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

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

CHEBI:15355

CHEBI acetylcholine

PCO:0000001

PCO population of organisms

GO:0003990

GO acetylcholinesterase activity

MP:0001393

MP ataxia

MP:0001399

MP hyperactivity

MP:0000753

MP paralysis

D009026

MESH mortality

PCO:0000008

PCO population growth rate

WIKI decreased

WIKI increased

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

7955

NCBI zebra fish

WikiUser_22

all species

1211424

NCBI Metapenaeus monoceros

63990

NCBI Philosamia ricini

58519

NCBI Rana cyanophlyetis

8127

NCBI Tilapia mossambica

10116

NCBI rat

10090

NCBI mouse

WCS_7955

common ecological species zebrafish

WCS_93934

common ecological species Japanese quail

WCS_90988

common ecological species fathead minnow

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

Acetylcholine accumulation in synapses

ACh Synaptic Accumulation

Cellular

<ul> <li dir="ltr"> Acetylcholine is a neurotransmitter that is stored in nerve endings at cholinergic synapses in the central and peripheral nervous systems (Soreq and Seidman, 2001; Lushington 2006). </li> <li dir="ltr"> Acetylcholine can bind multiple types of nicotinic and muscarinic receptors. The downstream consequences of those events are tissue and receptor-specific. </li> <li dir="ltr"> Acetylcholine is released into the synaptic cleft when stimulation of the nerve occurs, and then binds to a receptor protein; either muscarinic (metabotropic) or nicotinic (ionotropic). The binding to the receptor results in changes in the flow of ions across the cell, thereby signaling activity (Fukuto 1990; Mileson et al 1998; Soreq and Seidman 2001; Lushington 2006).   <ul> <li dir="ltr"> Inhibition of acetylcholine binding at the serine site via AChE inhibition results in an accumulation of acetylcholine in synapses associated with muscarinic and nicotinic receptors, resulting in unregulated excitation at neuromuscular junctions of skeletal muscle; pre-ganglionic neurotransmitters and post-ganglionic nerve endings of the autonomic nervous system; and neurotransmitters in the brain or central nervous system (CNS).  </li> </ul> </li> </ul>

<ul> <li dir="ltr"> Several techniques are available to measure acetylcholine levels, including the Hestrin method (Augustinsson 1957, Hestrin 1949, Stone 1955), molecular probes or assays, microdialysis techniques (Zapata, 2009, Russom, 2014) or by liquid chromatography - tandem mass spectrometer LC-MS/MS (Gómez-Canela et al., 2017). </li> <li dir="ltr"> Hestrin’s method involves a colorimetric measurement of esterase activity. The rate of hydrolysis of acetylcholine with hydroxylamine to form hydroxamic acid is measured to determine the amount of acetylcholine: </li> </ul> RCOOR’ + H2NOH -> RCONHOH + R’OH This method is performed at alkaline pH in water and is applicable over a wide range of ester concentrations (Hestrin 1949). <ul> <li>Hydrolysis of acetylcholine by acetylcholinesterase in the synaptic cleft is fast, so concentration in the extracellular fluid is low (0.1-6 nM). Brain microdialysate studies quantify nanomolar concentrations of acetylcholine in extracellular fluid using chromatographic mass spectrometric techniques (Nirogi 2009). Choice of analytical method should provide detection limits below the lowest concentration expected in the dialysate and requiring the smallest sample volume. High-pressure liquid chromatography coupled to electrochemical detection (HPLC-EC) is based on enzymatic conversion of acetylcholine into choline and acetate by acetylcholinesterase, and subsequent oxidation of choline by choline oxidase to betaine and hydrogen peroxide, which can be oxidized on a platinum electrode. This method permits detection of dialysate acetylcholine concentrations in the 5-10 nM range (Zapata, 2009). Other microdialysis techniques for quantification of acetylcholine are liquid chromatography mass spectrometry (Nirogi 2009) and pyrolysis-gas chromatography (Szilagyi 1968).</li> </ul>

<ul> <li dir="ltr"> Acetylcholine and cholinergic receptors are found in invertebrate and vertebrate species. Specific examples from the literature documenting acetylcholine accumulation include:  Penaeid prawn exposed to sublethal exposure of methylparathion and malathion showed significantly increased ACh levels, in nervous tissue (Reddy 1990). </li> <li dir="ltr"> Brain tissue of tadpoles exposed to single sublethal concentrations methyl parathion for 24 h showed an increase in acetylcholine levels (Nayeemunnisa and Yasmeen 1986).   </li> </ul> <ul> <li dir="ltr"> Acute (48h) sublethal exposure to methyl parathion resulted in increased AChE levels in brain tissue in fish (Oreochromis mossambicus) (Rao and Rao, 1984). Researchers found a significant increase in acetylcholine at all time points measured (12-48hr) with acetylcholine levels increasing from 33-83% as compared to controls over the same time span.  </li> </ul> <ul> <li dir="ltr"> A study of male quail (Coturnix japonica) exposed to lethal concentrations of two OP pesticides (i.e., DDVP or fenitrothion), found significant increases in total and free acetylcholine (Kobayashi et al., 1983). </li> <li dir="ltr"> Mice singly injected with propoxur displayed changes in cholinergic parameters in the brain: increased brain ACh content, decreased AChE activity, and high-affinity choline uptake into synaptosomes (Kobayashi 1988).  </li> <li dir="ltr"> AChE levels and acetylcholine synthesis in rat striatum were compared in controls and animals exposed to 0.3 and 1 times the maximum tolerated dose. Acetylcholine was present in significantly less concentrations than in the adult rats (Karanth, 2003). </li> </ul>

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High

<ul> <li dir="ltr"> Augustinsson, K.B. 1957. In: Glick,D.(Ed.); Methods of Biochemical Analysis, Interscience Publishers, Inc., New York, NY. </li> <li>Gómez-Canela, C., D. Tornero-Cañadas, E. Prats, B. Piña, R. Tauler and D. Raldúa (2018), "Comprehensive characterization of neurochemicals in three zebrafish chemical models of human acute organophosphorus poisoning using liquid chromatography-tandem mass spectrometry”, Analytical and Bioanalytical Chemistry 410(6): 1735-1748. DOI: 10.1007/s00216-017-0827-3.</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"> Hestrin, S. (1949). The Reaction of Acetylcholine and Other Carboxylic Acid Derivatives with Hydroxylamine, and its Analytical Application. J. Biol. Chem. 180(1): 249-61. </li> <li dir="ltr"> Karanth, S., Pope, C. 2003. Age-related effects of chlorpyrifos and parathion on acetylcholine synthesis in rat striatum. Neurotoixol. Teratol. 25(5): 599-606.   </li> </ul> <ul> <li dir="ltr"> 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. </li> <li dir="ltr"> Kobayashi, H., Yuyama, A., Ohkawa, T., and Kajita, T. 1988. Effect of Single or Chronic Injection with a Carbamate, Propoxur, on the Brain Cholinergic System and Behavior of Mice. Jpn.J.Pharmacol. 47[1], 21-27. </li> <li dir="ltr"> Lushington GH, Guo J-X, Hurley MM.  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"> Molecular Probes. (2004). Amplex Red Acetylcholine/Acetylcholinesterase Assay Kit (A12217). Retrieved from: <a href="http://tools.thermofisher.com/content/sfs/manuals/mp12217.pdf">http://tools.thermofisher.com/content/sfs/manuals/mp12217.pdf</a> </li> <li dir="ltr"> Nayeemunnisa, Yasmeen N. 1986. On the presence of calmodulin in the brain of control and methyl parathion‐exposed developing tadpoles of frog, Rana cyanophlictis. Curr Sci (Bangalore) 55:546–548. </li> <li dir="ltr"> Nirogi, R., Mudigonda, K., Kandikere, V. Ponnamaneni, R. (2010). Quantification of Acetylcholine, an Essential Neurotransmitter, in Brain Microdialysis Samples by Liquid Chromatography Mass Spectrometry. Biomed Chromatogr. 24(1), 39-48.  </li> <li dir="ltr"> Rao KSP, Rao KVR. 1984. Impact of methyl parathion toxicity and eserine inhibition on acetylcholinesterase activity in tissues of the teleost (Tilapia mossambica)—A correlative study. Toxicol Lett 22:351–356. </li> <li dir="ltr"> Reddy MS, Jayaprada P, Rao KVR. 1990. Impact of methyl parathion and malathion on cholinergic and non‐cholinergic enzyme systems of penaeid prawn, Metapenaeus monoceros. Biochem Int 22:769–780. </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"> Szilagyi, P.I.A., Schmidt, D.E., Green, J.P. (1968). Microanalytical determination of acetylcholine, other choline esters, and choline by pyrolysis-gas chromatography. Analytical Chemistry. 40(13), 2009-2013.  </li> <li dir="ltr"> Zapata, A., V.I. Chefer, T.S. Shippenberg, and L. Denoroy. 2009. Detection and quantification of neurotransmitters in dialysates. Curr. Protoc. Neurosci. Chapter 7:Unit 7.4.1-30. </li> </ul> AOPWiki 2016-11-29T18:41:22

2020-06-26T13:06:32

Increased Cholinergic Signaling

Organ

<h3 dir="ltr">Overview</h3> <ul> <li dir="ltr"> Cholinergic signalling refers to the activation of receptors bound with acetylcholine. Receptors for acetylcholine are collectively referred to as either acetylcholine or cholinergic receptors. They break down into 2 different classes, muscarinic and nicotinic. Each receptor type is associated with specific downstream effects. The lists below are manifestations of associated with each receptor class. <ul> <li dir="ltr"> Muscarinic: increased salivation, lacrimation, perspiration, miosis, blurred vision, abdominal cramps, vomiting, diarrhea, increased bronchial secretion, bronchoconstriction, urinary frequency, bradycardia, hypotension (Costa) </li> <li dir="ltr"> Nicotinic: tachycardia, transient hypertension, muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis (Costa) </li> </ul> </li> </ul>   <h3 dir="ltr">Signal Transduction</h3> <ul> <li dir="ltr"> The signal transmission mechanisms of both nicotinic and muscarinic cholinergic receptors has been intensively studied. <ul> <li dir="ltr"> The nicotinic acetylcholine receptor (nAchR) is associated with triggering excitatory responses in motor neurons and skeletal muscle cells (Lodish, 2000). Overstimulation of the diaphragm via nicotinic receptors can lead to respiratory arrest (De Candole, 1953). <ul> <li dir="ltr"> The nAchR has been extensively studied in neuromuscular junctions. It is a ligand-gated cation channel that allows passage of both potassium and sodium ions. Opening of nAchR ligand-gated ion channels produces a net depolarization at the muscle cell membrane, which leads to release of intracellular calcium, which triggers muscle contraction (Lodish, 2000). In this manner, acetylcholine accumulation can lead to paralysis via overstimulation of nicotinic receptors.   </li> </ul> </li> <li dir="ltr"> Muscarinic receptors can transmit inhibitory signals. They are expressed on pre- and postsynaptic neurons, and on non-neuronal tissues throughout the body (Lodish, 2000). </li> <li dir="ltr"> Muscarinic receptors in the peripheral nervous system are activated by parasympathetic nerves present in airway smooth muscle, submucosal glands, and blood vessels where they trigger bronchoconstriction, mucus secretion, and vasodilatation, respectively (Coulson, 2003).  <ul> <li dir="ltr"> All muscarinic receptors are G-protein coupled receptors, but the specific features depends on the subtype. </li> </ul> </li> </ul> </li> </ul> <h3 dir="ltr">Neuromodulator Role</h3> <ul> <li dir="ltr"> In addition to breaking down acetylcholine’s effects in terms of the receptor types, researchers have started to look at acetylcholine’s effects in terms of acting as a neurotransmitter and as a neuromodulator. Classical neurotransmitters act on a time scale of one millisecond to tens of milliseconds. Some researchers have proposed that acetylcholine also acts as a neuromodulator that influences synaptic transmission, plasticity and coordinated firing of groups of neurons over time scales that are much longer than the millisecond time frames associated with neurotransmitters (Picciotto, 2012, Luchicchi, 2014). </li> </ul>

<ul> <li dir="ltr"> In humans <ul> <li dir="ltr"> Pupils - human patients experiencing cholinergic poisoning constricted or pinpointed pupils are frequently reported in clinical cohort studies covering organophosphate exposure (Wadia, 1974, Peter, 2014).  </li> </ul> </li> <li dir="ltr"> In embryonic fish and frogs <ul> <li> Spontaneous movements in developing fish and frog embryos are defined as flexing or side-to-side motion of the trunk or tail and free-swimming activity, defined as bilateral rhythmic flexing of the tail. Embryos were observed under a dissection microscope and the number of movements per minute was recorded. Spontaneous motion is measured at 1 day post fertilization (dpf) in zebrafish embryos and at 2 dpf in Xenopus (Watson, 2014). </li> <li dir="ltr"> Embryonic swimming activity in fish and frogs was measured at 5 dpf by placing larvae-containing dishes above an 8-wedged pie chart grid and counting the number of times a larvae crossed a grid line during a 1-min interval (Watson, 2014). </li> </ul> </li> </ul>

UBERON:0001016

UBERON nervous system

<ul> <li dir="ltr"> Costa.  Toxic effects of pesticides.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106. </li> <li dir="ltr"> 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. </li> <li dir="ltr"> 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. </li> <li dir="ltr"> 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. </li> <li dir="ltr"> Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7. </li> <li dir="ltr"> Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45.<a href="https://doi.org/10.1002/etc.2559"> https://doi.org/10.1002/etc.2559</a>. </li> <li dir="ltr"> Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45.<a href="https://doi.org/10.4103/0972-5229.144017"> https://doi.org/10.4103/0972-5229.144017</a>. </li> <li dir="ltr"> Lodish, Harvey, Arnold Berk, S. Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell. 2000. “Neurotransmitters, Synapses, and Impulse Transmission.” Molecular Cell Biology. 4th Edition.<a href="https://www.ncbi.nlm.nih.gov/books/NBK21521/"> https://www.ncbi.nlm.nih.gov/books/NBK21521/</a>. </li> <li dir="ltr"> Coulson FR, Fryer AD. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12667888">Muscarinic acetylcholine receptors and airway diseases. </a>Pharmacol Ther. 2003 Apr;98(1):59-69. </li> </ul> AOPWiki 2016-11-29T18:41:22

2019-12-20T17:32:12

Impaired coordination and movement

Individual

AOPWiki 2019-12-20T15:59:38

2019-12-20T15:59:38

Increased Mortality

Population

Increased mortality refers to an increase in the number of individuals dying in an experimental replicate group or in a population over a specific period of time.

Mortality of animals is generally observed as cessation of the heart beat, breathing (gill or lung movement) and locomotory movements. Mortality is typically measured by observation. Depending on the size of the organism, instruments such as microscopes may be used. The reported metric is mostly the mortality rate: the number of deaths in a given area or period, or from a particular cause. Depending on the species and the study setup, mortality can be measured: <ul> <li>in the lab by recording mortality during exposure experiments</li> <li>in dedicated setups simulating a realistic situation such as mesocosms or drainable ponds for aquatic species</li> <li>in the field, for example by determining age structure after one capture, or by capture-mark-recapture efforts. The latter is a method commonly used in ecology to estimate an animal population's size where it is impractical to count every individual.</li> </ul>

All living things are susceptible to mortality.

Moderate Unspecific

High

All life stages

High

AOPWiki 2016-11-29T18:41:24

2022-07-08T07:32:26

Decrease, Population growth rate

Population

A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008).  As the population is the biological level of organization that is often the focus of ecological risk assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices. If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because  r is an instantaneous rate, its units can be changed via division.  For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).  Equation 1:  r = b - d This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate). Examining r in the context of population growth rate: ● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0).              ● The smaller the value of r below 1, the faster the population will decrease to zero.   ● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)            ● The larger the value that r exceeds 1, the faster the population can increase over time       ● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced).  For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).      Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate.   ● Example of direct effect on r:  Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004).              Alternatively, a stressor could indirectly impact survival and/or reproduction.   ● Example of indirect effect on r:  Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022) Density dependence can be an important consideration: ● The effect of density dependence depends upon the quantity of resources present within a landscape.  A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction.   ● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species.  In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species).        Closed versus open systems: ● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration.   ● When individuals depart (emigrate out of a population) the loss will diminish population growth rate.   Population growth rate applies to all organisms, both sexes, and all life stages.

Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1).  The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, Nt=0 (population size at time t=0), and the population size at the end of the interval, Nt=1 (population size at time t = 1), and then subsequently dividing by the initial population size.  Equation 2:  r = (Nt=1 - Nt=0) / Nt=0 The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021).   ● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval.   ● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1).    Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011).   Some examples of modeling constructs used to investigate population growth rate: ● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate.  Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (Pimephales promelas) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate.   ● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model.  Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate.   ● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007). ● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011).  Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. ● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021).  AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).

Consideration of population size and changes in population size over time is potentially relevant to all living organisms.

Not Specified Unspecific

Not Specified

All life stages

High

<ul> <li>Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</li> <li>Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</li> <li>Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</li> <li>Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R.  2016.  Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</li> <li>Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51:  4661-4672.</li> <li>Etterson MA, Ankley GT.  2021.  Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55:  15596-15608. </li> <li>Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</li> <li>Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155:  407–415.</li> <li>Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT.  2011.  Adverse outcome pathways and risk assessment: Bridging to population level effects.  Environ. Toxicol. Chem. 30, 64-76.</li> <li>McComb B, Zuckerberg B, Vesely D, Jordan C.  2021.  Monitoring Animal Populations and their Habitats: A Practitioner's Guide.  Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </li> <li>Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022.  A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</li> <li>Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7):  1623-1633.</li> <li>Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:  521–527.</li> <li>Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</li> <li>Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH.  2018.  Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment.  Integrated Environmental Assessment and Management 14(5):  615–624.</li> <li>Murray DL, Sandercock BK (editors).  2020.  Population ecology in practice.  Wiley-Blackwell, Oxford UK, 448 pp.</li> <li>Nisbet RM, Jusup M, Klanjscek T, Pecquerie L.  2011.  Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models.  The Journal of Experimental Biology 215: 892-902.</li> <li>Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69:  913–926.</li> <li>Perkins EJ,  Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S.  2019.  Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment.  Environmental Toxicology and Chemistry 38(9): 1850–1865. </li> <li>Vandermeer JH, Goldberg DE. 2003.  Population ecology: first principles.  Princeton University Press, Princeton NJ, 304 pp.</li> <li>Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320</li> <li>Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ.  2016.  Predicting fecundity of fathead minnows (Pimephales promelas) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11:  e0146594.</li> </ul> AOPWiki 2016-11-29T18:41:24

2023-01-03T09:09:06

<upstream-id>d770a9e6-6f2b-479d-a987-daeda69f6678</upstream-id> <downstream-id>c3ce6cbe-ed8d-47b9-bf1d-f55bc79c5377</downstream-id> <ul> <li dir="ltr"> AChE is an enzyme responsible for controlling the level of acetylcholine available at cholinergic synapses by degrading this neurotransmitter via hydrolysis to acetic acid and choline (Wilson 2010). Inhibition of AChE prevents degradation of acetylcholine which leads to accumulation of acetylcholine in synapses associated with muscarinic and nicotinic receptors (Soreq and Seidman, 2001; Lushington 2006). </li> <li>See <a href="https://www.genome.jp/dbget-bin/www_bget?rn:R01026">KEGG Reaction R01026</a></li> </ul>

<ul> <li>Acetylcholine is a critical neurotransmitter localized to neuronal synapses. Biological plausibility to support the relationship between AChE inhibition and accumulation of acetylcholine is rooted in evidence demonstrating that AChE catalyzes degradation of acetylcholine into choline and acetate. Therefore, inhibition of the AChE leads to acetylcholine accumulation.</li> </ul>

<ul> <li>In a study where female ICR mice were exposed to either the fenobucarb or propoxur, authors reported a significant increase in acetylcholine in brain tissue 10 minutes after injection, with a concurrent significant increase in AChE inhibition (Kobayashi et al., 1985).</li> <li>An acute (48h) sublethal exposure to methyl parathion found that AChE levels in brain tissue in fish (Oreochromis mossambicus) were significantly inhibited at all measured durations ranging from 12-48 hrs with inhibition increasing from 36-62% as compared to controls over the time span (Rao and Rao, 1984). The researchers found a significant increase in acetylcholine at all time courses measured (12-48hr) with acetylcholine levels increasing from 33-83% as compared to controls over the same time span (Rao and Rao, 1984).</li> <li>A study of quail (Coturnix japonica) exposed to lethal concentrations of two OP pesticides (i.e., DDVP or fenitrothion), found significant increases in total and free acetylcholine, and significant inhibition of AChE as compared to controls (Kobayashi et al., 1983).</li> <li>Measurements (in vitro) of AChE inhibition, acetylcholine and electrophysiological responses on the pedal ganglion of the gastropod Aplysia californica, were found to be dose-dependent, with increase in dose resulting in increased AChE inhibition, increased levels of acetylcholine, and a decrease in the electrophysiological response (Oyama et al., 1989).</li> <li>Wister rats injected with a sublethal concentration of dichlorvos found a significant decrease in AChE activity, increased acetylcholine concentrations, and enhanced contractile responses in jejunum muscle (Kobayashi et al., 1994).</li> <li>At sublethal concentrations ( 56% of the LD50), researchers found a statistically significant (18%) increase in the amount of acetylcholine in brain tissue of Charles River rats exposed to disulfoton for 3 days, with measured AChE inhibition of 68% as compared to controls (Stavinoha et al., 1969).</li> <li>An acute sublethal exposure of chlorpyrifos to Sprague-Dawley rats found significant dose and time related effects including increased inhibition of AChE, increased levels of acetylcholine, and significant impacts to motor activity (nocturnal rearing response) (Karanth et al., 2006).</li> <li>Tadpoles (20 d) were exposed to single sublethal concentration of the methyl parathion for 24 h.  Analysis of brain tissue found a significant inhibition in AChE activity and a concurrent increase in acetylcholine levels, as compared to controls (Nayeemunnisa and Yasmeen 1986). </li> <li>Study of fourth instar Ailanthus silkworm exposed to malathion for 5 days found increased mortality, decreased AChE, and increases in acetylcholine as compared to controls (Pant and Katiyar 1983).</li> <li>Faria et al (2015) exposed zebrafish (Danio rerio) larvae to different concentrations of chlorpyrifos oxon (CPO). A strong inhibitory effect on AChE activity was found as early as 1h after exposure with a 50% inhibitory concentration (IC50) of 64 nm CPO. The authors showed that the zebrafish model mimicked most of the effects seen in humans, including AChE inhibition, calcium dysregulation, ad inflammatory and immune responses.</li> </ul>

<ul> <li>No known qualitative inconsistencies or uncertainties associated with this relationship.</li> </ul>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> </thead> <tbody> <tr> <td>enzyme</td> <td>butylcholinesterase</td> <td>Butylcholinesterase can affect the substrate interaction and should be accounted for</td> <td>Wilson (2001)</td> </tr> </tbody> </table> </div>

The general kinetic equation is:  <img alt="" src="https://aopwiki.org/system/dragonfly/production/2019/12/19/73wb1lsj9l_AchE_equation.png" style="height:48px; width:470px" /> <ul> <li dir="ltr"> Where AX is the substrate, either acetylcholine or an inhibitor of AChE (e.g., OP or carbamate);  </li> <li dir="ltr"> AChE-AX is the enzyme-substrate complex;  </li> <li dir="ltr"> AChE-A is the acylated, carbamylated or phosphorylated enzyme;  </li> <li dir="ltr"> X is the leaving group (e.g., choline);  </li> <li dir="ltr"> AChE is the free enzyme; and  </li> <li dir="ltr"> A is acetic acid, phosphate (P(=O)(=O)(R2)or methylamine.  </li> <li dir="ltr"> In a normally functioning enzyme system k1 is the rate-limiting step for hydrolysis of acetylcholine, but k3 is the rate limiting step when AChE is inhibited by carbamates or OPs (Wilson 2010). </li> <li dir="ltr"> Some rate constants for OPs and carbamates have been published for use in PBPK models (Knaak et al., 2004, 2008) </li> </ul> Table 1: Summary of available quantitative data describing responses of ACh to AChE inhibition. Data are grouped by species. <table cellspacing="0" class="Table" style="border-collapse:collapse; width:114%"> <thead> <tr> <td rowspan="1" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:20px; width:16%"> AChE Inhibitor </td> <td rowspan="1" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:20px; width:13%"> CAS RN </td> <td rowspan="1" style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:1px solid black; height:20px; width:12%"> Inhibitor Dosage </td> <td rowspan="1" style="border-bottom:none; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:20px; width:16%"> Species / Model </td> <td rowspan="1" style="border-bottom:none; border-left:none; border-right:1px solid black; border-top:1px solid black; height:20px; width:26%"> Brief Summary </td> <td rowspan="1" style="border-bottom:none; border-left:none; border-right:1px solid black; border-top:1px solid black; height:20px; width:11%"> Reference </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; width:2%">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:15px; width:0px"> </td> </tr> </thead> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:16%"> Donezepil </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:13%"> 120014-06-4 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:50px; width:12%"> 0.625, 1.25, 2.5 (mg/kg) </td> <td rowspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:50px; width:16%"> Male Wistar rats (210-290 g | 7 weeks) </td> <td rowspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:50px; width:26%"> Timecourse data on both extracellular hippocampal ACh concentration and AChE activity given varying concentrations of inhibitor. Brain concentrations of drugs over time are also provided. </td> <td rowspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:50px; width:11%"> Kosasa et al., 1999 </td> <td style="height:50px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:38px; width:0px"> </td> </tr> <tr> <td style="border-bottom:none; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:16%"> Tacrine </td> <td style="border-bottom:none; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:13%"> 321-64-2 </td> <td style="border-bottom:none; border-left:1px solid black; border-right:1px solid black; border-top:none; height:50px; width:12%"> 1.25, 2.5, 5, 10 (mg/kg) </td> <td style="height:50px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:38px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; height:50px; width:16%"> ENA-713 (Rivastigmine) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:1px solid black; height:50px; width:13%"> 129101-54-8 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:50px; width:12%"> 0.625, 1.25, 2.5 (mg/kg) </td> <td style="height:50px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:38px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:60px; width:16%"> Dichlorvos (DDVP) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%"> 62-73-7 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%"> 5 (mg/kg) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:16%"> Male Wistar rats (180-230 g) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:26%"> AChE activity (μmol AthCh hydrolyzed/g tissue) and ACh content (nmol ACh/g tissue) in jejunum either 10 minutes after single injection or 1 day after 10 injections. </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:11%"> Kobayashi et al., 1994 </td> <td style="height:60px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:45px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:60px; width:16%"> Propoxur </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%"> 114-26-1 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%"> 10 (mg/kg) </td> <td style="height:60px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:45px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:83px; width:16%"> Paraquat (PQ) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:83px; width:13%"> 1910-42-5 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:83px; width:12%"> 0.1, 1, 10, 20, 30 (μM) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:83px; width:16%"> Wistar rats (fetal days 17-18) Primary hippocampal neurons </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:83px; width:26%"> In Vitro AChE activity (% control) and ACh concentration (pmol / mL) at 24h and 14 days post exposure </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:83px; width:11%"> Del Pino et al., 2017 </td> <td style="height:83px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:62px; width:0px"> </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:102px; width:16%"> Tacrine </td> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:102px; width:13%"> 321-64-2 </td> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:102px; width:12%"> 1.25, 2.5, 5 (mg/kg) </td> <td style="background-color:white; border-bottom:none; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:16%"> Male Wistar rats (210-290 g | 6 weeks) </td> <td style="background-color:white; border-bottom:none; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:26%"> Timecourse data on both extracellular hippocampal ACh concentration and AChE activity given varying concentrations of inhibitor. Note: Several sections of text are verbatim from Kosasa et al., 1999. </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:11%"> Kim 2003 </td> <td style="height:102px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:77px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:101px; width:16%"> Parathion (PS) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:101px; width:13%"> 56-38-2 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:101px; width:12%"> adult: 1.8, 3.4, 6, 9, 18, 27 (mg/kg) aged: 1.8, 3.4, 6, 9 (mg/kg) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:101px; width:16%"> Male Sprague-Dawley rats (adult: 3 months) (aged: 18 months) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:101px; width:26%"> Diaphragm and striatum AChE activity (% control). Striatal dialysates of ACh (fmol/60 μL fraction) on day 3 and 7 post-exposure </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:101px; width:11%"> Karanth et al., 2007 </td> <td style="height:101px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:76px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:121px; width:16%"> Chlorpyrifos (CPF) </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:121px; width:13%">  2921-88-2 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:121px; width:12%"> 84, 156, 279 (mg/kg) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:121px; width:16%"> Male Sprague-Dawley rats (325-350 g | 3 months) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:121px; width:26%"> Diaphragm and striatum cholinesterase activity (% control). ACh concentration (fmol/60 μL fraction) through In Vivo microdialysis at 1, 4, and 7 days post-exposure </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:121px; width:11%"> Karanth et al., 2006 </td> <td style="height:121px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:91px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:102px; width:16%"> Paraoxon </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:102px; width:13%"> 311-45-5 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:102px; width:12%"> 0.03, 0.1, 1, 10 (μM) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:16%"> Male Sprague-Dawley rats (275-299 g | 2-3 months) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:26%"> Timecourse data on changes in striatal AChE activity (% control) and ACh concentration (fmole/fraction (60  μL)) over 4 hours post exposure. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:11%"> Ray et al., 2009 </td> <td style="height:102px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:77px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:150px; width:16%"> Propoxur </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:150px; width:13%"> 114-26-1 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:150px; width:12%"> 10 (mg/kg) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:150px; width:16%"> Female ICR mice (30-40 g | 8-10 weeks) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:150px; width:26%"> AChE activity (μmol acetylthiocholine hydrolyzed /min/g wet tissue) and ACh content (nmol/g wet tissue) both measured at 0, 10, 60, 180 minutes after injection (and 360 minutes for AChE activity) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:150px; width:11%"> Kobayashi et al., 1988 </td> <td style="height:150px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:113px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:60px; width:16%"> BPMC </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%"> 3766‑81‑2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%"> 10 (mg/kg) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:16%"> Female ICR mice (30-40 g | 8-10 weeks) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:26%"> Timecourse data on AChE activity (μmole acetylthiocholine hydrolyzed / min / g tissue or ml blood) and ACh content (nmol/g tissue) of forebrain homogenate, taken at 0, 10 and 60 minutes. </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:11%"> Kobayashi et al., 1985 </td> <td style="height:60px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:45px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:60px; width:16%"> Propoxur </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%"> 114-26-1 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%"> 2 (mg/kg) </td> <td style="height:60px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:45px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:103px; width:16%"> DE-71 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:103px; width:13%"> 32534-81-9 </td> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:103px; width:12%"> 31.0, 68.7, 227.6 (μg/L) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:103px; width:16%"> Zebrafish larvae </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:103px; vertical-align:bottom; width:26%"> Changes in AChE activity (nmol / min / mg protein) and ACh concentration (nmol / mg protein) measured at 120 hours post-fertilization  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:103px; width:11%"> Chen  et al., 2012 </td> <td style="height:103px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:77px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:61px; width:16%"> Dichlorvos (DDVP) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:13%"> 62-73-7 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:12%"> 3 (mg/kg) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:16%"> Male Japanese quail (100 g | 8-14 weeks) </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:26%"> AChE activity (μmol ACh hydrolyzed/g) and ACh content (nmol ACh/g wet tissue) measured 10 and 60 minutes post exposure for DDVP and Fenitrothion, respectively. </td> <td rowspan="2" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:11%"> Kobayashi et al., 1983 </td> <td style="height:61px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:46px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:61px; width:16%"> Fenitrothion </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:13%"> 122-14-5 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:12%"> 300 (mg/kg) </td> <td style="height:61px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:46px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:122px; width:16%"> Methyl Parathion </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:13%"> 298-00-0 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:12%"> 0.09 (ppm) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:16%"> Tilapia mossambica </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:26%"> Timecourse data on AChE activity (μmol ACh hydrolysed/mg protein/h) and ACh content (μmole/g wt. tissue) in muscle, gill, liver, and brain tissue at 12, 24, 36, and 48 hr timepoints </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:11%"> Rao and Rao, 1984 </td> <td style="height:122px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:92px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:100px; width:16%"> Methyl Parathion </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:13%"> 298-00-0 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:12%"> 2.5 (ppm) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:16%"> Rana cyanophilicitus Frog tadpole (1.5-2 g | 20 days) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:26%"> AChE activity (μmol ACh hydrolyzed /min) and ACh content (μmol/g) measured after 24 hours post exposure </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:11%"> Yasmeen and Yasmeen, 1986 </td> <td style="height:100px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:75px; width:0px"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:75px; width:16%"> Malathion </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:13%"> 121-75-5 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:12%"> 60 µg each/g insect weight/day </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:16%"> Philosamia Ricini larvae </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:26%"> AChE activity and ACh concentration changes measured daily for 5 days. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:11%"> Pant and Katiyar, 1983 </td> <td style="height:75px; width:2%"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:56px; width:0px"> </td> </tr> </tbody> </table>

Striatal AChE activity and extracellular ACh levels were measured in rats intracerebrally perfused with paraoxon (0, 0.03, 0.1, 1, 10 or 100 μM, 1.5 μl/min for 45 min). Acetylcholine was below the limit of detection at the low dose of paraoxon (0.1 uM), but was  transiently elevated (0.5–1.5 hr) with 10 μM paraoxon. Concentration-dependent AchE inhibition was noted but reached a plateau of about 70% at 1 μM and higher concentrations (Ray, 2009).

The relationship between AChE inhibition and ACh accumulation at the synapse can be observed within 30 minutes after application of an AChE inhibitor (Ray, 2009).  Other experiments have shown significant differences in ACh after AChE inhibition as soon as an hour after application of a chemical stressor (Kim et al., 2003, Faria et al., 2015).

High Unspecific

Not Specified

All life stages

High High Moderate High High High Moderate Moderate

<big>Cholinergic transmissions mediated by acetylcholinesterase occur in a wide variety of species, both vertebrates and invertebrates, and cholinergic transmissions occur at all stages in life.</big> Taxonomic Applicability <ul> <li dir="ltr"> The literature includes many studies linking increases in acetylcholine in brain tissues after exposure to an OP or carbamate pesticide with increased AChE inhibition in various taxa. Examples include studies with crustacea (Reddy et al., 1990); tadpoles (Nayeemunnisa and Yasmeen, 1986); fish (Rao and Rao 1984; Verma et al., 1981); birds (Kobayashi et al., 1983); and rodents (Kobayashi et al., 1988). </li> </ul>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ab4c2b0> AOPWiki 2016-11-29T18:41:33

2023-07-11T20:54:34

<upstream-id>d770a9e6-6f2b-479d-a987-daeda69f6678</upstream-id> <downstream-id>0a1f6edb-85ff-4a7d-8ea2-24415ae800a4</downstream-id> 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): <ul> <li dir="ltr"> Salivation </li> <li dir="ltr"> Lacrimation (tears) </li> <li dir="ltr"> Urination </li> <li dir="ltr"> Defecations </li> <li dir="ltr"> Gastric Cramps </li> <li dir="ltr"> Emesis (vomiting) </li> </ul> Other signs of cholinergic poisoning are mediated by nicotinic cholinergic signalling. These include (Costa): <ul> <li dir="ltr"> Tachycardia,  </li> <li dir="ltr"> Transient hypertension </li> <li dir="ltr"> Muscle fasciculations </li> <li dir="ltr"> Twitching </li> <li dir="ltr"> Flaccid paralysis </li> </ul> 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.

<ul> <li dir="ltr"> 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). </li> </ul>

<ul> <li dir="ltr"> A study of 200 cases of suicidal ingestion of organophosphorus insecticides in India (1971-1973) documented the incidence of numerous neurological symptoms associated with cholinergic signalling. Miosis (constricted pupils) was nearly universal amongst the patients observed. The table below lists the “Neurological Findings Associated with Organophosphorus Insecticide Poisoning” (Wadia, 1974). </li> </ul> <table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>Neurological signs</td> <td>Patients (number)</td> <td>Incidence (%)</td> </tr> <tr> <td>Miosis</td> <td>190</td> <td>95</td> </tr> <tr> <td>Impaired consciousness</td> <td>20</td> <td>10</td> </tr> <tr> <td>Fasciculations</td> <td>54</td> <td>27</td> </tr> <tr> <td>Convulsions</td> <td>2</td> <td>1</td> </tr> <tr> <td>Paralytic signs</td> <td>52</td> <td>26</td> </tr> </tbody> </table>   <ul> <li dir="ltr"> Pigs exposed to the AChE inhibitor, dichlorvos showed signs of cholinergic overstimulation, which included miosis, cyanosis, tremor, excess secretions and fasciculations. Measurement of AChE levels confirmed that dichlorvos treatment inhibited AChE activity. (Cui, 2013). </li> <li dir="ltr"> Mice exposed to AChE inhibitor, propoxur, showed overt signs of cholinergic signalling at the highest dose tested (5 mg/kg) -  depression, tremor and salivation (Kobayashi, 1985) </li> <li dir="ltr"> In Japanese Quail, increased cholinergic signaling in the form of salivation and convulsions was seen in response to 2 different AchE inhibitors, dichlorvos and fenitrothion. (Kobayashi, 1983) </li> <li dir="ltr"> Sparrows exposed to lethal doses of the AChE inhibitor, fenthion, showed the following symptoms indicative of increased cholinergic signalling: body tremors, weakness, ataxia, loss of balance, partial paralysis (in the wings), full paralysis (of the legs), and salivation (Hunt, 1991)  </li> <li dir="ltr"> Spontaneous movement in zebrafish embryos is regulated by cholinergic nicotinic receptors and is associated with developing primary and secondary motor neurons. These spontaneous movements were enhanced by treatment with dichlorvos, diazinon, and chlorpyrifos (Watson, 2014) </li> </ul>

<ul> <li dir="ltr"> 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) </li> </ul>

<ul> <li dir="ltr"> Signs of cholinergic toxicity/poisoning can show up within minutes of exposure in humans and mammals. </li> <li dir="ltr"> In humans signs of increased cholinergic signalling… </li> <li dir="ltr"> Pigs exposed to the AChE inhibitor, dichlorvos showed signs of cholinergic overstimulation within 5 minutes of treatment. AChE levels measured within 30 minutes of dichlorvos treatment showed significant inhibition, which continued to decrease over the course of the experiment (6 hours)(Cui, 2013). </li> <li dir="ltr"> Dichlorvos treatment (3-4 mg/kg) led to nervous system disruption within 7-15 minutes, whereas the response to fenitrothion treatment took longer. Quail treated with 250-350 mg/kg fenitrothion showed cholinergic signs 6-120 minutes post-treatment (Kobayashi, 1983) </li> <li dir="ltr"> A comparison of 5 organophosphate and 2 carbamate pesticides in rats showed dose-response data for a number of cholinergic signs (Moser 1995).  The overall clinical picture of toxicity was similar but differences emerged in terms of specific signs, dose-response, and time-course. </li> <li dir="ltr"> Mice treated with propoxur demonstrated the following signs of increased cholinergic signalling within the timeframes noted in response to each tested dose. </li> </ul> <table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>AChE Inhibitor</td> <td>Dose</td> <td>Time (post injection)</td> <td>Cholinergic symptoms</td> </tr> <tr> <td>Propoxur</td> <td>2 mg/kg</td> <td>60 minutes</td> <td>no apparent toxic signs</td> </tr> <tr> <td>o-sec-butylphenyl methylcarbamate (BPMC)</td> <td>10 mg/kg</td> <td>60 minutes</td> <td>no apparent toxic signs</td> </tr> <tr> <td>o-sec-butylphenyl methylcarbamate (BPMC)</td> <td>50 mg/kg</td> <td>15-40 minutes</td> <td>depression</td> </tr> <tr> <td>Propoxur</td> <td>5 mg/kg</td> <td>5-30 minutes</td> <td>depression, tremor and salivation</td> </tr> </tbody> </table> Mice treated with sublethal doses of BPMC (10 mg/kg) and propoxur (2 mg/kg) had increased acetylcholine and decreased acetylcholinesterase activity in the forebrain at 10 min post-treatment (Kobayashi, 1985).

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).

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ab6c830> AOPWiki 2016-11-29T18:41:34

2019-12-20T11:07:22

<upstream-id>c3ce6cbe-ed8d-47b9-bf1d-f55bc79c5377</upstream-id> <downstream-id>0a1f6edb-85ff-4a7d-8ea2-24415ae800a4</downstream-id> 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.   <ul> <li dir="ltr"> 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). </li> </ul>

<ul> <li>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. </li> </ul>

<ul> <li dir="ltr"> 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. </li> <li dir="ltr"> 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). </li> <li dir="ltr"> 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). </li> <li dir="ltr"> 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).   </li> <li dir="ltr"> 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).  </li> </ul>

<ul> <li dir="ltr"> No known qualitative inconsistencies or uncertainties associated with this relationship. </li> </ul>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ab84c28> AOPWiki 2016-11-29T18:41:34

2019-12-20T09:16:35

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430aba2930> AOPWiki 2019-12-20T16:11:27

2019-12-20T16:11:27

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430abb5fa8> AOPWiki 2019-12-20T16:05:15

2019-12-20T16:05:15

<upstream-id>b011e054-8d90-4e74-8e74-82d0d448981a</upstream-id> <downstream-id>fec536d1-d067-4390-8310-eb5c577ed409</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430abe4ad8> AOPWiki 2019-12-20T16:18:31

2019-12-20T16:18:31

<upstream-id>b011e054-8d90-4e74-8e74-82d0d448981a</upstream-id> <downstream-id>27756eaa-8752-45d5-9993-2768543baf10</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ac0f8f0> AOPWiki 2019-12-20T16:06:58

2019-12-20T16:06:58

<upstream-id>27756eaa-8752-45d5-9993-2768543baf10</upstream-id> <downstream-id>fec536d1-d067-4390-8310-eb5c577ed409</downstream-id> Increased mortality in the reproductive population may lead to a declining population. This depends on the excess mortality due to the applied stressor and the environmental parameters such as food availability and predation rate. Most fish species are r-strategist, meaning they produce a lot of offspring instead of investing in parental care. This results in natural high larval mortality causing only a small percentage of the larvae to survive to maturity. If the excess larval mortality due to a stressor is small, the population dynamics might result in constant population size. Should the larval excess be more significant, or last on the long-term, this will affect the population. To calculate the long-term persistence of the population, population dynamic models should be used.

Survival rate is an obvious determinant of population size and is therefore included in population modeling (e.g., Miller et al., 2020).

<ul> <li>Survival to reproductive maturity is a parameter of demographic significance. Assuming resource availability (i.e., food, habitat, etc.) is not limiting to the extant population, sufficient mortality in the reproductive population may ultimately lead to declining population trajectories.</li> <li>Under some conditions, reduced larval survival may be compensated by reduced predation and increased food availability, and therefore not result in population decline (Stige et al., 2019).</li> </ul>

<ul> <li>According to empirical data, combined with population dynamic models, feeding larvae are the crucial life stage in zebrafish (and other r-strategists) for the regulation of the population. (Schäfers et al., 1993)</li> <li>In fathead minnow, natural survival of early life stages has been found to be highly variable and influential on population growth (Miller and Ankley, 2004)</li> <li>Rearick et al. (2018) used data from behavioural assays linked to survival trials and applied a modelling approach to quantify changes in antipredator escape performance of larval fathead minnows in order to predict changes in population abundance. This work was done in the context of exposure to an environmental oestrogen. Exposed fish had delayed response times and slower escape speeds, and were more susceptible to predation. Population modelling showed that this can result in population decline.</li> <li>In the context of fishing and fisheries, ample evidence of a link between increased mortality and a decrease of population size has been given. Important insights can result from the investigation of optimum modes of fishing that allow for maintaining a population (Alekseeva and Rudenko, 2018). Jacobsen and Essington (2018) showed the impact of varying predation mortality on forage fish populations.</li> <li>Boreman (1997) reviewed methods for comparing the population-level effects of mortality in fish populations induced by pollution or fishing.</li> </ul>

<ul> <li>The extent to which larval mortality affects population size could depend on the fraction of surplus mortality compared to a natural situation.</li> <li>There are scenarios in which individual mortality may not lead to declining population size. These include instances where populations are limited by the availability of habitat and food resources, which can be replenished through immigration. Effects of mortality in the larvae can be compensated by reduced competition for resources (Stige et al., 2019).</li> <li>The direct impact of pesticides on migration behavior can be difficult to track in the field, and documentation of mortality during migration is likely underestimated (Eng 2017).</li> </ul>

<ul> <li>Assuming other relevant demographic parameters are available, the effect of increased mortality rates on population status can be quantitatively predicted using standard population modeling approaches.</li> <li>Stage population matrix models (Caswell, 2000) simulate population growth rates based on age-specific parameters and can be adapted to a range of species (Pinceel et al., 2016). For zebrafish, individually based models (IBM) have been developed to link responses at the individual level to the population level (Beaudouin et al., 2015). However, authors agree that survival is one of the most uncertain parameters in the model and more research on the topic is needed.</li> </ul>

Moderate Unspecific

High

All life stages

High High

Taxonomic: All organisms must survive to reproductive age in order to reproduce and sustain populations. The additional considerations related to survival made above are applicable to other fish species in addition to zebrafish and fathead minnows with the same reproductive strategy (r-strategist as described in the theory of MaxArthur and Wilson (1967). The impact of reduced survival on population size is even greater for k-strategists that invest more energy in a lower number of offspring. Life stage: Density dependent effects start to play a role in the larval stage of fish when free-feeding starts (Hazlerigg et al., 2014). Sex: This linkage is independent of sex.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ac55ee0> AOPWiki 2019-12-20T16:07:12

2022-07-08T08:29:35

Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement

AChE inhibition - acute mortality via predation

Allie Always

CHRISTINE L. RUSSOM (1), DANIEL L. VILLENEUVE* (2), VIRGINIA HENCH (3), CATAIA IVES (3), VIRGINIA C. MOSER (1), CARLIE A. LALONE (2), STEPHEN EDWARDS (3), KRISTIE SULLIVAN (4), and GERALD T. ANKLEY (2) (1) U.S. Environmental Protection Agency (Retired) (2) National Health and Environmental Effects Research Laboratory, Office of Research and Development, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA (3) Research Computing Division, RTI International, Research Triangle Park, North Carolina, USA (4) Physicians Committee for Responsible Medicine, Washington, DC, USA <ul> <li>Corresponding author for wiki entry (Villeneuve.dan@epa.gov)</li> </ul>

BY-SA

2.0

<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>

Increased mortality is one of the most common regulatory assessment endpoints, along with reduced growth and reduced reproduction.

Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.

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AOPWiki 2019-12-20T15:55:10

2023-09-25T16:27:01