Page 458 - The Toxicology of Fishes

438 The Toxicology of Fishes

CI
H
CI
CI C CI
CI C CI CI CI
CI CI
CI
DDT LINDANE

CI
CI CI
CI
CI O
CI CI CI
CI CI
CI
CI
CI
HEPTACHLOROBORNANE
DIELDRIN
(toxic component of toxaphene)
FIGURE 9.8 Examples of organochlorine insecticides.

pyrethroids and DDT likely affect the same target site on the sodium channel. Hyperexcitability is also
associated with increased releases of neurotransmitters throughout the mammalian nervous system which
likely reflect secondary responses but could represent an additional neurotoxic mechanism.
In mammals, the cyclodienes and polychlorobornanes cause anorexia, salivation, vomiting, and con-
vulsions. During convulsions, insect and amphibian preparations exhibit excessive uptake of calcium
into synaptosomes. This synaptosomal calcium uptake is associated with increased release of neurotrans-
mitters. Subsequently, it was shown that cockroach strains resistant to cyclodiene insecticides, lindane,
and toxaphene were also resistant to picrotoxin. Picrotoxin acts at one of the receptor sites in the GABA
receptor–ionophore complex and is thought to block the channel. Normally, the GABA-gated chloride
channel opens upon GABA binding, causing an increased flow of chloride, neuronal hypopolarization,
and depression of excitability. Picrotoxin blockage of the GABA receptor eliminates normal chloride
modulation of neuronal activity, causing hyperexcitability and, potentially, even convulsions. As these
toxic effects are also induced by cyclodienes and polycholorbornanes, it was hypothesized that orga-
nochlorines may act by blocking GABA receptors. Confirmatory studies with insect and mammalian
preparations established that several cyclodiene insecticides, toxaphene, and lindane act specifically at
the picrotoxin site of the GABA receptor. In addition, binding at the picrotoxin site of the GABA receptor
tends to correlate with toxic potency. Furthermore, these compounds inhibit GABA-stimulated flows of
chloride across membrane vesicles (see reviews by Coats, 1990; Woolley, 1995).
Lindane is the gamma isomer of hexachlorohexane; it is approximately 10 times more acutely toxic
to the rat than the alpha isomer and roughly 100 times more potent than the beta and delta isomers. The
gamma isomer is strongly excitatory in both insect and mammalian nervous systems, while the alpha,
beta, and delta isomers are weakly active or have depressant effects. At acute doses, lindane increases
neuronal activity and neurotransmitter release. In addition to convulsant effects, lindane also causes
anorexia, diarrhea, and hyperthermia in the rat. As discussed above, lindane is thought to antagonize
GABA receptors in the CNS and the gastrointestinal tract. Consistent with this hypothesis, toxic effects
of lindane can be attenuated or eliminated by pretreatment with GABA receptor agonists (Woolley, 1995).
Although disruption of VSSCs and GABA receptors are well characterized mechanisms of acute
organochlorine neurotoxicity, there is little evidence for the role of these mechanisms in developmental
neurotoxicity. Lindane is known to inhibit mammalian embryonic development from the eight-cell stage
up to the blastocyst stage (Scascitelli and Pacchierotti, 2003). Several potential mechanisms of devel-
opmental neurotoxicity have been proposed, including disruption of endocrine homeostasis and alter-
ations in intercellular communication (Scascitelli and Pacchierotti, 2003).