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AchE Inhibition leads to Increased Cholinergic Signaling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Acetylcholinesterase inhibition leading to acute mortality||non-adjacent||Cataia Ives (send email)||Under Development: Contributions and Comments Welcome||Under Development|
|Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement||non-adjacent||Allie Always (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
AChE inhibition leading to increased cholinergic signaling manifests across a range of “cholinergic syndrome” symptoms appearing as organ-type-specific responses. In cases of acute cholinergic poisoning, certain signs are often measurable within just a few minutes after exposure to an AChE inhibitor.
One of the earliest and most frequent signs of cholinergic poisoning is constricted pupils (miosis) (Wadia, 1974), which is a manifestation mediated by muscarinic cholinergic receptors. Other manifestations observed in cases of cholinergic poisoning are collectively known as SLUDGE symptoms (Peter):
Other signs of cholinergic poisoning are mediated by nicotinic cholinergic signalling. These include (Costa):
Other signs of increased cholinergic signalling occurring in the lungs and heart include increased bronchial secretion, bronchoconstriction, bradycardia and tachycardia, hypotension and hypertension (Costa, Peter).
This KER is focussed on the signs of increased cholinergic signalling frequently described and/or measured in laboratory, field and clinical studies.
Evidence Supporting this KER
Extensive research provides evidence that AchE inhibition is associated with symptoms that are known to be mediated by increased cholinergic signalling. The interaction between increased acetylcholine and enhanced signalling via nicotinic and muscarinic receptors is well-established. Further, cholinergic neurons are known to innervate multiple physiological sites (reviewed in Costa, In Casarett and Doull's Toxicology, Lodish).
Uncertainties and Inconsistencies
Exposure to high levels of AchE inhibiting insecticides (organophosphates and carbamates) is considered a factor contributing to GWS, a collection of neurological symptoms experienced by soldiers after the Persian Gulf War. Symptoms included fatigue, mood-cognitive problems, musculoskeletal symptoms. Factor analysis indicated cognitive impairment, ataxia and arthro-myo-neuropathy in some veterans and these symptoms were interpreted to reflect exposure to centrally acting anti-AChEs (Soreq & Seidman, 2001, Haley, 1997, Golomb, 2008)
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Acetylcholine, the enzymes needed to generate it, and acetylcholine receptors have been described within metazoans in bilaterians (vertebrates, echinoderms, insects, nematodes, and annelids, etc.) and cnidarians (sea anemones, corals and hydrozoans). Acetylcholine receptors have not been described in placozoans, poriferans, and ctenophores, nor outside of metazoans. (Faltine-Gonzalez, 2018).
Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.
Golomb, BA, Acetylcholinesterase inhibitors and Gulf War illnesses, Proc Natl Acad Sci USA. 2008 Mar 18; 105(11):4295-300.
Haley, R. W., Kurt, T. L. & Hom, J. Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms. J. Am. Med. Assoc. 277, 215–222 (1997).
Cui J, Li CS, He XH, Song YG. Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine. Chin Med J (Engl). 2013; 126(24):4764-70.
Hunt KA, Bird DM, Mineau P, Shutt L. 1991. Secondary poisoning hazard of fenthion to American kestrels. Arch Environ Contam Toxicol 21:84–90.
Kobayashi H, Yuyama A, Kajita T, Shimura K, Ohkawa T, Satoh K. 1985. Effects of insecticidal carbamates on brain acetylcholine content, acetylcholinesterase activity and behavior in mice. Toxicol Lett 29:153–159.
Kobayashi H, Yuyama A, Kudo M, Matsusaka N. 1983. Effects of organophosphorus compounds, O,O‐dimethyl‐o‐(2,2‐dichlorovinyl)phosphate (DDVP) and O,O‐dimethyl‐o‐(3‐methyl 4‐nitrophenyl)phosphorothioate (fenitrothion), on brain acetylcholine content and acetylcholinesterase activity in Japanese quail. Toxicology 28:219–227
Faltine-Gonzalez, DZ, Layden, MJ., The origin and evolution of acetylcholine signaling through AchRs in metazoans. bioRxiv 424804; doi: https://doi.org/10.1101/424804
Moser, VC. (1995). Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats. Neurotoxicol. Teratol. 17:617-625.