Key Event Title
Key Event Component
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures||AdverseOutcome|
Level of Biological Organization
|eisenia fetida||eisenia fetida||Strong||NCBI|
How This Key Event Works
Blockage of the GABA-gated chloride channel reduces neuronal inhibition and induces focal seizure. This may further lead to generalized seizure, convulsions and death (Bloomquist 2003; De Deyn et al. 1990; Werner and Covenas 2011). For instance, exposure to fipronil produces hyperexicitation at low doses and convulsion or tonic-clonic seizure and seizure-related death at high doses (Gunasekara et al. 2007; Tingle et al. 2003; Jackson et al. 2009).
Seizure propagation, the process by which a partial seizure spreads within the brain, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum. The propagation of bursting activity is normally prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Repetitive discharges lead to: 1) an increase in extracellular K+, which blunts the extent of hyperpolarizing outward K+ currents, tending to depolarize neighboring neurons; 2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; and 3) depolarization-induced activation of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca2+ influx and neuronal activation. Of equal interest, but less well understood, is the process by which seizures typically end, usually after seconds or minutes, and what underlies the failure of this spontaneous seizure termination in the life-threatening condition known as status epilepticus (Bromfield et al. 2006).
How It Is Measured or Detected
Electrophysiological measurements and physical (visual) observation (for mortality) are the methods often used to detect epileptic seizure-related effects (Ulate-Campos et al. 2016). One may also visit http://www.mayoclinic.org/diseases-conditions/epilepsy/diagnosis-treatment/diagnosis/dxc-20117234 for more information on how medical doctors diagnose epilepsy in patients.
Evidence Supporting Taxonomic Applicability
A wide range of species including invertebrates and vertebrates have been documented (see Tingle et al. (2003) and Gunasekara et al. 2007 for reviews on the list of aquatic and terrestrial species affected by fipronil). For instance, fipronil can induce seizures in fruit flies (Stilwell et al. (2006)) and house flies (Gao et al. 2007).
Regulatory Examples Using This Adverse Outcome
As a neurotoxicity endpoint, information with regard to the seizure or epilepsy is often used by regulators such as EPA, FDA and DHS for human and environmental health assessment and regulation of chemicals, drugs and other materials. For instance, the Office of Pesticide Programs (OPP) in US EPA regulates, monitors and investigates the use of all pesticides in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (https://www.epa.gov/laws-regulations/summary-federal-insecticide-fungicide-and-rodenticide-act). Many pesticides like fipronil target the iGABAR causing seizure and mortality. Another example is the regulatory actions of US FDA to ensure drug saety (see https://www.fda.gov/Drugs/DrugSafety/ucm436494.htm).
Bloomquist JR. 2003. Chloride channels as tools for developing selective insecticides. Arch. Insect Biochem. Physiol 54(4), 145-156.
Bromfield EB, Cavazos JE, Sirven JI, editors. 2006. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society. Chapter 1 Basic Mechanisms Underlying Seizures and Epilepsy. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2510/
De Deyn PP, Marescau B, Macdonald RL. 1990. Epilepsy and the GABA-hypothesis a brief review and some examples. Acta Neurol. Belg. 90(2), 65-81.
Gao JR, Kozaki T, Leichter CA, Rinkevich FD, Shono T, Scott JG. 2007. The A302S mutation in Rdl that confers resistance to cyclodienes and limited crossresistance to fipronil is undetectable in field populations of house flies from the USA. Pestic. Biochem. Physiol. 88, 66−70.
Gunasekara AS, Truong T, Goh KS, Spurlock F, Tjeerdema RS. 2007. Environmental fate and toxicology of fipronil. J. Pestic. Sci. 32(3), 189-199.
Jackson D, Cornell CB, Luukinen B, Buhl K, Stone D. 2009. Fipronil Technical Fact Sheet. National Pesticide Information Center, Oregon State University Extension Services,
Stilwell GE, Saraswati S, J. Troy Littleton JT, Chouinard SW. 2006. Development of a Drosophila seizure model for in vivo high-throughput drug screening. European J Neurosci. 24, 2211-2222.
Tingle CC, Rother JA, Dewhurst CF, Lauer S, King WJ. 2003. Fipronil: environmental fate, ecotoxicology, and human health concerns. Rev. Environ. Contam Toxicol. 176, 1-66.
Ulate-Campos A, Coughlin F, Gaínza-Lein M, Fernández IS, Pearl PL, Loddenkemper T. 2016. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure. 40:88-101.
Werner FM, Covenas R. 2011. Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs. Curr. Med. Chem. 18(32), 4933-4948.