Upstream eventACh Synaptic Accumulation
Increased Cholinergic Signaling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||adjacent||High||Low|
|Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement||adjacent|
Life Stage Applicability
Key Event Relationship Description
Acetylcholine is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to. Acetylcholine mediates central and peripheral functions, including somatic and autonomic functions. Excessive accumulation of acetylcholine at neural synapses and at neural-muscular junctions results in increased cholinergic signalling.
Acetylcholine is generated in presynaptic neurons and released into the synaptic cleft where it can bind to both pre- and postsynaptic receptors. Acetylcholine availability is downregulated by the degratory effect of acetylcholinesterase and by negative feedback loops controlled by muscarinic M2 receptors on the presynaptic neuron within the synapse (Soreq and Seidman, 2001).
Evidence Supporting this KER
- Biological plausibility for acetylcholine accumulation at the synapse leading to nervous system dysfunction is rooted in the well-established understanding of acetylcholine’s function as a neurotransmitter and neuromodulator. By acting upstream of a range of cellular and physiological functions, it is biologically plausible that accumulation of acetylcholine at neurological synapses will lead to systemic dysfunctions, which are often readily noticeable and measurable in clinical and research settings.
The relationship between excess acetylcholine at synapses and nervous system dysfunction has been reviewed in Molecular Cell Biology, 4th Edition (Lodish, 2000). See Sections 21.4 Neurotransmitters, Synapses, and Impulse Transmission and Section 21.5 Neurotransmitter Receptors.
Acetylcholine is a neurotransmitter in most vertebrate and invertebrate species, but the mechanism of activity may differ. For example in insects, acetylcholine acts as a neurotransmitter between sensory neurons and the central nervous system but glutamate acts as a neurotransmitter between motor neurons and skeletal muscles (Stenersen, 2004).
Male quail (8-14 weeks old) were exposed to a single dose of either dichlorvos or fenitrothion via subcutaneous injection at four treatment levels. Analysis of brain tissue showed an 80% reduction of AChE, and a concurrent significant increase in acetylcholine as compared to controls. At the highest doses, mortality was preceded by vigorous tremors, lacrimation, salivation, ataxia, and respiratory distress (Kobayashi, 1984).
A study of male and female starlings of three age classes (5 days to >1 year), found that the LD50 for nestlings was about half of the LD50 for adult birds exposed to dicrotophos, with all exposed birds displaying impaired coordination, tremors and impaired muscle coordination. AChE inhibition increased as dose increased, and was observed in all three age classes, although to a lesser extent in the nestlings. No sex differences in LC50 or AChE inhibition were observed (Grue and Shipley, 1984).
Asian stinging catfish (Heteropneustes fossilis) exposed for 40 days to sublethal concentrations of oxydemeton-methyl, had a >71% inhibition of AChe in the brain and a concurrent increase of acetylcholine in brain (>200%) and muscles (>188%), with fish displaying violent body movements (tremors) followed by loss of equilibrium (Verma 1981).
Uncertainties and Inconsistencies
No known qualitative inconsistencies or uncertainties associated with this relationship.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.
De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.
Picciotto MR, Higley MJ, Mineur YS., Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.
Luchicchi A, Bloem B, Viaña JN, Mansvelder HD, Role LW., Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Front Synaptic Neurosci. 2014 Oct 27;6:24. doi: 10.3389/fnsyn.2014.00024. eCollection 2014.
Soreq H, Seidman S., Acetylcholinesterase--new roles for an old actor. Nat Rev Neurosci. 2001 Apr;2(4):294-302.
Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 21.4, Neurotransmitters, Synapses, and Impulse Transmission. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21521/
Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.
Coulson FR1, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther. 2003 Apr;98(1):59-69.
Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.
Stenersen J. 2004. Specific enzyme inhibitors. Chemical Pesticides: Mode of action and toxicology, CRC Press, Boca Raton, FL, USA.
Kobayashi, H., Yuyama, A., Kudo, M., and 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.
Grue CE, Shipley BK. 1984. Sensitivity of nestling and adult starling to dicrotophos, an organophosphate pesticide. Environ Res 35:454–465.
Verma, S.R., Tonk, I.P., Gupta, A.K., Dalela, R.C. 1981. In Vivo Enzymatic Alteration in Certain Tissues of Saccobranchus Fossilis Following Exposure to Four Toxic Substances. Environ. Pollut. (Series A). 26(2), 121-127.