MECHANISMS OF PYRETHROID INSECTICIDE NEUROTOXICITY

Project: Research project

Description

The objective of the proposed research is to elucidate the
molecular mechanisms by which pyrethroids exert their
neurotoxicological effects in mammalian species. Specifically,
these investigations will attempt to determine whether there are
toxicologically relevant differences in the interaction of Type I vs
Type II pyrethroids with the benzodiazepine-GABA receptor
ionophore complex. Moreover, the effects of chronic exposure to
pyrethroids on the characteristics and function of the GABA
receptor-ionophore complex and related sites will be determined.
The reported interactions of Type II pyrethroids with the GABA-
gated chloride channel will be characterized in vitro and in vivo
using (35S)t-butylbicyclophosphorothionate to label this ion
channel. The interaction of Type I and Type II pyrethroids with
the "peripheral-type" benzodiazepine receptor will also be
investigated using (3H)PK 11195 as a radioligand probe for this
recognition site in both in vitro and in vivo studies. The
hypothesis that a novel "peripheral type" benzodiazine receptor
may be functionally coupled to the GABA-gated chloride channel
will be evaluated using pyrethroids as probes in the study of the
allosteric modulation of (35S)-t-butylbicyclophosporothionate
binding. The potential influence of chronic exposure to
pyrethroids on the coupling efficiency between the chloride ion
channel and GABA and benzodiazepine receptors will be assessed.
The functional consequences of pyrethroid occupancy of these
receptor sites will be examined by characterization of the
proconvulsant actions of Type I and Type II pyrethroids against
seizures elicited from an epileptogenic site in the prepiriform
cortex. Correlations between receptor site occupancy in vivo and
pyrethroid modulation of seizure susceptibility will be obtained.
The effects of pyrethroids on GABA-gated chloride influx will be
investigated in intact neurons and in synaptoneurosome
preparations. Thus, both pyrethroid-neuroreceptor interaction as
well as the functional consequences of activation of various ligand
binding sites associated with the GABA/benzodiazepine receptor-
ionophore complex will be ascertained. The results of these
investigations will further our understanding of molecular
mechanisms operative in the pyrethroid modulation of seizure
susceptibility. The ability of PK 11195 to antagonize the
proconvulsant effects of pyrethroids will be further
characterized. Considered together, these results may have
important clinical implications concerning potential neurotoxic
sequelae of pyrethroid exposure.
StatusFinished
Effective start/end date8/1/887/31/92

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $77,512.00

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Pyrethrins
Insecticides
gamma-Aminobutyric Acid
GABA-A Receptors
Chlorides
Ionophores
Chloride Channels
Sensory Receptor Cells
Benzodiazepines
Seizures