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Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA toxCast high throughput screening data for hazard identification Please follow the link to snapshots page to view and create Snapshots of this AOP.
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This AOP page was last modified on 12/11/2016.
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Macrocylcic lactone (ML) antihelmintics, insecticides and acaricids (e.g. abamectin and ivermectin) target the alpha subunits of the glutamate-gated chloride channels (GluCl) present in nematodes, arthropods, crustaceans (daphnia), and mollusks. The binding of the ML may result in directly opening the ion channel, or may potentiate the effects of the endogenous agonist, glutamate, resulting in increased chloride entry into the cell. With the increased influx of chloride ions, the cell becomes hyperpolarized (neuron) or depolarized (myocyte), resulting in paralysis and death. Mammals do not possess glutamate-gated chloride channels, but the structure of the GluCl channel is similar to the glycine === Background (optional) ===
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Glutamate-gated chloride channel, Activation|
|Event||Support for Essentiality|
|Chloride conductance, Increased|
|Ataxia, paralysis, or hyperactivity, N/A|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
|Bombus impatiens||Bombus impatiens||NCBI|
|Radopholus similis||Radopholus similis||NCBI|
|Daphnia magna||Daphnia magna||NCBI|
|Orius insidiosus||Orius insidiosus||NCBI|
|Helicoverpa zea||Helicoverpa zea||NCBI|
|Liriomyza trifolii||Liriomyza trifolii||NCBI|
|Acyrthosiphon kondoi||Acyrthosiphon kondoi||NCBI|
Overall Assessment of the AOP
Strong evidence exists for population decline in pest species (e.g., worms, ticks and mites) resulting from targeted glutamate-gated chloride channels, as well for non-target species (bees, butterflies). However, this AOP has been developed with minimal research. Given GluCl channels exist in several cell types, specific key events likely vary among species, which are not elucidated here. The review by Wolstenholme (2012) describes specific GluCl-controlled sensory inputs in worms and flies (e.g., behavioral responses to odour, temperature and light) which suggest pathways other than paralysis may be more sensitive. As such, this AOP should be considered putative with minimally-researched support.
Domain of Applicability
Glutamate-gated chloride channels are absent in vertebrates (Slimko et al., 2002).
Life Stage Applicability,
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Weight of Evidence Summary
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Considerations for Potential Applications of the AOP (optional)
Slimko, E.M., McKinney, S., Anderson, D.J., Davisodn, N., and Lester, H.A. (2002) Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373-7379.
Wolstenholm, A. (2012) Glutamate-gated chloride channels. J. Biological Chem. 287: 48, 40232-40238.