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Cell injury/death leads to N/A, Neurodegeneration
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||adjacent||Moderate||Allie Always (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Acetylcholinesterase Inhibition Leading to Neurodegeneration||adjacent||High||Allie Always (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Evidence Collection Strategy
Evidence Supporting this KER
There is well established mechanistic understanding supporting the relationship between these two KEs.
Neurodegeneration in the strict sense of the word, is referring to any pathological condition primarily affecting brain cell populations (Przedborski et al., 2003). At histopathological level, neurodegenerative conditions are described by neuronal death and reactive gliosis (Przedborski et al., 2003).
Uncertainties and Inconsistencies
Zebrafish has been exposed for 36-weeks to DomA and has showed no excitotoxic neuronal death and no histopathological lesions in glutamate-rich brain areas (Hiolski et al., 2014).
Administration of DomA (9.0 mg DomA kg(-1) bw, i.p.) to Sparus aurata (seabream) leads to measurement of 0.61, 0.96, and 0.36 mg DomA kg(-1) of brain tissue at 1, 2 and 4 hours. At this dose but also at lower concentrations (0.45 and 0.9 mg DomA kg(-1) bw) no major permanent brain damage has been detected (Nogueira et al., 2010). Leopard sharks possess the molecular target for DomA but it has been shown to be resistant to doses of DomA that can cause neurotoxicity to other vertebrates, suggesting the presence of some protective mechanism (Schaffer et al., 2006).
All these reports support the view that there is possible a species specific susceptibility to DomA toxicity.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There is an overall agreement regarding the histopathology of the brain lesions related to acute DomA neurotoxicity across certain species. Data derived from humans, rodents, non-human primates and sea lions suggest that common neudegeneration features in selected brain areas are found despite the fact that study design, estimated exposure, processing of samples and history of event may differ (Pulido, 2008).
Furthermore, the distribution of brain damage by DomA has also been established by magnetic resonance imaging microscopy (MRM) for both human and rat, demonstrating similar distribution as that described by histopathological studies (Pulido, 2008).
It is important to notice that human sensitivity to DomA exposure is well documented in the published literature and seems to be much higher than in other species (Lefebvre and Robertson 210; Barlow et al., 2004).In 1987 in Canada, more than 200 people became acutely ill after ingesting of mussels contaminated with DomA. The outbreak resulted in 20 hospitalizations and four deaths. Clinical effects observed included gastrointestinal symptoms and neurotoxic effects such as hallucinations, memory loss and coma. For this reason, the condition was termed amnesic shellfish poisoning (Barlow et al., 2004). The neurotoxic properties of domoic acid result in neuronal degeneration and necrosis in specific regions of the hippocampus (Teitelbaum et al., 1990).
Ananth C, Thameem DS, Gopalakrishnakone P, Kaur C., Domoic acid-induced neuronal damage in the rat hippocampus: changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. J Neurosci Res., 2001, 66: 177-190.
Ananth C, Gopalakrishnakone P, Kaur C., Induction of inducible nitric oxide synthase expression in activated microglia following domoic acid (DA)-induced neurotoxicity in the rat hippocampus. Neurosci Lett., 2003, 338: 49-52.
Antequera D, Bolos M, Spuch C, Pascual C, Ferrer I, Fernandez-Bachiller MI, Rodríguez-Franco MI, Carro E., Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aβ accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease. Neurobiol Dis., 2012, 46: 682-691.
Appel NM, Rapoport SI, O'Callaghan JP., Sequelae of parenteral domoic acid administration in rats: comparison of effects on different anatomical markers in brain. Synapse, 1997, 25: 350-358.
Barlow Jeffery B, T, Moizer K, Paul S, and Boyle C., Amnesic shellfish poison. Food Chem Toxicol., 42: 545-557.
Cendes F, Andermann F, Carpenter S, Zatorre RJ, Cashman NR., Temporal lobe epilepsy caused by domoic acid intoxication: evidence for glutamate receptor-mediated excitotoxicity in humans. Ann Neurol., 1995, 37: 123-6.
Colman JR, Nowocin KJ, Switzer RC, Trusk TC, Ramsdell JS., Mapping and reconstruction of domoic acid-induced neurodegeneration in the mouse brain. Neurotoxicol Teratol., 2005, 27: 753-767.
Hiolski EM, Kendrick PS, Frame ER, Myers MS, Bammler TK, Beyer RP, Farin FM, Wilkerson HW, Smith DR, Marcinek DJ, Lefebvre KA., Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS. Aquat Toxicol., 2014, 155: 151-159.
Jakobsen B, Tasker A, Zimmer J., Domoic acid neurotoxicity in hippocampal slice cultures. Amino Acids, 2002, 23: 37-44.
Lefebvre Kathi A. and Robertson Alison, Domoic acid and human exposure risks: A review, Toxicon, 2010, 56: 218–230.
Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF., Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice. Free Radic Biol Med., 2012, 52: 646-659.
Nogueira I, Lobo-da-Cunha A, Afonso A, Rivera S, Azevedo J, Monteiro R, Cervantes R, Gago-Martinez A, Vasconcelos V., Toxic effects of domoic acid in the seabream Sparus aurata. Mar Drugs, 2010, 8: 2721-2732.
Przedborski S, Vila M, Jackson-Lewis V., Neurodegeneration: What is it and where are we? J Clin Invest., 2003, 111: 3-10.
Pulido OM., Domoic acid toxicologic pathology: a review. Mar Drugs, 2008, 6: 180-219.
Qiu S, Currás-Collazo MC., Histopathological and molecular changes produced by hippocampal microinjection of domoic acid. Neurotoxicol Teratol., 2006, 28: 354-362.
Scallet AC, Schmued LC., Johannessen JN. Neurohistochemical biomarkers of the marine neurotoxicant, domoic acid. Neurotoxicol Teratol., 2005, 27: 745-752.
Schaffer P, Reeves C, Casper DR, Davis CR., Absence of neurotoxic effects in leopard sharks, Triakis semifasciata, following domoic acid exposure. Toxicon., 2006, 47: 747-752.
Slikker W Jr, Scallet AC, Gaylor DW., Biologically-based dose-response model for neurotoxicity risk assessment. Toxicol Lett., 1998, 102-103: 429-433.
Teitelbaum JS, Zatorre RJ, Carpenter S, Gendron D, Evans AC, Gjedde A, and Cashman NR., Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N Engl J Med., 1990, 322: 1781-1787.
Tiedeken JA, Muha N, Ramsdell JS., A cupric silver histochemical analysis of domoic acid damage to olfactory pathways following status epilepticus in a rat model for chronic recurrent spontaneous seizures and aggressive behavior. Toxicol Pathol., 2013a, 41: 454-69.
Tiedeken JA, Ramsdell JS., Persistent neurological damage associated with spontaneous recurrent seizures and atypical aggressive behavior of domoic acid epileptic disease. Toxicol Sci., 2013b, 133: 133-43.
Truelove J, Mueller R, Pulido O, Martin L, Fernie S, Iverson F., 30-day oral toxicity study of domoic acid in cynomolgus monkeys: lack of overt toxicity at doses approaching the acute toxic dose. Nat Toxins., 1997, 5: 111-114.
Tryphonas L, Truelove J, Nera E, Iverson F., Acute neurotoxicity of domoic acid in the rat. Toxicol Pathol., 1990, 18: 1-9.