Page 459 - The Toxicology of Fishes

Toxic Responses of the Fish Nervous System 439

Manifestations of Organochlorine Insecticide Neurotoxicity in Fish
Organochlorine exposure affects behavior in many fish species. In unrestrained fish, cyclodiene exposure
caused hyperactivity in response to stimuli, followed by recurrent tremors, rapid pectoral fin movement,
and convulsions (Carlson et al., 1998). In spinally transected rainbow trout (Oncorhynchus mykiss),
endosulfan and endrin intoxication induced branchial tremors, increased cough rate, and increased
pectoral fin movement, with eventual tetany and convulsions anterior to the site of the transection
(Bradbury et al., 1991a). Hyperactivity and increased cough frequency have also been reported with
DDT intoxication in a number of fish species (Heath, 1995; Murty, 1986). DDT-induced hyperactivity
is thought to contribute to decreased schooling behavior (Murty, 1986). At sublethal concentrations of
endosulfan, medaka (Oryzias latipes) are less susceptible to predation, presumably due to hyperactivity;
however, at endosulfan concentrations approximating the LC level, medaka are more susceptible to
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predation than control fish (Carlson et al., 1998). Respiratory–cardiovascular responses of cyclodiene-
intoxicated rainbow trout included increased cough rate and ventilation volume, with no change in oxygen
uptake efficiency, resulting in an increase in oxygen consumption. In a consistent manner, arterial blood
oxygen remained near control levels until near death, while arterial blood carbon dioxide and pH levels
decreased only slightly. Overall, the seizure activity in the cyclodiene-exposed trout was not associated
with a shift to anaerobic metabolism. These responses were similar to those elicited by uncouplers of
oxidative phosphorylation and may suggest a secondary effect associated with inhibition of ATPase
activity (Bradbury et al., 1991a). Increased oxygen consumption has also been reported in a number of
species following exposure to DDT and methoxychlor (Murty, 1986). In vivo electrophysiological studies
of sublethal endosulfan exposures in medaka demonstrated increased motorneuron amplitude peaks and
significantly increased stimulus-response ratio on the Mauthner cell startle response. The hyper-respon-
siveness of the Mauthner cell to stimuli is consistent with cyclodiene acting at the picrotoxin site in the
GABA receptor–chloride complex. Furthermore, GABA is an important afferent inhibitory neurotrans-
mitter to the Mauthner cell (Carlson et al., 1998).

Ethanol
Ethanol is a well-known neurotoxicant in mammals. Women who consume large amounts of ethanol
during pregnancy often give birth to children exhibiting phenotypic abnormalities, collectively referred
to as the fetal alcohol syndrome (FAS). These anomalies include growth deficiency, cognitive impairment,
and distinctive craniofacial features (Coles and Platzman, 1993). The developmental potency of alcohol
consumption has led to intensive investigation into the mechanisms of ethanol neurotoxicity, with
particular emphasis on developmental neurotoxicity.

Mechanisms of Ethanol Neurotoxicity
Although many mechanisms have been postulated for the toxic effects of ethanol to the adult nervous
system, ethanol is thought to produce neurotoxic effects mainly through interaction with the glutamin-
ergic system, binding to the NMDA receptor and possibly interfering with the normal interaction of
glycine with that receptor (Tsai and Coyle, 1998). Ethanol is a well-known developmental neurotoxicant
in humans and laboratory animals. The mechanism for the toxic actions of ethanol on the developing
nervous system is, however, unknown (Goodlett et al., 2005). Many hypotheses exist, including inter-
action with neurotrophins (Kentroti, 1997), cell-adhesion molecules (Bearer, 2001), or specific receptors
(Costa and Guizzetti, 2002); increased apoptosis (Olney et al., 2002a,b); or increased oxidative stress
(Cohen-Kerem and Koren, 2003). Very few studies have delved into the mechanisms of the effects of
ethanol on the developing fish; however, it has been suggested that prechordal plate migration may be
preturbed in ethanol-treated zebrafish (Danio rerio) embryos (Blader and Strähle, 2000).

Manifestations of Ethanol Neurotoxicity in Fish
Ethanol affects the function of the adult fish nervous system (Dlugos and Rabin, 2003; Gerlai et al.,
2000), producing hyperactivity or hypoactivity (depending on dose), aggression, and changes in the