Background Information

Marine algal blooms, natural phenomena produced by the overgrowth of microscopic marine algae, have become a public health concern because of their increasing frequency and severity. About 300 phytoplanktonic species are known to have the ability to cause these blooms, and one-fourth of them are able to produce toxins, also called phycotoxins. Shellfish, mainly bivalve mollusks, and fish may accumulate these phycotoxins by direct filtration of the producer algal cells or by feeding on contaminated organisms. Human intoxications caused by phycotoxins occur worldwide through consumption of marine fishery products containing bioaccumulated toxins.

According to their toxic effects and chemical properties, phycotoxins are classified into different categories. Diarrheic shellfish poisoning (DSP) toxins are one of the most relevant groups of the phytoplanktonic toxins because its presence produces not only severe economic losses, but also health effects in human consumers. The first registered DSP episode after shellfish consumption occurred in 1961 in The Netherlands. However, no relationship with the phycotoxins was established at that time. It was in 1976 when the association between the frequent occurrence of gastroenteritis and the ingestion of phycotoxin-contaminated shellfish was proved the first time. Since then, a large number of DSP episodes have been documented worldwide. However, this number is believed to be much higher because these episodes are not often well documented for the reason that the acute symptoms are sometimes light and intoxicated people do not always require medical assistance.

Okadaic acid (OA) and its analogs, the dinophysistoxins (DTX), are lipophilic marine toxins produced by several phytoplanktonic species and responsible for DSP in humans. OA, the main representative toxin of this group, was first isolated in 1981 from the black sponge Halichondria okadai as well as from H. melanodocia. It is usually accumulated by several marine organisms, mainly bivalve mollusks, by eating phytoplankton containing OA. This toxin is highly distributed all over the world, but is especially abundant in Japan in Europe. OA exposure can represent a severe threat to human health beyond its DSP effects, because it was demonstrated to be a specific inhibitor of several types of serine/threonine protein phosphatases and a tumor promoter in animal carcinogenesis experiments.

Uses

OA is a natural marine toxin produced by different phytoplanktonic species mainly from the dynoflagellates group. It may pass through the food chain to humans who ingest OAcontaminated organisms. Thus, it does not have any commercial applications in medicine, food, construction, or similar industries. However, because of its well-known ability to selectively inhibit several types of serine/threonine protein phosphatases, it is often used in research as a useful tool for studying cellular processes regulated by reversible phosphorylation of proteins, including control of glycogen metabolism, coordination of the cell cycle and gene expression, and maintenance of cytoskeletal structure.
Furthermore, it was reported that other marine toxins, different from OA, can also act as specific protein phosphatase (mainly PP1 and PP2A) inhibitors. They are called OA class tumor promoters and were proved to be able to cause skin, stomach, and liver tumors in animals. This has led some authors to suggest a new concept of tumor promotion: the okadaic acid pathway. In this regard, studies with OA, as well as with other OA class tumor promoters, could deepen the knowledge of the mechanisms of cancer development in humans.

Mechanism of Toxicity

As the main representative DSP toxin, OA ingestion leads to the onset of acute gastrointestinal symptoms typical of this intoxication (e.g., diarrhea, nausea, vomiting, abdominal pain). It was suggested that diarrhea in humans is caused by hyperphosphorylation of ion channels in intestinal cells impairing the water balance, or by increased phosphorylation of cytoskeletal or junctional elements that regulate solute permeability, resulting in passive loss of fluids. It was also suggested that OA causes long-lasting contraction of smooth muscle from human and animal arteries.
At the molecular level, OA is a potent tumor promoter and a recognized inhibitor of serine/threonine protein phosphatases type 1 (PP1) and 2A (PP2A); PP2A is about 200 times more strongly inhibited than PP1. However, nowadays OA is also known to inhibit PP4, and less effi- ciently, PP5 and PP2B. This phosphatase activity inhibition causes a dramatic increase in the phosphorylation levels of numerous proteins that ultimately results in alterations of relevant cell processes.

Mostly because of this ability, OA was shown to induce severe cytotoxic effects that include cell cycle alterations, morphological changes, apoptosis, viability decreases, and cytoskeleton disruptions on different cell systems. Besides, genotoxicity after OA exposure was also reported, and it was also demonstrated to alter geneexpression patterns in OA-exposed cells. The existence of OA-binding proteins other than phosphatases has been demonstrated in several marine organisms but not in humans.

Although this toxin is not classified as a neurotoxin, it was shown to induce some neurotoxic effects both in vitro and in vivo. In vitro, OA induces apoptosis in a variety of human and animal neurons, generates redistribution of neuronal proteins, forces differentiated neuronal cells into the mitotic cycle, induces disintegration of neuritis, and generates changes in microtubule-associated proteins concomitant with early changes in neuronal cytoskeleton. In vivo, OA exposure was observed to produce inactivity and weakness in mice as well as hyperexcitation, spatial memory deficit, and neurodegeneration.