Acetylcholinesterase (AchE) Inhibition

56-38-2

LCCNCVORNKJIRZ-UHFFFAOYSA-N

Parathion

Diethyl O-p-nitrophenyl phosphorothioate Phosphorothioic acid, O,O-diethylO-(4-nitrophenyl) ester Alleron American Cyanamid 3422 Aphamite Bayer E-605 Bladan F Diethyl 4-nitrophenyl phosphorothioate Diethyl parathion Diethyl p-nitrophenyl phosphorothionate Diethyl p-nitrophenyl thionophosphate Ethyl parathion Folidol Folidol E Folidol E-605 Folidol oil Fosferno Gearphos Lirothion Nitrostigmine Nourithion NSC 8933 O,O-Diethyl O-(4-nitrophenyl) phosphorothioate O,O-Diethyl O-(p-nitrophenyl) phosphorothioate O,O-Diethyl O-p-nitrophenyl thiophosphate O,O-Diethyl-O-(4-nitrophenyl)phosphorothioate Oleoparathene Oleoparathion Paraphos Parathene Parathion [Phosphorothioic acid, O,O-diethyl-O-(4-nitrophenyl)ester] Parathion A Parathion-ethyl paration Penncap E Phosphorothioic acid O,O-diethyl O-(4-nitrophenyl)ester Phosphorothioic acid, O,O-diethyl O-(4-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl)ester Rhodiasol Rhodiatox Selephos Super Rodiatox Thiomex Thiophos Thiophos 3422 Ethylparathion

DTXSID7021100

121-75-5

JXSJBGJIGXNWCI-UHFFFAOYNA-N

JXSJBGJIGXNWCI-UHFFFAOYSA-N

Malathion

Butanedioic acid, [(dimethoxyphosphinothioyl)thio]-, diethyl ester [(Dimethoxyphosphinothioyl)thio]butanedioic acid diethyl ester American Cyanamid 4,049 Butanedioic acid, 2-[(dimethoxyphosphinothioyl)thio]-, 1,4-diethyl ester Carbetovur Carbetox Carbofos Carbophos Cimexan Cythion Derbac M Diethyl mercaptosuccinate S-ester with O,O-dimethyl phosphorodithioate DIETHYL MERCAPTOSUCCINATE, ESTER WITH DIMETHYLPHOSPHORODITHIOATE Diethyl(dimethoxyphosphinothioylthio) succinate Ethiolacar Extermathion Forthion Fosfothion Fosfotion Fyfanon Gammaxine Hilthion Hi-Yield Insecticide 4049 Insecticide no. 4049 Karbofos Malafor Malamar Malasol Malaspray Malataf Malathine Malathion E 50 Malathion ULV Malathyl Malathyne malation Malatol Malatol 500CE Maldison Mavidan Mercaptothion Moscarda NSC 6524 O,O-Dimethyl S-(1,2-dicarbethoxyethyl) dithiophosphate O,O-Dimethyl-S-(1,2-diethoxycarbonylethyl)-phosphoro dithioate Oleophosphothion Organoderm Ortho Malathion Phosphothion Prioderm Radotion Radotion P 5 S-[1,2-Bis(carbethoxy)ethyl] O,O-dimethyl dithiophosphate S-[1,2-Bis(ethoxycarbonyl)ethyl] O,O-dimethyl phosphorodithioate S-[1,2-Bis(ethoxycarbonyl)ethyl] O,O-dimethyl thiophosphate S-1,2-bis(Ethoxycarbonyl)ethyl O,O-dimethylphosphorodithioate Sadofos Sadophos Security Siptox I Succinic acid, mercapto-, diethyl ester, S-ester with O,O-dimethyl phosphorodithioate Suleo M Sumitox Zithiol

DTXSID4020791

2921-88-2

SBPBAQFWLVIOKP-UHFFFAOYSA-N

Chlorpyrifos

Dursban Phosphorothioic acid, O,O-diethylO-(3,5,6-trichloro-2-pyridinyl) ester Bonidel Chloroban Chloropyrifos Chloropyrifos-ethyl Chloropyriphos Chlorpyrifos E Chlorpyrifos-ethyl Clorpiran Clorpirifos Coroban Danusban Dhanusban Dursban 10CR Dursban Pro Dursban R Dursban TC Dursband Dursband 48 Emperor Ethyl chlorpyriphos Geodinfos Killmaster Lentrek Lock-On Lorsban Lorsban 50SL O,O-DIETHYL O-(3,5,6-TRICHLORO-2-PYRIDINYL PHOSPHOROTIOATE) O,O-Diethyl O-(3,5,6-trichloro-2-pyridinyl)phosphorothioate O,O-Diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate O,O-Diethyl O-(3,5,6-trichloro-2-pyridyl) thiophosphate O,O-Diethyl-O-(3,5,6-trichloro-2-pyridyl)phosphorothioate O,O-Diethyl-O-3,5,6-trichloro-2-pyridylphosphorothionate PHOSPHOROTHIOATE, O,O-DIETHYL O-(3,5,6-TRICHLORO- 2-PYRIDYL) Phosphorothioic acid, O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) ester Phosphorothioic acid, O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) ester Pyrifos Pyrinex Spannit Stipend suScon Green Tafaban Xinnongba CPF Chlorpyriphos O,O-Diethyl-o-(3,5,6-trichloro-2-pyridyl)phosphorothiolate

DTXSID4020458

85721-33-1

MYSWGUAQZAJSOK-UHFFFAOYSA-N

Ciprofloxacin

1-Cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid 3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-

DTXSID8022824

96-64-0

GRXKLBBBQUKJJZ-UHFFFAOYNA-N

GRXKLBBBQUKJJZ-UHFFFAOYSA-N

Soman

Soman Phosphonofluoridic acid, methyl-, 1,2,2-trimethylpropyl ester 1,2,2-Trimethylpropoxyfluorophosphine oxide 1,2,2-Trimethylpropyl methylphosphonofluoridate 3,3-Dimethyl-n-but-2-yl methylphosphonofluoridate Methyl pinacolyl phosphonofluoridate Methyl pinacolyloxy phosphorylfluoride Methylphosphonofluoridic acid 1,2,2-trimethylpropyl ester Phosphine oxide, fluoromethyl(1,2,2-trimethylpropoxy)- Phosphonofluoridic acid, P-methyl-, 1,2,2-trimethylpropyl ester Pinacoloxymethylphosphoryl fluoride Pinacolyl methylfluorophosphonate

DTXSID2031906

PR:000003626

PR acetylcholinesterase

PR:000001488

PR muscarinic acetylcholine receptor

D001145

MESH Arrhythmias, Cardiac

GO:0003990

GO acetylcholinesterase activity

GO:0031789

GO G-protein coupled acetylcholine receptor binding

GO:0001508

GO action potential

WIKI decreased

WIKI increased

WIKI abnormal

Donepezil

2024-11-22T11:21:17

Neostigmine

2024-11-22T11:21:30

Pyridostigmine

2024-11-22T11:21:42

Parathion

2016-11-29T18:42:22

Malathion

2020-03-30T15:59:42

Chlorpyrifos Chlorpyrifos is a widely used organophosphate insecticide, which has been suspected as a risk factor for infant and childhood leukaemia after the house-hold exposure of pregnant women. According to Lu et al (2015), chlorpyrifos and its metabolite chlorpyrifos oxon exhibit an inhibitory effect on in vitro TopoII activity. Chlorpyrifos causes DNA double strand breaks as measured by the neutral Comet assay and induces MLL gene rearrangements in human fetal liver-derived CD34+ hematopoietic stem cells via TopoII ’poisoning’ as detected by the Fluorescent In Situ Hybridization (FISH) assay and in vitro isolated TopoII inhibition assay, respectively (Lu et al 2015). Chlorpyrifos also stabilizes the TopoII-DNA cleavage complex. Etoposide was used a positive reference compound in these studies.. The lowest concentration of chlorpyrifos used was 1 µM and it gave a statistically significant effect in many in vitro assays. The point of departure of etoposide, which was calculated to be 0.01 to 0.1 µM (Li et al 2014), is at least 10- fold lower than that of chlorpyrifos.   <table align="center" cellspacing="0" class="OECD" style="border-collapse:collapse; border:none; width:14.0cm"> <tbody> <tr> <td colspan="3" style="border-bottom:1px solid #4e81bd; border-left:none; border-right:none; border-top:2px solid #4e81bd; vertical-align:top"> Environmental chemicals </td> </tr> <tr> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Aromatic compounds </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> benzene, PAHs </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:none; border-top:none; vertical-align:top">  Mondrola et al.2010 </td> </tr> <tr> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Nitrosamines </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Diethylnitrosamine </td> <td style="border-bottom:1px solid #bfbfbf; border-left:none; border-right:none; border-top:none; vertical-align:top"> Thys et al 2015 </td> </tr> <tr> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Organophosphates </td> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:1px solid #bfbfbf; border-top:none; vertical-align:top"> Chlorpyrifos </td> <td style="border-bottom:2px solid #4e81bd; border-left:none; border-right:none; border-top:none; vertical-align:top"> Lu et al 2015, Rodriguez et al.2020 </td> </tr> </tbody> </table>

2017-04-25T04:08:02

2022-07-27T04:02:33

Diazinon

2024-11-22T11:22:38

Sarin

2024-11-22T11:22:53

Tabun

2024-11-22T11:23:06

Carbaryl

2024-11-22T11:23:21

Aldicarb

2024-11-22T11:23:35

Physostigmine

2024-11-22T11:23:47

Ciprofloxacin

2018-12-04T04:26:23

Carbofuran

2024-11-22T11:24:25

Pilocarpine

2024-11-22T11:24:39

Bethanechol

2024-11-22T11:24:54

Organophosphates Organophosphate

repeated exposure

2016-11-29T18:42:20

2016-11-29T21:20:01

N-methyl Carbamates

2016-11-29T18:42:26

2019-10-07T14:19:19

WCS_7955

common ecological species zebrafish

10095

NCBI mice

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

10116

NCBI Rattus norvegicus

9615

NCBI dogs

9823

NCBI Sus scrofa

1186497

NCBI Insecta sp. BOLD:AAN5199

Acetylcholinesterase (AchE) Inhibition

AchE Inhibition

Cellular

"Acetylcholinesterase is found primarily in blood, brain, and muscle, and regulates the level of the neurotransmitter ACh [acetylcholine] at cholinergic synapses of muscarinic and nicotinic receptors. Acetylcholinesterase features an anionic site (glutamate residue), and an esteratic site (serine hydroxyl group) (Wilson, 2010; Soreq, 2001). In response to a stimulus, ACh is released into the synaptic cleft and binds to the receptor protein, resulting in changes to the flow of ions across the cell, thereby signaling nerve and muscle activity. The signal is stopped when the amine of ACh binds at the anionic site of AChE, and aligns the ester of ACh to the serine hydroxyl group of the enzyme. Acetylcholine is subsequently hydrolyzed, resulting in a covalent bond with the serine hydroxyl group and the subsequent release of choline, followed by a rapid hydrolysis of the enzyme to form free AChE and acetic acid (Wilson, 2010; Soreq, 2001)." [From Russom et al. 2014. Environ. Toxicol. Chem. 33: 2157-2169] Molecular target gene symbol: ACHE KEGG enzyme: EC 3.1.1.7

<ul> <li>Direct measures of AChE activity levels can be made using the modified Ellman method, although selective inhibitors that remove other cholinesterases not directly related to cholinergic responses (e.g., butyrylcholinesterase) are required [45,46].</li> <li>Radiometric methods have been identified as better for measuring inhibition because of carbamylation (carbamate exposure) [20,46,47].</li> <li>TOXCAST: NVS_ENZ_hAChE</li> <li>A direct measure of cholinesterase activity levels can be made within the relevant tissues after in vivo exposure, specifically the brain as well as red blood cells in mammals. Some analytical methods used to measure cholinesterase activity may not distinguish between butyrylcholinesterase, which is found with AChE in plasma and some skeletal and muscle tissues. Although the structure of butyrylcholinesterase is very similar to AChE, its biological function is not clear, and its activity is not associated with cholinergic response covered under this AOP (Lushington et al., 2006). Therefore experimental procedures used to measure cholinesterase as well as the tissue analyzed should be considered when evaluating studies reporting AChE inhibition (Wilson 2010; Wilson and Henderson 2007). For measuring AChE levels, the Ellman method is recommended with some modifications (Ellman et al., 1961; Wilson et al., 1996) while radiometric methods have been identified as better for measuring inhibition due to carbamylation (carbamate exposure) (see Wilson 2010; Wilson et al., 1996; Johnson and Russell 1975).</li> </ul> <ul> <li>In order to effectively bind to the AChE enzyme, thion forms of OPs (i.e., RO)3P=S) must first undergo a metabolic activation via mixed function oxidases to yield the active, oxon form (Fukuto 1990). Estimating the potential toxicity in whole organisms based on in vitro data may be problematic since metabolic activation may be required (e.g., phosphorothionates) and may not be reflected in the in vitro test result (Guo et al. 2006; Lushington et al. 2006).</li> <li>Typically, carbamates do not require metabolic activation in order to bind to the enzyme, although some procarbamates (e.g., carbosulfan) have been developed that are not direct inhibitors of AChE, but take advantage of metabolic distinctions between taxa, resulting in a toxic form in invertebrates (e.g., carbofuran) but not vertebrate species (Stenersen 2004). Therefore in vitro assays measuring AChE inhibition for procarbamates in invertebrate species will not account for metabolic activation and therefore may not represent the actual enzyme activity.</li> </ul>

AChE is present in all life stages of both vertebrate and invertebrate species (Lu et al 2012). <ul> <li dir="ltr"> Acetylcholinesterase associated with cholinergic responses in most insects is coded by the ace1 gene and in vertebrates by the ace gene (Lu et al 2012; Taylor 2011. </li> <li dir="ltr"> Plants have AChE but it is most likely involved in regulation of membrane permeability and the ability of a leaf to unroll (Tretyn and Kendrick 1991). </li> </ul> <ul> <li dir="ltr"> The primary amino acid sequence of the AChE enzyme is relatively well conserved across vertebrate and invertebrate species, suggesting that chemicals are likely to interact with the enzyme in a similar manner across a wide range of animals. From the sequence similarity analyses, the taxonomic domain of applicability of this MIE likely includes species belonging to many lineages, including branchiopoda (crustaceans, e.g., daphnids), insecta (insects), arachnida (arachnids, e.g., spiders, ticks, scorpions), cephalopoda (molluscans, e.g., octopods, squids), lepidosauria (reptiles, e.g., snakes, lizards), chondrichthyes (cartilaginous fishes, e.g., sharks), amphibia (amphibians), mammalian (mammals), aves (birds), actinopterygii (bony fish), ascidiacea (sac-like marine invertebrates), trematoda (platyhelminthes, e.g., flatworms), and gastropoda (gastropods, e.g., snails and slugs) Species within these taxonomic lineages and others are predicted to be intrinsically susceptible to chemicals that target functional orthologs of the daphnid AChE (Russom, 2014). </li> <li dir="ltr"> Advanced computational approaches such as crystal structures of the enzyme and transcriptomics have provided empirical evidence of the enzyme structure, relevant binding sites, and function across species (Lushington et al., 2006; Lu et al., 2012; Wallace 1992). </li> </ul> Studies have found that AChE activity increases as the organism develops. <ul> <li dir="ltr"> Prakesh and Kaur 1982 looked at AChE inhibition across three insect species; controls and those exposed to DDVP. They saw little difference in the larval stages but did see increased inhibition in pupal and adult stages (greatest inhibition).  </li> <li dir="ltr"> Karanth and Pope 2003 looked at AChE and acetylcholine synthesis in rat striatum in controls and animals exposed to 0.3 and 1 times the maximum tolerated dose. Although these doses are below the lethal concentrations and they mention that not observed cholinergic responses were observed, they do provide differences related to life stages of the rodents.  </li> <li dir="ltr"> Grue et al 1981 present baseline (no toxicity exposure) in wild starlings (both sexes) of brain cholinesterase and found activity increased as birds aged from 1-20 days until it reached a steady state at adulthood. </li> <li dir="ltr"> A study with Red Flour Beetle found that the gene associated with cholinergic functions (Ace1) was expressed at all life-stages, with increases as the organism developed from egg to larva to pupa to adult. (Lu et al., 2012 cited in Russom et al 2014.) </li> <li dir="ltr"> In mammals and birds, studies have determined that skeletal muscles of immature birds and mammals contain both butyrylcholinesterase and AChE, with butyrylcholinesterase decreasing and AChE increasing as the animal develops (Tsim et al. 1988; Berman et al, 1987).   </li> <li dir="ltr"> Another study found that changes in AChE within the developing pig brain were dependent on the area of the brain, and life stage of the animal, with significant decreases in activity within the pons and hippocampus from birth to 36 months, and no significant change in activity in the cerebellum, where activity increased up to four months of age, leveling off thereafter (Adejumo and Egbunike, 2004). </li> </ul>

UBERON:0001016

UBERON nervous system

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

<ul> <li dir="ltr"> Augustinsson KB. 1957. Assay methods for cholinesterases. Methods of Biochemical Analysis, Vol 5, Interscience Publishers, Inc., New York, NY, USA, pp 1-63. </li> <li dir="ltr"> Ecobichon, D.J. 2001. Toxic effects of pesticides. In: C.D. Klaassen (Ed.), Casarett and Doull’s Toxicology: The Basic Science of Poisons; Sixth Edition. (pp. 763-810). McGraw-Hill, New York, NY. </li> <li dir="ltr"> Ellman GL, Courtney KD, Andres V Jr, Featherstone RM. 1961. A new and rapid colormetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88-95. </li> <li dir="ltr"> Fukuto, TR. 1990. Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect. 87:245-254. </li> <li dir="ltr"> Guo, J.-X., J.J.-Q. Wu, J.B. Wright, and G.H. Lushington. 2006. Mechanistic insight into acetylcholinesterase inhibition and acute toxicity of organophosphorus compounds: A molecular modeling study. Chem. Res. Toxicol. 19: 209-216. </li> <li dir="ltr"> Johnson CD, Russell RL. 1975. A rapid, simple radiometric assay for cholinesterase suitable for multiple determinations. Anal Biochem 64:229-238. </li> <li dir="ltr"> Kropp, T.J., and Richardson, R.J. 2003. Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase. J. Toxicol. Environ.l Health, Part A, 66:1145–1157. </li> <li dir="ltr"> Lu Y, Park Y, Gao X, Zhang X, Yoo J, Pang X-P, Jiang H, Zhu KY. 2012. Cholinergic and non-cholinergic functions of two acetylcholinesterase genes revealed by gene-silencing in Tribolium castaneum. Sci Rep 2:1-7. </li> <li dir="ltr"> Ludke JL, Hill EF, Dieter MP. 1975. Cholinesterase (ChE) response and related mortality among birds fed ChE inhibitors. Arch Environ ContamToxicol 3:1–21. </li> <li dir="ltr"> Lushington, G.H., J-X. Guo, and M.M. Hurley. 2006. Acetylcholinesterase: Molecular modeling with the whole toolkit. Curr. Topics Medic. Chem. 6: 57-73. </li> <li dir="ltr"> Mileson, BE, Chambers JE, Chen WL, Dettbarn W, Ehrich M, Eldefrawi AT, Gaylor DW, Hamernik K, Hodgson E, Karczmar AG, Padilla S, Pope CN, Richardson RJ, Saunders DR, Sheets LP, Sultatos LG, Wallace KB.  1998. Common mechanism of toxicity: A case study of organophosphorus pesticides. Toxicol Sci 41:8-20. </li> <li dir="ltr"> Moser, Virginia C. 2011. “Age-Related Differences in Acute Neurotoxicity Produced by Mevinphos, Monocrotophos, Dicrotophos, and Phosphamidon.” Neurotoxicology and Teratology 33 (4): 451–57.<a href="https://doi.org/10.1016/j.ntt.2011.05.012"> https://doi.org/10.1016/j.ntt.2011.05.012</a>. </li> <li dir="ltr"> Monserrat, J.M. and A. Bianchini. 2001. Anticholinesterase effect of eserine (physostigmine) in fish and crustacean species. Braz. Arch. Biol. Technol. 44(1): 63-68. </li> <li dir="ltr"> Russom, Christine L., Carlie A. LaLone, Daniel L. Villeneuve, and Gerald T. Ankley. 2014. “Development of an Adverse Outcome Pathway for Acetylcholinesterase Inhibition Leading to Acute Mortality.” Environmental Toxicology and Chemistry 33 (10): 2157–69.<a href="https://doi.org/10.1002/etc.2662"> https://doi.org/10.1002/etc.2662</a>. </li> <li dir="ltr"> Schűűrmann G. 1992. Ecotoxicology and structure-activity studies of organophosphorus compounds. Rational Approaches to Structure, Activity, and Ecotoxicology of Agrochemicals, CRC Press, Boca Raton, FL, USA pp 485-541 </li> <li dir="ltr"> Sogob MA, Vilanova E. 2002. Enzymes involved in the detoxification of organophosphorus, carbamate and pyrethroid insecticides through hydrolysis. Toxicol Lett 128:215-228. </li> <li dir="ltr"> Soreq H, Seidman S. 2001. Acetylcholinesterase -- New roles for an old actor. Nature Reviews Neurosci 2:294-302. </li> <li dir="ltr"> Stenersen, J. 2004. Specific enzyme inhibitors. In: Chemical Pesticides: Mode of action and toxicology. (41 p). CRC Press, Boca Raton, FL. </li> <li dir="ltr"> Taylor P. 2011. Anticholinesterase agents. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th ed, McGraw Hill, New York, NY, USA, pp 255-276. </li> <li dir="ltr"> Tretyn A, Kendrick RE. 1991. Acetylcholine in plants: Metabolism and mechanism of action. Bot Rev 57:33-73. </li> <li dir="ltr"> Wilson BW, Padilla S, Henderson JD, Brimijoin S, Dass PD, Elliot G, Jaeger B, Lanz D, Pearson R, Spies R. 1996. Factors in standardizing automated cholinesterase assays. J Toxicol Environ Health 48:187-195. </li> <li dir="ltr"> Wilson, B.W. and J.D. Henderson. 2007. Determination of cholinesterase in blood and tissue. Current Protocols in Toxicology 12.13.1-12.13.16. </li> <li dir="ltr"> Wilson BW. 2010. Cholinesterases. Hayes’ Handbook of Pesticide Toxicology, 3rd ed, Vol 2. Elsevier, Amsterdam, The Netherlands, pp 1457-1478. </li> </ul> AOPWiki 2016-11-29T18:41:22

2020-04-29T17:21:36

Increased Muscarinic Acetylcholine Receptors

Activation, Muscarinic Acetylcholine Receptors

Molecular

Muscarinic acetylcholine receptors (mAChRs) are G-protein-coupled receptors (GPCRs) with five different subtypes (M1, M2, M3, M4, and M5). GPCRs are transmembrane receptors that detect extracellular signals and activate internal pathways which modulate a variety of processes such as locomotion, learning and memory, thermoregulation and epileptic seizures (Gainetdinov and Caron, 1999).  Subtypes M1, M3, and M5 are Gq- coupled receptors that activate phospholipase C enzyme resulting in two secondary messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Subtypes M2 and M4 are inhibitory and signal using the Gi pathway (Haga, 2013). Gi protein activation inhibits adenylyl cyclase, and reduces the conversion of ATP to cAMP (Jett and Lein, 2011).            In its resting state, the mAChR G-protein subunits (alpha, beta and gamma) are clustered together and the alpha subunit is bound to GDP.  Once a ligand binds to an mAChR, the receptor undergoes a conformation change that allows the alpha subunit to exchange its bound GDP with GTP<ins>,</ins> then the alpha subunit dissociates from the beta and gamma subunits. Once the alpha subunit is free of the beta and gamma subunits, it moves along the cell membrane to affect its target enzyme, which typically sends out secondary messenger signals (Kandel et al., 2013)

Most studies investigating the function of mAChRs involve blocking signaling from these receptors through use of selective antagonists like atropine or scopolamine, or the use of gene targeted knockout specimens (Bymaster et al. 2003; Faria et al. 2017). The distribution and density of mAChRs can be measured using radiolabeled agonists that bind to the mAChR binding site. The receptor activity can be measured by detecting secondary-messengers regulated by the G-protein. <ul> <li>Use mAChR agonist [3H] quinuclidinyl benzilate (QNB) to label mAChRs (all subtypes; see Fonnum and Sterri (2011) and measure binding levels as described by Fitzgerald and Costa (1993) and Gazit et al. (1979)</li> <li>Determination of the relative levels of specific mAChR subtypes in tissues has been found through the use of subtype-specific antisera as described by Dörje et al. (1991)</li> <li>Kinetic measurements of DAG production and IP3 release can be obtained through fluorescent reporters as in Falkenburger et al. (2013) and Dickson et al. (2013).</li> <li>Changes in the activity and quantity of cAMP and the cAMP-dependent protein kinases can serve as an indicator of the activity of mAChRs bound to Gi-proteins (M2 and M4). cAMP content can be determined using a radioimmunoassay (RIA) kit (Heikkilä et al., 1991).</li> <li>Adenylyl cyclase activity can be determined through an assay as described by Salomon et al. (1974) and used by Raheja and Dip Gill (2007).</li> </ul>

Taxa:            mAChRs are found in most vertebrates, many of the studies cited are conducted using zebrafish and mice. Zebrafish are frequently used for high-throughput assays as they have well-conserved neurotransmitter structures, including acetylcholine transmitters (Garcia et al., 2016). This can provide valuable data regarding the activation of mAChRs in mammalian systems. Knockout mice also help to elucidate the functions of specific mAChR subtypes (Gainetdinov and Caron, 1999).   Life stage:            mAChRs signal neurons throughout all life stages (Miller and Yeh, 2016). They do not only affect individuals during developmental stages, but there have been some studies conducted specifically on the developmental effects of chemicals that affect acetylcholine signaling (Burke et al., 2017). Most of the whole animal experimental data are from younger specimens, but there have also been experiments on adult individuals (Fitzgerald and Costa, 1993).   Sex:            mAChRs are found in both males and females, with similar functions (Burke et al., 2017).

CL:0000255

CL eukaryotic cell

Moderate Unspecific

Moderate

Embryo

Moderate

Juvenile

Moderate Moderate

Burke, R. D., S. W. Todd, E. Lumsden, R. J. Mullins, J. Mamczarz, W. P. Fawcett, R. P. Gullapalli, W. R. Randall, E. F. R. Pereira and E. X. Albuquerque (2017), "Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms”, Journal of Neurochemistry 142: 162-177. DOI: 10.1111/jnc.14077. Dickson, E. J., B. H. Falkenburger and B. Hille (2013), "Quantitative properties and receptor reserve of the IP3 and calcium branch of Gq-coupled receptor signaling”, Journal of General Physiology 141(5): 521-535. DOI: 10.1085/jgp.201210886. Dörje, F., A. I. Levey and M. R. Brann (1991), "Immunological detection of muscarinic receptor subtype proteins (m1-m5) in rabbit peripheral tissues”, Molecular Pharmacology 40(4): 459-462. Falkenburger, B. H., E. J. Dickson and B. Hille (2013), "Quantitative properties and receptor reserve of the DAG and PKC branch of Gq-coupled receptor signaling”, The Journal of General Physiology 141(5): 537-555. DOI: 10.1085/jgp.201210887. Faria, M., Prats, E., Padrós, F., Soares, A. M., & Raldúa, D. (2017). Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication. Archives of toxicology, 91(4), 1891-1901. Fitzgerald, B. B. and L. G. Costa (1993), "Modulation of Muscarinic Receptors and Acetylcholinesterase Activity in Lymphocytes and in Brain Areas Following Repeated Organophosphate Exposure in Rats”, Fundamental and Applied Toxicology 20(2): 210-216. DOI: 10.1006/faat.1993.1028. Fonnum, F. and S. H. Sterri (2011), “Tolerance Development to Toxicity of Cholinesterase Inhibitors”, in Toxicology of organophosphate and carbamate compounds, R. C. Gupta, Ed., Academic Press: 257-267. Gainetdinov, R. R. and M. G. Caron (1999), "Delineating muscarinic receptor functions”, Proceedings of the National Academy of Sciences of the United States of America 96(22): 12222-12223. DOI: 10.1073/pnas.96.22.12222. Garcia, G. R., P. D. Noyes and R. L. Tanguay (2016), "Advancements in zebrafish applications for 21st century toxicology”, Pharmacology and Therapeutics 161: 11-21. DOI: 10.1016/j.pharmthera.2016.03.009. Gazit, H., I. Silman and Y. Dudai (1979), "Administration of an organophosphate causes a decrease in muscarinic receptor levels in rat brain”, Brain Research 174(2): 351-356. DOI: 10.1016/0006-8993(79)90861-8. Haga, T. (2013), "Molecular properties of muscarinic acetylcholine receptors”, Proceedings of the Japan Academy Series B: Physical and Biological Sciences 89(6): 226-256. DOI: 10.2183/pjab.89.226. Heikkilä, J., C. Jansson and K. E. O. Åkerman (1991), "Differential coupling of muscarinic receptors to Ca2+ mobilization and cyclic AMP in SH-SY5Y and IMR 32 neuroblastoma cells”, European Journal of Pharmacology: Molecular Pharmacology 208(1): 9-15. DOI: 10.1016/0922-4106(91)90045-J. Jett, D. A. and P. J. Lein (2011), “Noncholinesterase Mechanisms of Central and Peripheral Neurotoxicity: Muscarinic Receptors and Other Targets”, in Toxicology of organophosphate and carbamate compounds, R. C. Gupta, Ed., Academic Press: 233-245. Kandel, E., J. Schwartz, T. Jessell, S. Siegelbaum and A. J. Hudspeth (2013), “Modulation of Synaptic Transmission: Second Messengers”, in Principles of Neural Science, Fifth Edition, Blacklick, United States, McGraw-Hill Publishing: 236-259. Miller, S. L. and H. H. Yeh (2016), “Neurotransmitters and Neurotransmission in the Developing and Adult Nervous System”, in Conn's Translational Neuroscience: 49-84. Raheja, G. and K. Dip Gill (2007), "Altered cholinergic metabolism and muscarinic receptor linked second messenger pathways after chronic exposure to dichlorvos in rat brain”, Toxicology and Industrial Health 23(1): 25-37. DOI: 10.1177/0748233707072490. Salomon, Y., C. Londos and M. Rodbell (1974), "A highly sensitive adenylate cyclase assay”, Anal Biochem 58(2): 541-548. DOI: 10.1016/0003-2697(74)90222-x.   AOPWiki 2019-02-06T20:02:30

2024-12-02T03:35:16

Altered, Action Potential

Cellular

CL:0000255

CL eukaryotic cell

AOPWiki 2016-11-29T18:41:26

2022-03-31T06:49:25

Increased delay in heart electrical conduction

Prolonged atrioventricular (AV)

Organ

Prolonged atrioventricular (AV) conduction time, also referred to as first-degree AV block, occurs when there is an abnormal delay in the conduction of electrical impulses from the atria to the ventricles via the AV node or the His-Purkinje system. This delay is characterized by a longer-than-normal PR interval on an electrocardiogram (ECG), typically exceeding 200 milliseconds in adults.

Electrocardiogram (ECG) Findings Prolonged PR Interval: >200 ms (in adults), reflecting delayed conduction through the AV node. Normal P-wave to QRS relationship: Every P wave is followed by a QRS complex. Holter Monitoring Used to evaluate intermittent or progressive AV conduction abnormalities. Electrophysiology Study (EPS) Provides detailed mapping of conduction pathways for diagnostic clarification in complex cases. Blood Tests Evaluate potential reversible causes (e.g., electrolyte levels, thyroid function). <h3>Electrophysiological Studies</h3> <h4>a. Patch-Clamp Recording</h4> Purpose: Measures ionic currents and action potentials in single AV nodal cells. Key Measurements: Action Potential Duration (APD): Prolonged APD can contribute to delayed conduction. Ion Currents: Calcium Current (ICa): Reduced L-type Ca²⁺ channel activity delays depolarization in the AV node. Potassium Currents (IK): Altered repolarization currents (e.g., delayed rectifier K⁺ currents) may slow conduction. Funny Current (If): Dysfunctional pacemaker currents may indirectly affect conduction timing. Application: Provides detailed insights into the contribution of ion channel dysfunction to conduction delay. <h4>Microelectrode Studies</h4> Purpose: Measures transmembrane potentials in tissue slices or isolated nodal regions. Key Features: Detects conduction delay between atrial and ventricular regions. Identifies specific regions within the AV node where delay occurs. <h3>Optical Mapping</h3> Purpose: Visualizes electrical activity across cardiac tissue at the cellular level. Key Method: Use voltage-sensitive dyes to record changes in membrane potential. Tracks conduction velocity across the AV node and surrounding regions. Application: Identifies areas of delayed conduction or functional block in the AV node. <h3>Molecular and Cellular Analysis</h3> <h4>a. Ion Channel Expression Studies</h4> Purpose: Assesses the expression and function of ion channels critical for AV node conduction. Key Techniques: qPCR and Western Blot: Quantify the expression of ion channels like: L-type Ca²⁺ channels (Cav1.2): Key for depolarization in AV node cells. HCN Channels: Contribute to pacemaker activity. Potassium Channels (e.g., Kv, Kir): Involved in repolarization. Immunostaining: Localizes ion channels in AV nodal cells. Relevance: Reduced expression or dysfunction of these channels correlates with conduction delays. <h4>b. Connexin Analysis</h4> Purpose: Evaluates gap junction proteins (e.g., Connexin 43, Connexin 45) responsible for cell-to-cell conduction. Techniques: Immunohistochemistry or confocal microscopy. Genetic or pharmacological modulation of connexin function. Relevance: Decreased gap junction connectivity slows conduction velocity. <h3>Cellular Calcium Handling</h3> Purpose: Measures intracellular calcium transients critical for AV nodal conduction. Key Method: Use calcium-sensitive fluorescent dyes (e.g., Fluo-4, Fura-2). Relevance: Impaired calcium cycling (e.g., reduced Ca²⁺ channel activity) slows depolarization and conduction. <h3>Tissue-Level Functional Studies</h3> AV Node Tissue Slices: Isolated tissue preparations allow for measurement of conduction delays using extracellular electrodes or optical mapping. Langendorff-Perfused Hearts: Enables study of the whole heart, including AV node function, under controlled conditions. <h3>Genetic and Pharmacological Modulation</h3> <h4>a. Genetic Models</h4> Knockout or Transgenic Mice: Models with specific ion channel or connexin mutations (e.g., HCN4, Cav1.3) help study the cellular basis of AV conduction delay. <h4>b. Drug Studies</h4> Calcium Channel Blockers (e.g., Verapamil): Induce AV conduction delay to study mechanisms. Beta-adrenergic Agonists (e.g., Isoproterenol): Test enhancement of AV conduction. <h3>Computational Modeling</h3> Purpose: Simulates ionic currents, action potential propagation, and AV node conduction at the cellular level. Relevance: Predicts how molecular or cellular changes contribute to prolonged conduction.

<h3>Causes of Prolonged AV Conduction Time</h3> <ol> <li> Intrinsic Factors <ul> <li>Age-related degeneration: Fibrosis or sclerosis of the conduction system.</li> <li>Congenital heart disease: Structural abnormalities affecting conduction pathways.</li> <li>Primary conduction system disease: Diseases like Lev's or Lenegre's disease.</li> </ul> </li> <li> Extrinsic Factors <ul> <li>Medications: Drugs that slow AV node conduction, such as: <ul> <li>Beta-blockers.</li> <li>Calcium channel blockers (non-dihydropyridines like verapamil and diltiazem).</li> <li>Digoxin.</li> <li>Antiarrhythmics (e.g., amiodarone).</li> </ul> </li> <li>Electrolyte imbalances: Hyperkalemia or hypokalemia affecting conduction.</li> <li>Autonomic factors: Increased parasympathetic (vagal) tone.</li> </ul> </li> <li> Cardiac Conditions <ul> <li>Ischemic heart disease (e.g., myocardial infarction involving the AV nodal artery).</li> <li>Myocarditis or infiltrative diseases (e.g., sarcoidosis, amyloidosis).</li> <li>Valvular heart disease (e.g., calcification of the mitral or aortic valve).</li> </ul> </li> <li> Systemic Causes <ul> <li>Infections such as Lyme disease or Chagas disease.</li> <li>Endocrine disorders like hypothyroidism.</li> </ul> </li> </ol> <h3>Clinical Presentation</h3> <ul> <li>Asymptomatic: Often detected incidentally during ECG.</li> <li>Symptomatic (rare): <ul> <li>Fatigue.</li> <li>Lightheadedness.</li> <li>Syncope (if associated with progression to higher-degree AV block).</li> </ul> </li> </ul>

<h3>Boyett MR, Honjo H, and Kodama I. "The sinoatrial node, a heterogeneous pacemaker structure." Cardiovascular Research, 2000.</h3> Jalife J, Moe GK. "Factors Controlling Pacemaker Action in Cells of the Sinoatrial Node." Circulation Research, 1965. Mangoni ME, Nargeot J. "Genesis and regulation of the heart automaticity." Physiological Reviews, 2008. Lev M, Lenegre J. "Pathology of atrioventricular block." American Heart Journal, 1955. Antzelevitch, C., & Yan, G.-X. (2016). "J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge." Heart Rhythm, 13(10), e295–e324. Choi, B.-R., Ziv, O., & Salama, G. (2023). "Conduction delays across the specialized conduction system of the heart: Revisiting atrioventricular node (AVN) and Purkinje-ventricular junction (PVJ) delays." Frontiers in Cardiovascular Medicine, 10, 1158480 Markiewicz-Łoskot, G., Kolarczyk, E., Mazurek, B., Łoskot, M., & Szydłowski, L. (2020). "Prolongation of electrocardiographic T wave parameters recorded during the head-up tilt table test as independent markers of syncope severity in children." International Journal of Environmental Research and Public Health, 17(18), 6605. Schwartz, P. J., Ackerman, M. J., Antzelevitch, C., Bezzina, C. R., Borggrefe, M., Cuneo, B. F., & Wilde, A. A. M. (2020). "Inherited cardiac arrhythmias." Nature Reviews Disease Primers, 6(1), 58. Di Diego, J. M., Patocskai, B., Barajas-Martinez, H., Borbáth, V., Ackerman, M. J., Burashnikov, A., & Antzelevitch, C. (2020). "Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes." PLOS ONE, 15(11), e0242747. AOPWiki 2024-11-20T11:10:49

2024-11-26T12:31:25

Occurrence, cardiac arrhythmia

Organ

UBERON:0000948

UBERON heart

AOPWiki 2016-11-29T18:41:29

2017-09-16T10:17:22

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AOPWiki 2024-11-22T09:45:26

2024-11-22T09:45:26

<upstream-id>49cdc8f9-dddc-436a-9ee9-c5b6dc43ed0d</upstream-id> <downstream-id>da11ae69-0162-4ec2-85f7-db4f4e401e6b</downstream-id>

AOPWiki 2024-11-22T09:45:49

2024-11-22T09:45:49

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AOPWiki 2024-11-22T09:46:14

2024-11-22T09:46:14

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AOPWiki 2024-11-20T11:15:56

2024-11-20T11:15:56

Inhibition of acetylcholinesterase (AChE) leading to arrhythmias

Inhibition of acetylcholinesterase (AChE), arrhythmias

Young Jun Kim

Sun-Woong Kanga, Myeong Hwa Songb  ,Do-Sun Lim b and Kim Young Junc  aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany

2.7

Inhibition of acetylcholinesterase (AChE) can lead to arrhythmias by disrupting parasympathetic regulation of cardiac activity. AChE normally terminates the action of acetylcholine (ACh) at muscarinic M2 receptors in the heart, maintaining a balance in autonomic control. Inhibition of AChE, such as in organophosphate poisoning or carbamate toxicity, results in excessive ACh accumulation, causing prolonged parasympathetic stimulation. This leads to bradyarrhythmias, including sinus bradycardia, atrioventricular (AV) block, and in severe cases, asystole. Excessive vagal stimulation also contributes to electrical instability through early and delayed afterdepolarizations, increasing the risk of polymorphic ventricular tachycardia, such as Torsades de Pointes (TdP), and ventricular fibrillation (VF). Additionally, autonomic imbalance caused by prolonged parasympathetic overdrive may predispose to alternating bradyarrhythmias and tachyarrhythmias. Clinical scenarios such as organophosphate poisoning and the therapeutic use of cholinesterase inhibitors in myasthenia gravis or Alzheimer’s disease illustrate the potential cardiac effects of AChE inhibition. While mild bradycardia is manageable in controlled settings, severe AChE inhibition can cause life-threatening arrhythmias, emphasizing the importance of understanding these mechanisms for effective management of AChE-related cardiac dysfunction. AOP: Inhibition of Acetylcholinesterase (AChE) Leading to Arrhythmias provides a mechanistic framework linking the disruption of acetylcholine (ACh) regulation at synapses to the development of cardiac arrhythmias. AChE is a critical enzyme responsible for breaking down ACh, a neurotransmitter that mediates parasympathetic signaling in the autonomic nervous system. When AChE is inhibited, ACh accumulates excessively at synaptic junctions, particularly within the cardiac parasympathetic system, leading to overstimulation of muscarinic acetylcholine receptors (M2 receptors) in the heart. The overstimulation of M2 receptors triggers potassium efflux through G-protein-coupled inwardly rectifying potassium channels (IK,ACh), resulting in hyperpolarization of cardiac cells. This disrupts the normal electrical activity of the heart by prolonging or destabilizing cardiac action potentials. The altered electrical signaling can cause conduction delays, reentrant circuits, and early afterdepolarizations (EADs), which ultimately manifest as bradyarrhythmias, tachyarrhythmias, or fibrillation.  This AOP has applications in regulatory toxicology, where it can be used to screen for cardiotoxic effects of environmental toxins and pharmaceuticals, and in therapeutic development, where targeting intermediate key events (e.g., using muscarinic receptor antagonists) can help mitigate arrhythmias. It also provides a framework for assessing combined risks from multiple stressors affecting AChE activity or parasympathetic signaling.

<h3>1. Problem Formulation</h3> <h4>Objective</h4> To describe the mechanistic progression from AChE inhibition to arrhythmias. To identify key events (KEs), key event relationships (KERs), and modulating factors influencing this pathway. To enable applications in toxicology, pharmacology, and therapeutic development. <h4>Relevance</h4> AChE inhibitors, such as organophosphates and carbamates, are widely used pesticides and chemical warfare agents, posing risks of cardiac arrhythmias. Therapeutic agents like donepezil for Alzheimer's disease also inhibit AChE and may induce adverse cardiac effects. <h3>2. Identification of Key Events (KEs)</h3> The pathway begins with the Molecular Initiating Event (MIE) of AChE inhibition and progresses through several KEs to the adverse outcome (AO): MIE: Inhibition of AChE Prevents the breakdown of acetylcholine (ACh), leading to its accumulation at synaptic junctions. KE1: Increased ACh Levels Accumulated ACh overstimulates parasympathetic signaling. KE2: Overactivation of Muscarinic Receptors Activation of M2 receptors in the heart disrupts ionic balance and electrical signaling. KE3: Altered Cardiac Action Potential Hyperpolarization and increased potassium efflux through IK,ACh channels impair excitation-contraction coupling. KE4: Prolonged atrioventricular (AV) conduction time Conduction blocks and reentrant circuits emerge, causing electrical instability. AO: Arrhythmias Sustained electrical instability leads to bradyarrhythmias, tachyarrhythmias, or fibrillation. <h3>3. Evidence Collection and Screening</h3> <h4>Data Sources</h4> In Vitro Studies: Cardiac cell models assessing ACh accumulation, muscarinic receptor activation, and ionic currents. In Vivo Studies: Animal models exposed to AChE inhibitors to monitor cardiac electrophysiology and arrhythmic patterns. Clinical Data: Observations of arrhythmias in patients exposed to pesticides or receiving therapeutic AChE inhibitors. Computational Models: Simulations of parasympathetic signaling and cardiac action potential dynamics. <h4>Screening Criteria</h4> Relevance: Data must address the MIE or KEs in the pathway. Quality: Prioritize studies with robust experimental designs and reproducibility. Consistency: Focus on findings that align with the proposed mechanistic progression. <h3>4. Validation and Refinement</h3> Validate the AOP using experimental, computational, and clinical data. Refine KERs and quantitative models based on emerging evidence.

<ul> <li>Organophosphate and carbamate insecticides are prototypical AChE inhibitors. The OP and carbamate pesticides were synthesized specifically to act as inhibitors of AChE, with OPs developed from early nerve agents (e.g., sarin) and carbamate pesticides based on the natural plant alkaloid physostigmine (Ecobichon 2001).</li> <li>A positive and significant correlation between the log of the Eserine IC50 (in vitro) for AChE inhibition and the log Km value for the AChE in the fish and crustacea species has been reported, explaining 92% of the variation in enzyme inhibition (Monserrat and Bianchini, 2001). Similar success was found in relating the rate constants for inhibition of AChE in housefly and the pseudo first-order hydrolysis rate constant for active forms of OPs (Fukuto 1990).</li> </ul> <ul> <li>The open literature includes many studies on vertebrate and invertebrate species that demonstrate a clear dependence of AChE activity on the dose or concentration of the substance with increased concentrations leading to an increase in the inhibition of AChE (e.g., fish ( Karen et al., 2001), birds (Hudson et al., 1984 (see dimethoate and disulfoton), Grue and Shipley 1984; and Al-Zubaidy et al., 2011); cladocera (Barata et al., 2004); nematodes (Rajini et al., 2008); rodents (Roberts et al., 1988; and mollusk (Bianco et al., 2011)).</li> <li>The open literature includes many studies on vertebrate and invertebrate species that demonstrate a clear relationship between increasing AChE inhibition as duration of exposure increases (e.g., amphibians ( Venturino et al., 2001); fish (Rao 2008; Ferrari et al., 2004); insects (Rose and Sparks 1984); birds (Ludke 1985; Grue and Shipley 1984); annelids (Reddy and Rao 2008); cladocera (Barata et al., 2004)).</li> <li>Rao et al. 2008 exposed the estuarine fish Oreochromis mossambicus to a 24 h LC50 concentration of chlorpyrifos and reported that it took 6 hr to reach >40% AChE inhibition and 24 hr to reach 90% AChE inhibition. It took >100 days to recover to normal AChE levels when fish were placed in clean water.</li> <li>A time course study of earthworms (Eisenis foetida) exposed to the 48 hr LC50 of profenofos found a significant relationship (between increases in percent inhibition of AChE and increase in time of exposure from 8-48 hrs (Chakra Reddy and Rao 2008).</li> </ul>

adjacent

High

High adjacent

High

High adjacent

Moderate

High adjacent

Low

High

Moderate Mixed

Moderate

Not Otherwise Specified

High High High Moderate Moderate Moderate

<table cellspacing="0" style="border-collapse:collapse; width:580px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Contents</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:341px">Evaluation</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:41px; vertical-align:middle; white-space:normal; width:239px">Biological Plausibility</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Strong: Mechanisms linking AChE inhibition to arrhythmias are well-established.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:41px; vertical-align:middle; white-space:normal; width:239px">Empirical Evidence</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Robust: Consistent support across experimental and clinical studies.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:41px; vertical-align:middle; white-space:normal; width:239px">Quantitative Understanding</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Moderate: Well-characterized for early events; limited for late-stage effects.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:41px; vertical-align:middle; white-space:normal; width:239px">Modulating Factors</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Identified: Age, genetics, comorbidities, and stress influence outcomes.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:41px; vertical-align:middle; white-space:normal; width:239px">Regulatory Relevance</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">High: Applicable to toxicology, drug safety, and therapeutic development.</td> </tr> </tbody> </table> <table cellspacing="0" style="border-collapse:collapse; width:580px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Domain</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:341px">Description</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Taxonomic Relevance</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Humans, rodents, and dogs are most relevant; pigs and zebrafish are moderately applicable.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Life Stage</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Highly relevant to adults and elderly; moderately applicable to neonates and children.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Sex</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Applicable to both sexes, with potential hormonal modulation of outcomes.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Molecular/Cellular Level</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Focuses on AChE, M2 muscarinic receptors, and cardiac myocytes.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Stressors</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:341px">Includes organophosphates, carbamates, therapeutic AChE inhibitors, and physiological vagal activation.</td> </tr> </tbody> </table>

<table cellspacing="0" style="border-collapse:collapse; width:680px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Key Event</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:162px">Essentiality</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:278px">Evidence</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:left; vertical-align:middle; white-space:normal; width:239px">MIE: AChE Inhibition</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:162px">High</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:left; vertical-align:middle; white-space:normal; width:278px">Directly causes ACh accumulation, initiating downstream effects.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:left; vertical-align:middle; white-space:normal; width:239px">KE1: Overactivation of M2 Receptors</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:162px">High</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:left; vertical-align:middle; white-space:normal; width:278px">Necessary for potassium efflux and action potential disruption.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:left; vertical-align:middle; white-space:normal; width:239px">KE2: Altered Cardiac Action Potential</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:162px">High</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:left; vertical-align:middle; white-space:normal; width:278px">Central to the development of conduction blocks and arrhythmic activity.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:39px; text-align:left; vertical-align:middle; white-space:normal; width:239px">KE3: Prolonged atrioventricular (AV) conduction time</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:162px">Moderate-High</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:left; vertical-align:middle; white-space:normal; width:278px">Directly leads to arrhythmias but can be modulated by other factors.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; text-align:left; vertical-align:middle; white-space:normal; width:239px">AO: Arrhythmias</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:162px">Endpoint</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:left; vertical-align:middle; white-space:normal; width:278px">Result of sustained electrical instability.</td> </tr> </tbody> </table>

<table cellspacing="0" style="border-collapse:collapse; width:655px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Key Event </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:99px">Biological Plausibility</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:317px">Evidence Assessment</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:112px; vertical-align:middle; white-space:normal; width:239px">MIE: AChE Inhibition</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:99px">Strong</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Numerous studies have demonstrated that exposure to AChE inhibitors, such as organophosphates and carbamates, results in dose-dependent increases in ACh levels. Measurement tools such as Ellman’s assay provide reliable quantification of AChE activity.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:112px; vertical-align:middle; white-space:normal; width:239px">KE1: Overactivation of M2 Receptors</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:99px">Strong</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Electrophysiological studies in isolated cardiac myocytes demonstrate M2 receptor-mediated activation of inwardly rectifying potassium channels (IK,ACh). Muscarinic agonists mimic the effects of AChE inhibitors, supporting the role of receptor overactivation.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:112px; vertical-align:middle; white-space:normal; width:239px">KE2: Altered Cardiac Action Potential</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:99px">Strong</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Patch-clamp recordings show alterations in action potential duration and repolarization under conditions of muscarinic receptor overstimulation. Clinical ECG data from organophosphate poisoning cases reveal bradyarrhythmias and conduction delays.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:112px; vertical-align:middle; white-space:normal; width:239px">KE3: Prolonged atrioventricular (AV) conduction time</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:99px">Moderate</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">In vivo studies in animal models exposed to organophosphates demonstrate conduction blocks and reentrant arrhythmias. Human clinical reports support associations between AChE inhibitor exposure and conduction disturbances.</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:112px; vertical-align:middle; white-space:normal; width:239px">AO: Arrhythmias</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:99px">Strong</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Extensive clinical documentation links AChE inhibitor exposure to arrhythmias. Animal studies confirm dose-dependent progression from conduction disturbances to arrhythmias.</td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> Age Genetic Variants Electrolyte Imbalances Chemical Interactions </td> <td> Older individuals are more susceptible to arrhythmias due to reduced cardiac plasticity and slower compensatory responses to parasympathetic overstimulation. Variants in muscarinic receptors or ion channels can affect the sensitivity of key cellular processes, amplifying or reducing responses to AChE inhibitors. Hypokalemia (low potassium) and hypercalcemia (high calcium) exacerbate ionic imbalances caused by AChE inhibition, worsening conduction abnormalities and arrhythmias. Co-administration of β-adrenergic agonists (e.g., isoproterenol) or other parasympathomimetic agents exacerbates the effects of AChE inhibitors. Conversely, muscarinic antagonists (e.g., atropine) can mitigate these effects </td> <td> Inhibition of AChE → Prolonged atrioventricular (AV) conduction time Increased ACh → Overactivation of Muscarinic Receptors Overactivation of Muscarinic Receptors → Altered Action Potential Overactivation of Muscarinic Receptors → Altered Action Potential Overactivation of Muscarinic Receptors → Altered Action Potential </td> </tr> </tbody> </table> </div>

<h3>MIE: Inhibition of AChE</h3> Quantitative Relationship: AChE inhibition is directly proportional to the dose of the stressor (e.g., organophosphates, carbamates). IC50 values for AChE inhibition are well-established for various chemicals, ranging from nanomolar to micromolar concentrations depending on the compound. Measurement: AChE activity can be quantified using Ellman’s assay or biosensor-based techniques. Thresholds: Substantial ACh accumulation occurs when AChE activity is reduced by >50%. Time Course: AChE inhibition is rapid, occurring within minutes to hours following exposure. <h3>KE1: Overactivation of Muscarinic Receptors</h3> Quantitative Relationship: Muscarinic receptor activation depends on the concentration of ACh. EC50 for M2 receptor activation by ACh is approximately 1 µM. Overactivation occurs when ACh levels exceed the physiological range (e.g., >10 µM). Measurement: Muscarinic receptor activity is assessed using radioligand binding assays or electrophysiological recordings of IK,ACh currents. Thresholds: Overactivation of M2 receptors is correlated with prolonged IK,ACh channel opening and increased potassium efflux. Time Course: Receptor activation occurs within seconds to minutes after ACh levels rise. <h3>KE2: Altered Cardiac Action Potential</h3> Quantitative Relationship: The degree of action potential alteration (e.g., prolongation, amplitude reduction) is proportional to M2 receptor activation and potassium efflux through IK,ACh. Dose-response studies demonstrate significant changes in action potential duration at ACh concentrations >10 µM. Measurement: Patch-clamp techniques are used to measure action potential duration (APD) and ionic currents in cardiac myocytes. ECG analysis provides indirect measurements of action potential changes (e.g., QT prolongation). Thresholds: A >20% change in APD is associated with electrical instability. Time Course: Action potential alterations manifest within minutes to hours of AChE inhibition. <h3>KE3: Prolonged atrioventricular (AV) conduction time</h3> Quantitative Relationship: Electrical conduction delays increase with the degree of action potential alteration and ionic imbalance. Conduction blocks are observed at higher ACh concentrations (>50 µM) or prolonged receptor overstimulation. Measurement: ECG analysis detects conduction blocks, PR interval prolongation, and QRS widening. Thresholds: Prolonged PR intervals (>200 ms) and QRS widening (>120 ms) are indicative of conduction delays. Time Course: Conduction disruptions are observed shortly after action potential changes, often within hours. <h3>AO: Arrhythmias</h3> Quantitative Relationship: The likelihood of arrhythmias increases with the severity of conduction disruption and action potential instability. Dose-response studies in animal models link higher AChE inhibitor concentrations with increased incidence of bradyarrhythmias, tachyarrhythmias, or fibrillation. Measurement: Arrhythmias are diagnosed using ECG, measuring irregularities in heart rate, rhythm, and intervals (e.g., bradycardia, tachycardia, QT prolongation). Thresholds: Severe arrhythmias typically occur when ACh levels are >10-fold above physiological levels. Time Course: Arrhythmias can occur within hours of exposure, depending on the dose and stressor. <table cellspacing="0" style="border-collapse:collapse; width:695px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:39px; text-align:center; vertical-align:middle; white-space:normal; width:239px">Key Event or Relationship</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:138px">Quantitative Relationship</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:317px">Measurement Tools</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:58px; vertical-align:middle; white-space:normal; width:239px">MIE: AChE Inhibition</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">Dose-response (IC50 well-characterized)</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Ellman’s assay, LC-MS</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:77px; vertical-align:middle; white-space:normal; width:239px">KE1: Increased ACh Levels</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">Linear relationship with AChE inhibition</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">LC-MS, ELISA</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:77px; vertical-align:middle; white-space:normal; width:239px">KE2: Overactivation of M2 Receptors</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">ACh EC50 (~1 µM) for receptor activation</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Radioligand binding, IK,ACh</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:77px; vertical-align:middle; white-space:normal; width:239px">KE3: Altered Cardiac Action Potential</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">Dose-response for APD changes with ACh >10 µM</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px">Patch-clamp,  Electrocardiogram</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:97px; vertical-align:middle; white-space:normal; width:239px">KE4: Prolonged atrioventricular (AV) conduction time</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">Conduction blocks proportional to APD changes</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px"> Electrocardiogram</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:97px; vertical-align:middle; white-space:normal; width:239px">AO: Arrhythmias</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:138px">Incidence correlates with severity of conduction disruptions</td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:317px"> Electrocardiogram</td> </tr> </tbody> </table>

Potential applications of this AOP include hazard identification, chemical screening, and prioritization of AChE inhibitors, as well as preclinical drug safety evaluations. In regulatory toxicology, it can assess the cardiotoxic risks of pesticides and environmental toxins. For therapeutic development, it supports the design of safer cholinesterase inhibitors and post-exposure treatments targeting intermediate key events. Personalized medicine applications include genetic risk stratification and precision therapies for at-risk populations. This AOP framework advances the understanding of how AChE inhibition leads to arrhythmias, with significant implications for toxicology, pharmacology, and regulatory science. It enables predictive risk assessments, therapeutic innovation, and enhanced regulatory decision-making to mitigate the cardiotoxic effects of AChE inhibition.

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