exposure data, special attention has been paid to the detection and quantification of nodularins in biological samples.
Section snippets
Congeners of nodularins
Nodularin-R is the first and most abundant form of nodularins in natural blooms [13]. In addition to Adda and Mdhb, as described above, nodularin-R also contains two d-amino acids, i.e., d-glutamic acid (d-Glu) and d-erythro-B-methylaspartic acid (d-MeAsp), and l-arginine (l-Arg) at position 2.
Nine naturally occurring isoforms of nodularin-R have been reported to date (Fig. 1): linear nodularin-R, nodularin-V (l-valine moiety instead of arginine, motuporin), nodularin-Har (l-Homoarginine
Toxicology
The primary target organ of nodularins is the liver. There is evidence indicating that nodularins accumulate in the liver after the intravenous injection of a non-lethal dose into mice [22]. The intestines and blood also retain significant amounts of nodularins [23]. Generally, nodularins diffuse from the small intestine into the liver due to active uptake by an unspecific organic anion transporter, i.e., the bile acid carrier transport system. Nodularins are potent specific hepatotoxins [24].
Bioaccumulation and poisoning
To date, nodularins have not been studied as extensively as microcystins. One of reasons for this lack of study is that microcystins are produced by several cyanobacterial species, whereas nodularins are thus far known to be produced mainly by cyanobacteria from the genus Nodularia. In addition, the genus Nodularia occurs rarely in freshwater that is commonly used for drinking purposes, but does occur mainly in slightly saline or brackish waters and in saline and coastal lakes [11].
Analytical approaches
There is no guidance available for the safe human exposure to nodularins, predominantly due to a lack of exposure data [26]. Because the concentration of toxins is often used as a straight guide to assess exposure, the analytical approaches to determine nodularins in biological matrices are given attention in this review.
One of the biggest challenges in monitoring nodularins is that very few of them are available as standards and reliable reference materials [93]. Furthermore, most of
Protection
Many studies have demonstrated that nodularins are relatively stable compounds and not easily degraded by light, temperature and microwaves [35], [57]. The majority of these compounds normally persist within living cells and are then transferred up the trophic levels [53]. Therapy is likely to have little or no value, so effective protection is critical. Because cyanobacteria contain many types of toxins (known and unknown), impairments from nodularins cannot be easily differentiated from the
Conclusions
Nodularins can be present and bioaccumulate in a wide range of organisms. Exposure to nodularins can pose hepatotoxic and carcinogenic threats to human and animal health. Although nodularins are currently not classifiable as carcinogens due to the lack to exposure data, they may be more toxic than microcystins [22]. In addition to managing the recreational use of water systems and monitoring the nodularins amount in water bodies, cyanobacterial blooms and aquatic animals at present, new data
Acknowledgments
We gratefully acknowledge the National Natural Science Fund (21175071) and the SRF-sponsored Project grants to ROCS, SEM (39), in addition to Jiangsu Six-Type Top Talents Program (D) and Open Foundation of Nanjing University (SKLACLS1102) grants to Dr. Chen. The authors would also like to thank American Journal Experts for proofreading the article.
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National Natural Science Fund (21175071) and the SRF-sponsored project grants to ROCS, SEM (39), in addition to Jiangsu Six-Type Top Talents Program (D) and Open Foundation of Nanjing University (SKLACLS1102) grants to Dr. Chen. The authors would also like to thank American Journal Experts for proofreading the article.