Page 464 - The Toxicology of Fishes

444 The Toxicology of Fishes

Toxins stabilize sodium channels by inhibiting inactivation of the sodium current during depolarization,
thus keeping the sodium channel in the open state. This sodium channel stabilization causes a prolonged
period of calcium influx through VSCCs, causing increased calcium-mediated secretions and contractions
(Strichartz and Castle, 1990). Toxins that stabilize sodium channels bind different sites than toxins that
activate sodium channels; consequently, sodium-channel-stabilizer toxins can synergize with sodium-
channel-activator toxins, causing larger membrane depolarizations at lower doses. Small peptides pro-
duced by anemones and larger proteins produced by mollusks in the family Conidae are examples of
sodium-channel-stabilizer toxins. Sodium-channel-occluder toxins are small organic cations that are
high-affinity, but reversible, blockers of the channel (Strichartz and Castle, 1990). The subsequent
inhibition of sodium conductance renders excitable membranes inactive and halts impulse propagation.
Tetrodotoxins and saxitoxins are classic examples of sodium-channel-occluding toxins. Tetrodotoxin is
produced by some fish in the order Tetraodontiformes and the Costa Rican frog Atelopus (Ritchie and
Greene, 1985). Saxitoxins are produced by marine dinoflagellates in the genera Gonyaulax and freshwater
cyanobacteria in the genera Anabaena and Aphanizomenon (Carmichael, 1997). Some sodium-channel-
occluding toxins discriminate between sodium-channel types; for example, the µ-conotoxins, from the
mollusk Conus geographus potently block muscle sodium channels but only weakly inhibit sodium
currents in neuronal and cardiac sodium channels.
Some toxins create ion permeabilities without affecting ion channels. Palytoxin, derived from coral,
irreversibly increases cation permeability, perhaps by converting the sodium/potassium pump to a passive
channel (Strichartz and Castle, 1990). Other aquatic neurotoxins have mechanisms that do not center
on ion regulation; for example, cyanobacteria of the genera Anabaena and Oscillatoria produce anatoxins
that disrupt acetylcholine function at neuromuscular junctions. Anatoxin-a acts as an acetylcholine mimic,
binding nicotinic acetylcholine receptors at vertebrate muscle endplates, and is reported to be eight times
more potent than acetylcholine. Furthermore, anatoxin-a is resistant to acetylcholinesterase hydrolysis,
causing an overstimulation of muscle cells to the point of fatigue. The similarly named anatoxin-a(s)
causes the same symptoms of neurotoxicity as anatoxin-a but by a different mechanism. Anatoxin-a(s)
is a naturally occurring organophosphate that inhibits acetylcholinesterase activity in a manner similar
to the organophosphate insecticides discussed previously.
In addition to aquatic toxins, terrestrial plant toxins can affect the CNS of vertebrates, including fish.
Notable examples are the pyrethrins, derived from Chrysanthemum cinerariifolium, whose structures
were subsequently modified synthetically to develop the pyrethroid insecticides, as summarized previ-
ously. Certain plant toxins have also been exploited by several cultures as an aid in harvesting; for
example, piscicidal plants derived from plants of the Garhwall hills of India are of great ethnobiological
importance. Bhatt (1991) has described how a flavonoid derived from Engelhardtia colebrookiana
(Lindle) causes degeneration of neurons and neural tracts in the medulla oblongata of freshwater fish.
Strychnine, an alkaloid derived from Strychnos nux-vomica, has long been known as a central nervous
system stimulant in animals. Strychnine selectively antagonizes GABA in the brain and glycine in the
spinal cord (Dorling et al., 1995) and has been exploited in fish neurotoxicology studies to elucidate the
role of these inhibitory neurotransmitters.

Manifestations of Neurotoxin Toxicity in Fish
Brevetoxins and ciguatera toxins elicit similar effects in fish, consistent with their identical mechanisms
of neurotoxicity summarized previously. Red tides caused by Ptychodiscus brevis brevotoxins are asso-
ciated with massive fish kills. Exposure of ciguatera toxins to coney (Epinephelus fulvus), schoolmaster
(Lutjanus apodus), mahogany snapper (Lutjanus mahogoni), largemouth bass (Micropterus salmoides),
blueheads (Thalassoma bifasciatum) (Davin et al., 1986, 1988), and western mosquitofish (Gambusia
affinis) (Lewis 1992) caused skin color variations, rapid opercular movement, inactivity, loss of equilib-
rium, erratic swimming, jerky feeding movements, loss of orientation, and death. Exposure to another
toxic dinoflagellate, Pfiesteria piscicida, has been reported to induce sudden sporadic movement, dis-
orientation, lethargy, and apparent suffocation followed by death in 11 species of fish, including striped
bass (Morone saxatilis), southern flounder (Paralichthys lethostigma), Atlantic menhaden (Brevoortia
tyrannus), and American eel (Anguilla rostrata) (Burkholder et al., 1992; Glasgow et al., 1995).