Nodularins in poisoning

doi:10.1016/j.cca.2013.07.005

Clinica Chimica Acta

Volume 425, 21 October 2013, Pages 18-29

https://doi.org/10.1016/j.cca.2013.07.005 Get rights and content

Highlights

•
A comprehensive review of nodularins in poisoning was conducted.
•
Bioaccumulation of nodularins in water, cyanobacterial blooms and aquatic animals was surveyed.
•
The IC₅₀, LC₅₀ and LD₅₀ values determined in laboratories were presented.
•
Cases of wild, domestic and laboratory animals were summarized.
•
The mechanisms of potential hepatotoxicity and carcinogenicity were elucidated.

Abstract

Nodularins are an important class of hepatotoxic cyclic pentapeptides that are produced by the cyanobacteria Nodularia spumigena. These peptides have been found worldwide and have been implicated in the deaths of animals as well as a potent cyanotoxin in humans. To date, approximately 10 variants have been discovered, among which nodularin-R is the most abundant. Though the mechanisms of their potential hepatotoxicity and carcinogenicity are not well understood, the most frequently proposed mechanisms are described here. Most importantly, a comprehensive review of nodularins in poisoning is presented, including their bioaccumulation in water, cyanobacterial blooms and aquatic animals, the IC₅₀, LC₅₀ and LD₅₀ values determined in laboratories, and wild, domestic and laboratory animal cases. However, the hazard of these toxins to humans has not been fully elucidated, predominantly due to the lack of exposure data. One of reasons underlying is that most current methods are ill suited for clinical monitoring. Thus, the available assays for the detection and quantification of nodularins are described with an emphasis on the problems encountered with each assay. Our ultimate aim is to demonstrate the urgency of better understanding the toxicity of nodularins, especially in humans, and thus effectively protecting ourselves from their 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.

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Invited critical reviewNodularins in poisoning☆

Highlights

Abstract

Introduction

Section snippets

Congeners of nodularins

Toxicology

Bioaccumulation and poisoning

Analytical approaches

Protection

Conclusions

Acknowledgments

Toxicon

Toxicology

Anal Chim Acta

J Chromatogr A

Phytochemistry

J Mol Biol

Toxicon

Toxicology

Toxicol In Vitro

Mutat Res

J Biol Chem

J Mol Biol

Toxicon

Toxicon

Toxicon

Biochim Biophys Acta

Toxicol Lett

Toxicol Lett

Fish Shellfish Immunol

Ecotoxicol Environ Saf

Toxicon

Ecotoxicol Environ Saf

Environ Pollut

Harmful Algae

Toxicon

Toxicon

Aquat Toxicol

J Chromatogr A

Anal Chim Acta

Clin Chim Acta

The toxins of cyanobacteria

Sci Am

Human fatalities from cyanobacteria: chemical and biological evidence for cyanotoxins

Environ Health Perspect

Analysis of cyanobacterial toxins by physicochemical and biochemical methods

J AOAC Int

Toxicity and partial structure of a hepatotoxic peptide produced by the cyanobacterium Nodularia spumigena Mertens emend. L575 from New Zealand

Appl Environ Microbiol

Nodularin, microcystin, and the configuration of Adda

J Am Chem Soc

Structure and biosynthesis of toxins from blue-green algae (cyanobacteria)

J Appl Phycol

Toxic cyanobacteria in water: a guide to their public health consequences, monitoring and management

On the chemistry, toxicology and genetics of the cyanobacteri al toxins, microcystin, nodularin, saxitoxin and cylindrospermopsin

Mar Drugs

Hepatotoxic cyanobacteria: a review of the biological importance of microcystins in freshwater environments

J Toxicol Environ Health B Crit Rev

Characterization of nodularin variants in Nodularia spumigena from the Baltic Sea using liquid chromatography/mass spectrometry/mass spectrometry

Rapid Commun Mass Spectrom

Chemical characterization and toxicity of dihydro derivatives of nodularin and microcystin-LR, potent cyanobacterial cyclic peptide hepatotoxins

Chem Res Toxicol

Motuporin, a potent protein phosphatase inhibitor isolated from the Papua New Guinea Sponge Theonella swinhoei Gray

Tetrahedron Lett

Total synthesis of Motuporin and 5-[l-Ala]-Motuporin

J Org Chem

Nodularin, a potent inhibitor of protein phosphatases 1 and 2A, is a new environmental carcinogen in male F344 rat liver

Cancer Res

Ingested Nitrate and Nitrite and Cyanobacterial Peptide Toxins

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans

Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases

Toxicon

The photocatalytic destruction of the cyanotoxin, nodularin using TiO2

J Appl Catal B Environ

Colorimetric immuno-protein phosphatase inhibition assay for specific detection of microcystins and nodularins of cyanobacteria

Appl Environ Microbiol

A model for binding of structurally diverse natural product inhibitors of protein phosphatases PP1 and PP2A

J Med Chem

Invited critical review
Nodularins in poisoning☆