Natural and Derivative Brevetoxins: Historical Background, Multiplicity, and Effects

Abstract

Symptoms consistent with inhalation toxicity have long been associated with Florida red tides, and various causal agents have been proposed. Research since 1981 has centered on a group of naturally occurring trans-fused cyclic polyether compounds called brevetoxins that are produced by a marine dinoflagellate known as Karenia brevis. Numerous individual brevetoxins have been identified from cultures as well as from natural bloom events. A spectrum of brevetoxin derivatives produced by chemical modification of the natural toxins has been prepared to examine the effects of functional group modification on physiologic activity. Certain structural features of natural and synthetic derivatives of brevetoxin appear to ascribe specific physiologic consequences to each toxin. Differential physiologic effects have been documented with many of the natural toxins and derivatives, reinforcing the hypothesis that metabolism or modification of toxin structures modulates both the specific toxicity (lethality on a per milligram basis) and potentially the molecular mechanism(s) of action. A series of naturally occurring fused-ring polyether compounds with fewer rings than brevetoxin, known as brevenals, exhibit antagonistic properties and counteract the effects of the brevetoxins in neuronal and pulmonary model systems. Taken together, the inhalation toxicity of Florida red tides would appear to depend on the amount of each toxin present, as well as on the spectrum of molecular activities elicited by each toxin. Toxicity in a bloom is diminished by the amount brevenal present.

Osmotic stress triggers toxin production by the dinoflagellate Karenia brevis

“…Karenia brevis, the major HAB dinoflagellate in the Gulf of Mexico, produces potent neurotoxins, known as brevetoxins (2). Brevetoxins can lead to human health concerns through the consumption of shellfish contaminated by accumulated brevetoxins, known as neurological shellfish poisoning, or through reduced respiratory function from aerosolized brevetoxins in sea spray (1,3,4). In addition, K. brevis blooms have led to massive fish kills and compromise sea turtle, sea bird, and marine mammal health, playing a major role in the ecology of the Gulf of Mexico (1,5).…”

Osmotic stress does not trigger brevetoxin production in the dinoflagellateKarenia brevis

“…However, there is no known mechanism for this to occur. Brevetoxins bind with the voltage-gated sodium channels of cell membranes and hold these channels in an open configuration (2,3). This allows sodium ions to flux into the cells, driven by the electrochemical gradient for these ions across the outer cell membrane (31).…”

“…The physiology, ecology, and adverse effects of K. brevis have been well studied since the species was described in the 1940s (1). Notably, K. brevis produces brevetoxins, a family of potent polyether neurotoxins that bind to voltage-activated sodium channels in cell membranes, preventing normal nerve and muscle activity (2,3). A nontoxic polyether that inhibits brevetoxin function, brevenal, is also produced in small amounts by this species (4).…”

“…A nontoxic polyether that inhibits brevetoxin function, brevenal, is also produced in small amounts by this species (4). In humans, brevetoxins cause neurotoxic shellfish poisoning, and brevetoxin-contaminated aerosols cause respiratory irritation and illness (2,5). Blooms also cause massive fish kills (6), as well as bird and marine mammal mortalities (7,8).…”

Brevetoxin-Induced Neural Insult in the Retrosplenial Cortex of Mouse Brain

“…Ten brevetoxins have been isolated and identified from field blooms and K. brevis cultures (Baden, 1989;Baden et al, 2005). Brevetoxin 2 (PbTx-2) and brevetoxin 3 (PbTx-3) are the most predominant brevetoxins produced by K. brevis.…”