56-38-2LCCNCVORNKJIRZ-UHFFFAOYSA-NLCCNCVORNKJIRZ-UHFFFAOYSA-N
ParathionDiethyl 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
DTXSID702110096-64-0GRXKLBBBQUKJJZ-UHFFFAOYNA-NGRXKLBBBQUKJJZ-UHFFFAOYSA-N
SomanSoman
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
DTXSID2031906311-45-5WYMSBXTXOHUIGT-UHFFFAOYSA-NWYMSBXTXOHUIGT-UHFFFAOYSA-N
ParaoxonDiethyl-p-nitrophenyl phosphate
Phosphoric acid, diethyl 4-nitrophenyl ester
4-Nitrophenyl diethyl phosphate
Chinorto
DIAETHYL-(P-NITROPHENYL)-PHOSPHAT
diethyl 4-nitrophenyl phosphate
Diethyl p-nitrophenyl phosphate
Diethyl-4-nitrophenylphosphat
Ethyl paraoxon
Fosfakol
fosfato de dietilo y 4-nitrofenilo
Mintacol
Miotisal
Miotisal A
NSC 404110
O-(4-Nitrophenyl) O,O-diethyl phosphate
O,O-Diethyl O-p-nitrophenyl phosphate
Oxyparathion
Paraoxan
Paraoxon-ethyl
Phosphachole
Phosphacol
Phosphakol
phosphate de diethyle et de 4-nitrophenyle
Phosphoric acid, diethyl p-nitrophenyl ester
p-Nitrophenyl diethyl phosphate
DTXSID6024046298-00-0RLBIQVVOMOPOHC-UHFFFAOYSA-NRLBIQVVOMOPOHC-UHFFFAOYSA-N
Methyl parathionParathion-methyl
Phosphorothioic acid, O,O-dimethylO-(4-nitrophenyl) ester
Azophos
Bravik 600CE
Demethylfenitrothion
Dimethyl 4-nitrophenyl phosphorothioate
Dimethyl parathion
Dimethyl p-nitrophenyl phosphorothionate
Dimethyl p-nitrophenyl thiophosphate
Folidol 600
Folidol M
Folidol M 40
Folidol M 50
Mentox 600CE
Metacid
Metacide
Metaphos
Methyl 1605
Methyl Bladan
Methyl E 605
Methylthiophos
Metil paration
Morphos
M-Parathion
O,O-Dimethyl O-(4-nitrophenyl) phosphorothioate
O,O-Dimethyl O-(4-nitrophenyl) thiophosphate
O,O-Dimethyl O-(p-nitrophenyl) phosphorothioate
O,O-Dimethyl O-(p-nitrophenyl) thiophosphate
O,O-Dimethyl O-p-nitrophenyl phosphorothioate
Oleovofotox
Parataf
Parathion M
Parathion methyl homolog
PARATHION, METHYL
paration-metil
Paratuf
Penncap M
Penncap MLS
Phosphorothioic acid, O,O-dimethyl O-(4-nitrophenyl) ester
Phosphorothioic acid, O,O-dimethyl O-(p-nitrophenyl) ester
Probel MP 2
Quinophos
Sinafid M 48
Thiophenit
Vofatox
Wofatox
DTXSID102085560-56-0PMRYVIKBURPHAH-UHFFFAOYSA-NPMRYVIKBURPHAH-UHFFFAOYSA-N
Methimazole2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-
1,3-Dihydro-1-methyl-2H-imidazole-2-thione
1-Methyl-1,3-dihydroimidazole-2-thione
1-Methyl-1H-imidazole-2-thiol
1-Methyl-2-mercapto-1H-imidazole
1-Methyl-2-mercaptoimidazole
1-Methyl-4-imidazoline-2-thione
1-Methylimidazole-2(3H)-thione
1-Methylimidazole-2-thiol
1-Methylimidazole-2-thione
2-Mercapto-1-methyl-1H-imidazole
2-Mercapto-1-methylimidazole
2-Mercapto-N-methylimidazole
4-Imidazoline-2-thione, 1-methyl-
Basolan
Danantizol
Favistan
Frentirox
Imidazole-2-thiol, 1-methyl-
Mercaptazole
Mercazole
Mercazolyl
Metazolo
Methimazol
Methylmercaptoimidazole
Metothyrin
Metothyrine
Metotirin
N-Methyl-2-mercaptoimidazole
N-Methylimidazolethiol
NSC 38608
Strumazol
Tapazole
Thacapzol
Thiamazol
thiamazole
Thycapzol
Thymidazol
Thymidazole
tiamazol
DTXSID402082051-52-5KNAHARQHSZJURB-UHFFFAOYSA-NKNAHARQHSZJURB-UHFFFAOYSA-N
6-Propyl-2-thiouracil6-Propyl-2 thiouracil (PTU)
4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-
2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
2-Mercapto-4-hydroxy-6-n-propylpyrimidine
2-Mercapto-4-hydroxy-6-propylpyrimidine
2-Mercapto-6-propylpyrimidin-4-ol
2-Thio-4-oxo-6-propyl-1,3-pyrimidine
2-Thio-6-propyl-1,3-pyrimidin-4-one
6-n-Propyl-2-thiouracil
6-n-Propylthiouracil
6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione
6-Propylthiouracil
NSC 6498
NSC 70461
Procasil
Propacil
propiltiouracilo
Propycil
Propyl-Thiorist
Propylthiorit
propylthiouracil
Propylthiouracile
Propyl-Thyracil
Prothiucil
Prothiurone
Prothycil
Prothyran
Protiural
Thiuragyl
Thyreostat II
URACIL, 4-PROPYL-2-THIO-
Uracil, 6-propyl-2-thio-
DTXSID5021209PR:000003626acetylcholinesteraseCHEBI:15355acetylcholineGO:0003990acetylcholinesterase activityMP:0001393ataxiaMP:0001399hyperactivityMP:0000753paralysisGO:0099536synaptic signalingGO:0007611learning or memoryGO:0050890cognition2decreased1increasedOrganophosphates<p>Organophosphate
</p><p>repeated exposure
</p>2016-11-29T18:42:202016-11-29T21:20:01Paraoxon2021-06-24T18:47:462021-06-24T18:47:46Methyl parathion2021-06-24T18:49:512021-06-24T18:49:51Ethyl Parathion2021-06-24T18:52:022021-06-24T18:52:02N-methyl Carbamates2016-11-29T18:42:262019-10-07T14:19:19Methimazole2016-11-29T18:42:192016-11-29T18:42:19Propylthiouracil2016-11-29T18:42:222016-11-29T18:42:22Iodine deficiency2017-03-26T11:37:442017-03-26T11:37:447955zebra fishWCS_9606humans10116rat10095mice9685catWCS_9606human10090mouse9606Homo sapiens10116Rattus norvegicus10090Mus musculus1211424Metapenaeus monoceros63990Philosamia ricini58519Rana cyanophlyetis8127Tilapia mossambicaWCS_7955zebrafishWCS_93934Japanese quailWCS_7227Drosophila melanogasterAcetylcholinesterase (AchE) InhibitionAchE InhibitionCellular<p>"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]</p>
<p>Molecular target gene symbol: ACHE</p>
<p>KEGG enzyme: EC 3.1.1.7</p>
<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>
<p dir="ltr">AChE is present in all life stages of both vertebrate and invertebrate species (Lu et al 2012).</p>
<ul>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
<ul>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
<p dir="ltr">Studies have found that AChE activity increases as the organism develops.</p>
<ul>
<li dir="ltr">
<p 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). </p>
</li>
<li dir="ltr">
<p 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. </p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.)</p>
</li>
<li dir="ltr">
<p 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). </p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
UBERON:0001016nervous systemCL:0000255eukaryotic cellHighUnspecificHighAll life stages<ul>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Fukuto, TR. 1990. Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect. 87:245-254.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Johnson CD, Russell RL. 1975. A rapid, simple radiometric assay for cholinesterase suitable for multiple determinations. Anal Biochem 64:229-238.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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>.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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>.</p>
</li>
<li dir="ltr">
<p 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</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Soreq H, Seidman S. 2001. Acetylcholinesterase -- New roles for an old actor. Nature Reviews Neurosci 2:294-302.</p>
</li>
<li dir="ltr">
<p dir="ltr">Stenersen, J. 2004. Specific enzyme inhibitors. In: Chemical Pesticides: Mode of action and toxicology. (41 p). CRC Press, Boca Raton, FL.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Tretyn A, Kendrick RE. 1991. Acetylcholine in plants: Metabolism and mechanism of action. Bot Rev 57:33-73.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Wilson BW. 2010. Cholinesterases. Hayes’ Handbook of Pesticide Toxicology, 3rd ed, Vol 2. Elsevier, Amsterdam, The Netherlands, pp 1457-1478.</p>
</li>
</ul>
2016-11-29T18:41:222020-04-29T17:21:36Acetylcholine accumulation in synapsesACh Synaptic AccumulationCellular<ul>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p dir="ltr">Acetylcholine can bind multiple types of nicotinic and muscarinic receptors. The downstream consequences of those events are tissue and receptor-specific.</p>
</li>
<li dir="ltr">
<p 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). </p>
<ul>
<li dir="ltr">
<p 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). </p>
</li>
</ul>
</li>
</ul>
<ul>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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:</p>
</li>
</ul>
<p dir="ltr" style="text-align:center">RCOOR’ + H2NOH -> RCONHOH + R’OH</p>
<p dir="ltr">This method is performed at alkaline pH in water and is applicable over a wide range of ester concentrations (Hestrin 1949).</p>
<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">
<p 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).</p>
</li>
<li dir="ltr">
<p 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). </p>
</li>
</ul>
<ul>
<li dir="ltr">
<p 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. </p>
</li>
</ul>
<ul>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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). </p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
CL:0000255eukaryotic cellHighUnspecificHighAll life stagesHigh<ul>
<li dir="ltr">
<p dir="ltr">Augustinsson, K.B. 1957. In: Glick,D.(Ed.); Methods of Biochemical Analysis, Interscience Publishers, Inc., New York, NY.</p>
</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”, <em>Analytical and Bioanalytical Chemistry</em> <strong>410</strong>(6): 1735-1748. DOI: 10.1007/s00216-017-0827-3.</li>
<li dir="ltr">
<p dir="ltr">Fukuto TR. 1990. Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect 87:245-254. </p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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. </p>
</li>
</ul>
<ul>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Lushington GH, Guo J-X, Hurley MM. 2006. Acetylcholinesterase: Molecular modeling with the whole toolkit. Curr Topics Medic Chem 6:57-73.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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></p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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. </p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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. </p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
</ul>
2016-11-29T18:41:222020-06-26T13:06:32Increased Cholinergic SignalingIncreased Cholinergic SignalingOrgan<h3 dir="ltr"><em>Overview</em></h3>
<ul>
<li dir="ltr">
<p 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.</p>
<ul>
<li dir="ltr">
<p dir="ltr">Muscarinic: increased salivation, lacrimation, perspiration, miosis, blurred vision, abdominal cramps, vomiting, diarrhea, increased bronchial secretion, bronchoconstriction, urinary frequency, bradycardia, hypotension (Costa)</p>
</li>
<li dir="ltr">
<p dir="ltr">Nicotinic: tachycardia, transient hypertension, muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis (Costa)</p>
</li>
</ul>
</li>
</ul>
<p> </p>
<h3 dir="ltr"><em>Signal Transduction</em></h3>
<ul>
<li dir="ltr">
<p dir="ltr">The signal transmission mechanisms of both nicotinic and muscarinic cholinergic receptors has been intensively studied.</p>
<ul>
<li dir="ltr">
<p 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).</p>
<ul>
<li dir="ltr">
<p 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. </p>
</li>
</ul>
</li>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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). </p>
<ul>
<li dir="ltr">
<p dir="ltr">All muscarinic receptors are G-protein coupled receptors, but the specific features depends on the subtype.</p>
</li>
</ul>
</li>
</ul>
</li>
</ul>
<h3 dir="ltr"><em>Neuromodulator Role</em></h3>
<ul>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr"><em>In humans</em></p>
<ul>
<li dir="ltr">
<p 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). </p>
</li>
</ul>
</li>
<li dir="ltr">
<p dir="ltr"><em>In embryonic fish and frogs</em></p>
<ul>
<li>
<p>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).</p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
</li>
</ul>
UBERON:0001016nervous system<ul>
<li dir="ltr">
<p dir="ltr">Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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>.</p>
</li>
<li dir="ltr">
<p 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>.</p>
</li>
<li dir="ltr">
<p 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>.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
</ul>
2016-11-29T18:41:222019-12-20T17:32:12Decrease of neuronal network functionNeuronal network function, DecreasedOrgan<p><strong>Biological state:</strong> There are striking differences in neuronal network formation and function among the developing and mature brain. The developing brain shows a slow maturation and a transient passage from spontaneous, long-duration action potentials to synaptically-triggered, short-duration action potentials.</p>
<p>Furthermore, at this precise developmental stage the neuronal network is characterised by "hyperexcitability”, which is related to the increased number of local circuit recurrent excitatory synapses and the lack of γ-amino-butyric acid A (GABAA)-mediated inhibitory function that appears much later. This “hyperexcitability” disappears with maturation when pairing of the pre- and postsynaptic partners occurs and synapses are formed generating population of postsynaptic potentials and population of spikes followed by developmental GABA switch. Glutamatergic neurotransmission is dominant at early stages of development and NMDA receptor-mediated synaptic currents are far more times longer than those in maturation, allowing more calcium to enter the neurons. The processes that are involved in increased calcium influx and the subsequent intracellular events seem to play a critical role in establishment of wiring of neural circuits and strengthening of synaptic connections during development (reviewed in Erecinska et al., 2004). Neurons that do not receive glutaminergic stimulation are undergoing developmental apoptosis.</p>
<p>During the neonatal period, the brain is subject to profound alterations in neuronal circuitry due to high levels of synaptogenesis and gliogenesis. For example, in neuroendocrine regions such as the preoptic area-anterior hypothalamus (POA-AH), the site of gonadotropin-releasing hormone (GnRH) system is developmentally regulated by glutamatergic neurons. The changes in the expression of the N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B system begin early in postnatal development, before the onset of puberty, thereby playing a role in establishing the appropriate environment for the subsequent maturation of GnRH neurons (Adams et al., 1999).</p>
<p><strong>Biological compartments:</strong> Neural network formation and function happen in all brain regions but it appears to onset at different time points of development (reviewed in Erecinska et al., 2004). Glutamatergic neurotransmission in hippocampus is poorly developed at birth. Initially, NMDA receptors play important role but the vast majority of these premature glutamatergic synapses are “silent” possibly due to delayed development of hippocampal AMPA receptors. In contrast, in the cerebral cortex the maturation of excitatory glutamatergic neurotransmission happens much earlier. The “silent” synapses disappear by PND 7-8 in both brain regions mentioned above.</p>
<p>There is strong evidence suggesting that NMDA receptor subunit composition controls synaptogenesis and synapse stabilization (Gambrill and Barria, 2011). It is established fact that during early postnatal development in the rat hippocampus, synaptogenesis occurs in parallel with a developmental switch in the subunit composition of NMDA receptors from NR2B to NR2A. It is suggested that early expression of NR2A in organotypic hippocampal slices reduces the number of synapses and the volume and dynamics of spines. In contrast, overexpression of NR2B does not affect the normal number and growth of synapses. However, it does increase spine motility, adding and retracting spines at a higher rate. The C terminus of NR2B, and specifically its ability to bind CaMKII, is sufficient to allow proper synapse formation and maturation. Conversely, the C terminus of NR2A was sufficient to stop the development of synapse number and spine growth. These results indicate that the ratio of synaptic NR2B over NR2A controls spine motility and synaptogenesis, and suggest a structural role for the intracellular C terminus of NR2 in recruiting the signalling and scaffolding molecules necessary for proper synaptogenesis. Interestingly, it was found that genetic deletion of NR3A accelerates glutamatergic synaptic transmission, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1. Consistent, the deletion of NR3A accelerates the expression of the glutamate receptor subunits NR1, NR2A, and GluR1 sugesting that glutamatergic synapse maturation is critically dependent upon activation of NMDA-type glutamate receptors (Henson et al., 2012).</p>
<p><strong>General role in biology:</strong> The development of neuronal networks can be distinguished into two phases: an early ‘establishment’ phase of neuronal connections, where activity-dependent and independent mechanisms could operate, and a later ‘maintenance’ phase, which appears to be controlled by neuronal activity (Yuste and Sur, 1999). These neuronal networks facilitate information flow that is necessary to produce complex behaviors, including learning and memory (Mayford et al., 2012).</p>
<p><em>Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? </em></p>
<p><strong>In vivo:</strong> The recording of brain activity by using electroencephalography (EEG), electrocorticography (ECoG) and local field potentials (LFP) assists towards the collection of signals generated by multiple neuronal cell networks. Advances in computer technology have allowed quantification of the EEG and expansion of quantitative EEG (qEEG) analysis providing a sensitive tool for time-course studies of different compounds acting on neuronal networks' function (Binienda et al., 2011). The number of excitatory or inhibitory synapses can be functionally studied at an electrophysiological level by examining the contribution of glutamatergic and GABAergic synaptic inputs. The number of them can be determined by variably clamping the membrane potential and recording excitatory and inhibitory postsynaptic currents (EPSCs or IPSCs) (Liu, 2004).</p>
<p><strong>In vitro:</strong> Microelectrode array (MEA) recordings are also used to measure electrical activity in cultured neurons (Keefer et al., 2001, Gramowski et al., 2000; Gopal, 2003; Johnstone et al., 2010). MEAs can be applied in high throughput platforms to facilitate screening of numerous chemical compounds (McConnell et al., 2012). Using selective agonists and antagonists of different classes of receptors their response can be evaluated in a quantitative manner (Novellino et al., 2011; Hogberg et al., 2011).</p>
<p>Patch clamping technique can also be used to measure neuronal network activity.In some cases, if required, planar patch clamping technique can also be used to measure neuronal networks activity (e.g., Bosca et al., 2014).</p>
<p>In vitro studies in brain slices applying electrophysiological techniques showed significant variability among species (immature rats, rabbits and kittens) related to synaptic latency, duration, amplitude and efficacy in spike initiation (reviewed in Erecinska et al., 2004).</p>
UBERON:0000955brainHighMixedHighDuring brain developmentHighHighHighHigh<p>Adams MM, Flagg RA, Gore AC., Perinatal changes in hypothalamic N-methyl-D-aspartate receptors and their relationship to gonadotropin-releasing hormone neurons. Endocrinology. 1999 May;140(5):2288-96.</p>
<p>Binienda ZK, Beaudoin MA, Thorn BT, Ali SF. (2011) Analysis of electrical brain waves in neurotoxicology: γ-hydroxybutyrate. Curr Neuropharmacol. 9: 236-239.</p>
<p>Bosca, A., M. Martina, and C. Py (2014) Planar patch clamp for neuronal networks--considerations and future perspectives. Methods Mol Biol, 2014. 1183: p. 93-113.</p>
<p>Erecinska M, Cherian S, Silver IA. (2004) Energy metabolism in mammalian brain during development. Prog Neurobiol. 73: 397-445.</p>
<p>Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A. 2011:108(14):5855-60.</p>
<p>Gopal K. (2003) Neurotoxic effects of mercury on auditory cortex networks growing on microelectrode arrays: a preliminary analysis. Neurotoxicol Teratol. 25: 69-76.</p>
<p>Gramowski A, Schiffmann D, Gross GW. (2000) Quantification of acute neurotoxic effects of trimethyltin using neuronal networks cultures on microelectrode arrays. Neurotoxicology 21: 331-342.</p>
<p>Henson MA, Larsen RS, Lawson SN, Pérez-Otaño I, Nakanishi N, Lipton SA, Philpot BD. (2012) Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One. 7(8).</p>
<p>Hogberg HT, Sobanski T, Novellino A, Whelan M, Weiss DG, Bal-Price AK. (2011) Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32: 158-168.</p>
<p>Johnstone AFM, Gross GW, Weiss D, Schroeder O, Shafer TJ. (2010) Use of microelectrode arrays for neurotoxicity testing in the 21st century Neurotoxicology 31: 331-350.</p>
<p>Keefer E, Norton S, Boyle N, Talesa V, Gross G. (2001) Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays. Neurotoxicology 22: 3-12.</p>
<p>Liu G. (2004) Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites. Nat Neurosci. 7: 373-379.</p>
<p>Mayford M, Siegelbaum SA, Kandel ER. (2012) Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751.</p>
<p>McConnell ER, McClain MA, Ross J, LeFew WR, Shafer TJ. (2012) Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology 33: 1048-1057.</p>
<p>Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. (2011) Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng. 4: 4.</p>
<p>Yuste R, Peinado A, Katz LC. (1992) Neuronal domains in developing neocortex. Science 257: 665-669.</p>
2016-11-29T18:41:242018-05-28T11:36:00Cognitive Function, Decreased Cognitive Function, Decreased Individual<p>Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition of, or retrieval of, a learned event, the hippocampal-based memory systems have received the most study. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990; Squire, 2004).</p>
<p>In humans, the hippocampus is involved in recollection of an event’s rich spatial-temporal contexts and distinguished from simple semantic memory which is memory of a list of facts (Burgess et al., 2000). Hemispheric specialization has occurred in humans, with the left hippocampus specializing in verbal and narrative memories (i.e., context-dependent episodic or autobiographical memory) and the right hippocampus, more prominently engaged in visuo-spatial memory (i.e., memory for locations within an environment). The hippocampus is particularly critical for the formation of episodic memory, and autobiographical memory tasks have been developed to specifically probe these functions (Eichenbaun, 2000; Willoughby et al., 2014). In rodents, there is obviously no verbal component in hippocampal memory, but reliance on the hippocampus for spatial, temporal and contextual memory function has been well documented. Spatial memory deficits and fear-based context learning paradigms engage the hippocampus, amygdala, and prefrontal cortex (Eichenbaum, 2000; Shors et al., 2001; Samuels et al., 2011; Vorhees and Williams, 2014; D’Hooge and DeDeyn, 2001; Lynch, 2004; O’Keefe and Nadal, 1978). These tasks are impaired in animals with hippocampal dysfunction (O’Keefe and Nadal, 1978; Morris and Frey, 1987; Gilbert et al., 2016).</p>
<p>In rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, and most commonly, the Morris water maze (MWM). Test of novelty such as novel object recognition, and fear based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. A brief description of these tasks follows.</p>
<p style="margin-left:.5in">1) RAM, Barnes, MWM are examples of spatial tasks in which animals are required to learn: the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze); or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014).</p>
<p style="margin-left:.5in">2) Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention (i.e., I have seen one of these objects before, but not this one. Cohen and Stackman, 2015).</p>
<p style="margin-left:.5in">3) Contextual Fear conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009).</p>
<p style="margin-left:.5in">4) Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2004).</p>
<p>Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD 426) both require testing of learning and memory (USEPA, 1998; OECD, 2007). These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009).</p>
<p>A variety of standardized learning and memory tests have been developed for human neuropsychological testing. These include episodic autobiographical memory, word pair recognition memory; object location recognition memory. Some components of these tests have been incorporated in general tests of adult intelligence (IQ) such as the WAIS and the Wechsler. Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include:</p>
<p style="margin-left:.5in">1) Rey Osterieth Complex Figure (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006).</p>
<p style="margin-left:.5in">2) Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1995; Talley, 1986). </p>
<p style="margin-left:.5in">3) Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994).</p>
<p style="margin-left:.5in">4) Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986).</p>
<p style="margin-left:.5in">5) Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2015).</p>
<p style="margin-left:.5in">6) Staged Autobiographical Memory Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buy lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014).</p>
<p>Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans.</p>
HighMaleHighFemaleHighDuring brain developmentHighHighHigh<p>Alexander RD (1990) Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development. Ethology and Sociobiology 11:241-303.</p>
<p>Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 120:501-507.</p>
<p>Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080.</p>
<p>Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176.</p>
<p>Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents. In: Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009</p>
<p>D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60-90.</p>
<p>Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41-50.</p>
<p>Fivush R. The development of autobiographical memory. Annu Rev Psychol. 2011. 62:559-82.</p>
<p>Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.</p>
<p>Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.</p>
<p>Herold, C, Lässer, MM, Schmid, LA, Seidl, U, Kong, L, Fellhauer, I, Thomann, PA, Essig, M and Schröder, J. (2015). Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia. Front. Psychiatry, 6: 53.</p>
<p>Lezak MD (1984) Neuropsychological assessment in behavioral toxicology--developing techniques and interpretative issues. Scand J Work Environ Health 10 Suppl 1:25-29.</p>
<p>Lezak MD (1994) Domains of behavior from a neuropsychological perspective: the whole story. Nebr Symp Motiv 41:23-55.</p>
<p>Lynch, M.A. (2004). Long-Term Potentiation and Memory. Physiological Reviews. 84:87-136.</p>
<p>Makris SL, Raffaele K, Allen S, Bowers WJ, Hass U, Alleva E, Calamandrei G, Sheets L, Amcoff P, Delrue N, Crofton KM. A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect. 2009 Jan;117(1):17-25.</p>
<p>Morris RG, Frey U. Hippocampal synaptic plasticity: role in spatial learning or the automaticrecording of attended experience? Philos Trans R Soc Lond B Biol Sci. 1997 Oct 29;352(1360):1489-503. Review</p>
<p>O’Keefe, J. and Nadel, L. (1978). The Hippocampus as a Cognitive Map. Oxford: Oxford University Press.</p>
<p>OECD. 2007. OECD guidelines for the testing of chemicals/ section 4: Health effects. Test no. 426: Developmental neurotoxicity study. www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed May 21, 2012].</p>
<p>Samuels BA, Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33:1152-1159.</p>
<p>Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical appliations fo the Rey-Osterrieth complex figure test. Nature Protocols, 1: 892-899.</p>
<p>Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376.Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82:171-177.</p>
<p>Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267.</p>
<p>Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver.</p>
<p>U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances.</p>
<p>Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332.</p>
<p>Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014. 9:1-11.</p>
2016-11-29T18:41:242018-08-09T11:55:05af428cec-5f56-4654-838f-8f981898c6ee7b749554-324d-4d50-a028-5496ddf941bc<ul>
<li dir="ltr">
<p dir="ltr"><span style="font-size:10.5pt"><span style="font-family:"Helvetica Neue"">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).</span></span></p>
</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 <em>Ailanthus</em> 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>
<p><span style="font-size:16px">Faria et al (2015) exposed zebrafish (<em>Danio rerio</em>) 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.</span></p>
</li>
</ul>
<ul>
<li>No known qualitative inconsistencies or uncertainties associated with this relationship.</li>
</ul>
<p dir="ltr">The general kinetic equation is: </p>
<p dir="ltr" style="margin-left:80px"><img alt="" src="https://aopwiki.org/system/dragonfly/production/2019/12/19/73wb1lsj9l_AchE_equation.png" style="height:48px; width:470px" /></p>
<ul>
<li dir="ltr">
<p>Where AX is the substrate, either acetylcholine or an inhibitor of AChE (e.g., OP or carbamate); </p>
</li>
<li dir="ltr">
<p dir="ltr">AChE-AX is the enzyme-substrate complex; </p>
</li>
<li dir="ltr">
<p dir="ltr">AChE-A is the acylated, carbamylated or phosphorylated enzyme; </p>
</li>
<li dir="ltr">
<p dir="ltr">X is the leaving group (e.g., choline); </p>
</li>
<li dir="ltr">
<p dir="ltr">AChE is the free enzyme; and </p>
</li>
<li dir="ltr">
<p dir="ltr">A is acetic acid, phosphate (P(=O)(=O)(R2)or methylamine. </p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p dir="ltr">Some rate constants for OPs and carbamates have been published for use in PBPK models (Knaak et al., 2004, 2008)</p>
</li>
</ul>
<p dir="ltr">Table 1: Summary of available quantitative data describing responses of ACh to AChE inhibition. Data are grouped by species.</p>
<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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">AChE Inhibitor</span></span></span></strong></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">CAS RN</span></span></span></strong></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Inhibitor Dosage</span></span></span></strong></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Species / Model</span></span></span></strong></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Brief Summary</span></span></span></strong></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Reference</span></span></span></strong></span></span></p>
</td>
<td style="border-bottom:none; border-left:none; border-right:none; border-top:none; width:2%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"> </span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Donezepil </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">120014-06-4</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">0.625, 1.25, 2.5 (mg/kg)</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Wistar rats<br />
(210-290 g | 7 weeks)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Timecourse data on both extracellular hippocampal ACh concentration and AChE activity given varying concentrations of inhibitor.<br />
Brain concentrations of drugs over time are also provided.</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kosasa et al., 1999</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Tacrine </span></span></span></span></p>
</td>
<td style="border-bottom:none; border-left:1px solid black; border-right:none; border-top:none; height:50px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">321-64-2</span></span></span></span></p>
</td>
<td style="border-bottom:none; border-left:1px solid black; border-right:1px solid black; border-top:none; height:50px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">1.25, 2.5, 5, 10 (mg/kg)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">ENA-713 (Rivastigmine)</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">129101-54-8</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">0.625, 1.25, 2.5 (mg/kg)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Dichlorvos (DDVP)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">62-73-7</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">5 (mg/kg)</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Wistar rats<br />
(180-230 g)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">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.</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kobayashi et al., 1994</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Propoxur</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">114-26-1</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">10 (mg/kg)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Paraquat (PQ)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:none; border-top:none; height:83px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">1910-42-5</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">0.1, 1, 10, 20, 30 (μM)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:83px; width:16%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Wistar rats (fetal days 17-18)<br />
Primary hippocampal neurons</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif"><span style="color:black">In Vitro</span></span></em><span style="font-family:"Calibri",sans-serif"><span style="color:black"> AChE activity (% control) and ACh concentration (pmol / mL) at 24h and 14 days post exposure</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Del Pino et al., 2017</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Tacrine </span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">321-64-2</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">1.25, 2.5, 5 (mg/kg)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Wistar rats<br />
(210-290 g | 6 weeks) </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">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.</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kim 2003</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Parathion (PS)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">56-38-2</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">adult: 1.8, 3.4, 6, 9, 18, 27 (mg/kg)<br />
aged: 1.8, 3.4, 6, 9 (mg/kg)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Sprague-Dawley rats<br />
(adult: 3 months)<br />
(aged: 18 months)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Diaphragm and striatum AChE activity (% control).<br />
Striatal dialysates of ACh (fmol/60 μL fraction) on day 3 and 7 post-exposure</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Karanth et al., 2007</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Chlorpyrifos (CPF)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black"> 2921-88-2</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">84, 156, 279 (mg/kg)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Sprague-Dawley rats<br />
(325-350 g | 3 months)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:121px; width:26%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Diaphragm and striatum cholinesterase activity (% control). ACh concentration (fmol/60 μL fraction) through <em>In Vivo</em> microdialysis at 1, 4, and 7 days post-exposure</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Karanth et al., 2006</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Paraoxon</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">311-45-5</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">0.03, 0.1, 1, 10 (μM)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Sprague-Dawley rats<br />
(275-299 g | 2-3 months)</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:102px; width:26%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Timecourse data on changes in striatal AChE activity (% control) and ACh concentration (fmole/fraction (60 μL)) over 4 hours post exposure.</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Ray et al., 2009</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Propoxur</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">114-26-1</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">10 (mg/kg)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Female ICR mice<br />
(30-40 g | 8-10 weeks)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">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)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kobayashi et al., 1988</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">BPMC</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">3766‑81‑2</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">10 (mg/kg)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Female ICR mice<br />
(30-40 g | 8-10 weeks)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Timecourse data on AChE activity (</span></span><span style="font-family:"Calibri",sans-serif">μmole acetylthiocholine hydrolyzed / min / g tissue or ml blood<span style="color:black">) and ACh content (nmol/g tissue) of forebrain homogenate, taken at 0, 10 and 60 minutes.</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kobayashi et al., 1985</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Propoxur</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">114-26-1</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:60px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">2 (mg/kg)</span></span></span></span></p>
</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>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">DE-71</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">32534-81-9</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">31.0, 68.7, 227.6 (μg/L)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Zebrafish larvae</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Changes in AChE activity (nmol / min / mg protein) and ACh concentration (nmol / mg protein) measured at 120 hours post-fertilization </span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Chen et al., 2012 </span></span></span></span></p>
</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>
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<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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Dichlorvos</span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">(DDVP)</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">62-73-7</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:61px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">3 (mg/kg)</span></span></span></span></p>
</td>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Male Japanese quail<br />
(100 g | 8-14 weeks)</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">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.</span></span></span></span></p>
</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%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Kobayashi et al., 1983</span></span></span></span></p>
</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Fenitrothion</span></span></span></span></p>
</td>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">122-14-5</span></span></span></span></p>
</td>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">300 (mg/kg)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Methyl Parathion</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">298-00-0</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">0.09 (ppm)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:16%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif"><span style="color:black">Tilapia mossambica</span></span></em></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:26%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">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</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:122px; width:11%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Rao and Rao, 1984</span></span></span></span></p>
</td>
<td style="height:122px; width:2%"> </td>
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</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%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Methyl Parathion</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">298-00-0</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">2.5 (ppm)</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:16%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif"><span style="color:black">Rana cyanophilicitus</span></span></em><br />
<span style="font-family:"Calibri",sans-serif"><span style="color:black">Frog tadpole<br />
(1.5-2 g | 20 days)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:26%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">AChE activity (μmol ACh hydrolyzed /min) and ACh content (μmol/g) measured after 24 hours post exposure</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:100px; width:11%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Yasmeen and Yasmeen, 1986 </span></span></span></span></p>
</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>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:75px; width:16%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Malathion</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:13%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">121-75-5</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:12%">
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">60 µg each/g insect weight/day</span></span></span></span></p>
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<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><em><span style="font-family:"Calibri",sans-serif"><span style="color:black">Philosamia Ricini<br />
larvae</span></span></em></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">AChE activity and ACh concentration changes measured daily for 5 days.</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:75px; width:11%">
<p style="text-align:center"><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="color:black">Pant and Katiyar, 1983</span></span></span></span></p>
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<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>
<p> </p>
HighUnspecificNot SpecifiedAll life stagesHighHighModerateHighHighHighModerateModerate<p dir="ltr"><small><big><span style="font-size:11pt">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.</span></big></small></p>
<p dir="ltr"><em>Taxonomic Applicability</em></p>
<ul>
<li dir="ltr">
<p 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).</p>
</li>
</ul>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Chen, L., Huang, C., Hu, C., Yu, K., Yang, L. & Zhou, B. 2012. Acute exposure to DE-71: Effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae. <em>Environmental Toxicology and Chemistry,</em> 31<strong>,</strong> 2338-2344. DOI: 10.1002/etc.1958.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Del Pino, J., Moyano, P., Díaz, G. G., Anadon, M. J., Diaz, M. J., García, J. M., Lobo, M., Pelayo, A., Sola, E. & Frejo, M. T. 2017. Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption. <em>Toxicology,</em> 390<strong>,</strong> 88-99. DOI: 10.1016/j.tox.2017.09.008.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Faria, M., Garcia-Reyero, N., Padrós, F., Babin, P. J., Sebastián, D., Cachot, J., Prats, E., Arick Ii, M., Rial, E., Knoll-Gellida, A., Mathieu, G., Le Bihanic, F., Escalon, B. L., Zorzano, A., Soares, A. M. & Raldúa, D. 2015. Zebrafish Models for Human Acute Organophosphorus Poisoning. <em>Sci Rep,</em> 5<strong>,</strong> 15591. DOI: 10.1038/srep15591.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Karanth, S., Liu, J., Mirajkar, N. & Pope, C. 2006. Effects of acute chlorpyrifos exposure on in vivo acetylcholine accumulation in rat striatum. <em>Toxicology and Applied Pharmacology,</em> 216<strong>,</strong> 150-156. DOI: <a href="https://doi.org/10.1016/j.taap.2006.04.006" style="color:blue; text-decoration:underline">https://doi.org/10.1016/j.taap.2006.04.006</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Karanth, S., Liu, J., Ray, A. & Pope, C. 2007. Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats. <em>Toxicology,</em> 239<strong>,</strong> 167-179. DOI: <a href="https://doi.org/10.1016/j.tox.2007.07.004" style="color:blue; text-decoration:underline">https://doi.org/10.1016/j.tox.2007.07.004</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kim, Y. K., Koo, B. S., Gong, D. J., Lee, Y. C., Ko, J. H. & Kim, C. H. 2003. Comparative effect of Prunus persica L. BATSCH-water extract and tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) on concentration of extracellular acetylcholine in the rat hippocampus. <em>J Ethnopharmacol,</em> 87<strong>,</strong> 149-54. DOI: 10.1016/s0378-8741(03)00106-5.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kobayashi, H., Sato, I., Akatsu, Y., Fujii, S., Suzuki, T., Matsusaka, N. & Yuyama, A. 1994. Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats. <em>J Appl Toxicol,</em> 14<strong>,</strong> 185-90. DOI: 10.1002/jat.2550140307.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kobayashi, H., Yuyama, A., Kajita, T., Shimura, K., Ohkawa, T. & Satoh, K. 1985. Effects of insecticidal carbamates on brain acetylcholine content, acetylcholinesterase activity and behavior in mice. <em>Toxicology Letters,</em> 29<strong>,</strong> 153-159. DOI: <a href="https://doi.org/10.1016/0378-4274(85)90036-0" style="color:blue; text-decoration:underline">https://doi.org/10.1016/0378-4274(85)90036-0</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">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. <em>Toxicology,</em> 28<strong>,</strong> 219-227. DOI: <a href="https://doi.org/10.1016/0300-483X(83)90119-1" style="color:blue; text-decoration:underline">https://doi.org/10.1016/0300-483X(83)90119-1</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kobayashi, H., Yuyama, A., Ohkawa, T. & Kajita, T. 1988. Effect of Single or Chronic Injection with a Carbamate, Propoxur, on the Brain Cholinergic System and Behavior of Mice. <em>The Japanese Journal of Pharmacology,</em> 47<strong>,</strong> 21-27. DOI: 10.1254/jjp.47.21.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kosasa, T., Kuriya, Y., Matsui, K. & Yamanishi, Y. 1999. Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. <em>European Journal of Pharmacology,</em> 380<strong>,</strong> 101-107. DOI: 10.1016/S0014-2999(99)00545-2.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Lushington, G. H., Guo, J. X. & Hurley, M. M. 2006. Acetylcholinesterase: molecular modeling with the whole toolkit. <em>Curr Top Med Chem,</em> 6<strong>,</strong> 57-73. DOI: 10.2174/156802606775193293.</span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">Nayeemunnisa and 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[11], 546-548.</span></span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Oyama, Y., Hori, N., Evans, M. L., Allen, C. N. & Carpenter, D. O. 1989. Electrophysiological estimation of the actions of acetylcholinesterase inhibitors on acetylcholine receptor and cholinesterase in physically isolated Aplysia neurones. <em>Br J Pharmacol,</em> 96<strong>,</strong> 573-82. DOI: 10.1111/j.1476-5381.1989.tb11855.x.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Pant, R. & Katiyar, S. K. 1983. Effect of malathion and acetylcholine on the developing larvae ofPhilosamia ricini (Lepidoptera: Saturniidae). <em>Journal of Biosciences,</em> 5<strong>,</strong> 89-95. DOI: 10.1007/BF02702598.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Rao, K. S. P. & Rao, K. V. R. 1984. Impact of methyl parathion toxicity and eserine inhibition on acetylcholinesterase activity in tissues of the teleost (Tilapia mossambica) — a correlative study. <em>Toxicology Letters,</em> 22<strong>,</strong> 351-356. DOI: <a href="https://doi.org/10.1016/0378-4274(84)90113-9" style="color:blue; text-decoration:underline">https://doi.org/10.1016/0378-4274(84)90113-9</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Ray, A., Liu, J., Karanth, S., Gao, Y., Brimijoin, S. & Pope, C. 2009. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats. <em>Toxicology and applied pharmacology,</em> 236<strong>,</strong> 341-347. DOI: 10.1016/j.taap.2009.02.022.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Reddy, M. S., Jayaprada, P. & Rao, K. V. 1990. Impact of methylparathion and malathion on cholinergic and non-cholinergic enzyme systems of penaeid prawn, Metapenaeus monoceros. <em>Biochem Int,</em> 22<strong>,</strong> 769-79. </span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Soreq, H. & Seidman, S. 2001. Acetylcholinesterase--new roles for an old actor. <em>Nat Rev Neurosci,</em> 2<strong>,</strong> 294-302. DOI: 10.1038/35067589.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Stavinoha, W. B., Ryan, L. C. & Smith, P. W. 1969. Biochemical effects of an organophosphorus cholinesterase inhibitor on the rat brain. <em>Ann N Y Acad Sci,</em> 160<strong>,</strong> 378-82. DOI: 10.1111/j.1749-6632.1969.tb15859.x.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Verma, S. R., Tonk, I. P., Gupta, A. K. & Dalela, R. C. 1981. In vivo enzymatic alterations in certain tissues of Saccobranchus fossilis following exposure to four toxic substances. <em>Environmental Pollution Series A, Ecological and Biological,</em> 26<strong>,</strong> 121-127. DOI: <a href="https://doi.org/10.1016/0143-1471(81)90042-8" style="color:blue; text-decoration:underline">https://doi.org/10.1016/0143-1471(81)90042-8</a>.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Wilson, B. W. 2001. CHAPTER 48 - Cholinesterases. <em>In:</em> KRIEGER, R. I. & KRIEGER, W. C. (eds.) <em>Handbook of Pesticide Toxicology (Second Edition).</em> San Diego: Academic Press.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Wilson, B. W. 2010. Cholinesterases. <em>In:</em> KRIEGER, R. (ed.) <em>Hayes' Handbook of Pesticide Toxicology. </em>Third ed. Amsterdam, The Netherlands: Elsevier.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Yasmeen, N. & Yasmeen, N. 1986. ON THE PRESENCE OF CALMODULIN IN THE BRAIN OF CONTROL AND METHYL PARATHION-EXPOSED DEVELOPING TADPOLES OF FROG, RANA CYANOPHLICTIS. <em>Current Science,</em> 55<strong>,</strong> 546-548. <a href="http://www.jstor.org/stable/24090019" style="color:blue; text-decoration:underline">http://www.jstor.org/stable/24090019</a></span></span></li>
</ul>
2016-11-29T18:41:332023-09-10T19:16:32f61e4f1a-cebe-4925-b825-4301d3bf16320f61d01d-9558-495e-a8a3-1ba6c9c0de9f<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt">An upstream key event decrease in neuronal network function leads to deficiency of learning and memory which is the sign of cognitive deficits (downstream, adverse outcome) (Anna<span style="color:#333333"> Bal-Price et al., 2017)</span>. Learning and memory- a cognitive function is dependent to neuronal network function. Experimental approach advocates that in hippocampal neurons cognitive-induced enhancement in neuronal excitability, as a measurement of neural network function (Anna<span style="color:#333333"> Bal-Price et al., 2017; </span>Saar and Barkai, 2003).<span style="color:#333333"> Cognitive defect is the functional output of neural networks of mammalian. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment (aopwiki.org/relationships/359).</span></span></span></span></span><br />
<span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Cognitive defects like learning and memory are measured using behavioral test. It is well attested that the changes in behavior are the outcome of structural/ functional changes in neuronal network. Functional impairments are typically measured by field potentials of critical synaptic circuits in hippocampus. (Wang et al., 2012; Gilbert et al., 2016). </span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Morris water maze (MWM) test as a means to investigate spatial learning and memory in laboratory rats reveals that the disconnection among neuronal networks are responsible for the performance impairment of MWM test rather than the damage or injury of certain part of brain . (aopwiki.org/relationships/359; D'Hooge and De Deyn, 2001). However, it is well established that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function (aopwiki.org/relationships/359). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#212121">Although the exact causes and pathophysiological consequences of neuronal network alterations yet to define but interneuron dysfunction and neuronal network aberrations have appeared as impending mechanisms of cognitive defects (Palop JJ et al., 2016). </span></span></span><span style="font-size:11.0pt"><span style="color:#333333">But very limited data establishing these two KEs in the case of human simultaneously reduction in IQ is directly linked with impairments in hippocampus mediated function (aopwiki.org/relationships/359). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">One of the major difficult concerns for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is quiet blind that what alterations of neuronal circuits essential to observe change in motor behavior including learning and memory (Mayford et al., 2012), thus there is no any strong evidence defining that how these two KEs are connected (aopwiki.org/relationships/359). Thus it’s difficult to establish the direct relationship of alterations in neural network function and specific cognitive deficits due to the complexity of synaptic interactions in even the simplest brain circuit. (aopwiki.org/relationships/359).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">There is lack of sufficient quantitative information ascertain that how much change decrease of neuronal network functions leads to cognitive defects. Thus very limited information on the degree of quantitative change in neural network function required to alter cognitive behaviors. Though, qualitatively is well accepted that decrease of long term synaptic potential is directly linked to learning and memory deficits (aopwiki.org/relationships/359). This is a outcome of the diversity of testing methods for measuring both neuronal network function and cognitive deficits, which impede cross-study analyses. Thus empirical data based models of this KER is require to develop (aopwiki.org/relationships/359).</span></span></span></span></span></p>
HighMixedHighDuring brain developmentNot SpecifiedNot SpecifiedNot Specified<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">A common mechanisms across the taxonomies is working for synaptic transmission and plasticity. Long term synaptic potential has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats (aopwiki.org/relationships/359; aopwiki.org/relationships/384). </span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Anna Bal-Price, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, Marta Barenys, Ellen Fritsche, Magdalini Sachana, M.E. (Bette) Meek. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity, NeuroToxicology, Volume 59, 2017, Pages 240-255, ISSN 0161-813X, <a href="https://doi.org/10.1016/j.neuro.2016.05.010" style="color:blue; text-decoration:underline">https://doi.org/10.1016/j.neuro.2016.05.010</a>.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">D'Hooge R, De Deyn PP. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 36: 60-90.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Mayford M, Siegelbaum SA, Kandel ER. (2012). Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#212121">Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. doi: 10.1038/nrn.2016.141. Epub 2016 Nov 10. PMID: 27829687; PMCID: PMC8162106</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Saar, D. and Barkai, E. (2003), Long-term modifications in intrinsic neuronal properties and rule learning in rats. European Journal of Neuroscience, 17: 2727-2734. <a href="https://doi.org/10.1046/j.1460-9568.2003.02699.x" style="color:blue; text-decoration:underline">https://doi.org/10.1046/j.1460-9568.2003.02699.x</a>.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848</span></span></span></span></span></p>
2021-06-24T18:35:462021-08-27T12:24:497b749554-324d-4d50-a028-5496ddf941bc3dba98e7-be4b-4a0c-87b4-a4e3b242be8f<p dir="ltr">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.</p>
<p> </p>
<ul>
<li dir="ltr">
<p 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).</p>
</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">
<p 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.</p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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).</p>
</li>
<li dir="ltr">
<p 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). </p>
</li>
<li dir="ltr">
<p 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). </p>
</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr">No known qualitative inconsistencies or uncertainties associated with this relationship.</p>
</li>
</ul>
<ul>
<li dir="ltr">
<p dir="ltr">Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Soreq H, Seidman S., Acetylcholinesterase--new roles for an old actor. Nat Rev Neurosci. 2001 Apr;2(4):294-302.</p>
</li>
<li dir="ltr">
<p dir="ltr">Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 21.4, Neurotransmitters, Synapses, and Impulse Transmission. Available from: <a href="https://www.ncbi.nlm.nih.gov/books/NBK21521/">https://www.ncbi.nlm.nih.gov/books/NBK21521/</a></p>
</li>
<li dir="ltr">
<p dir="ltr">Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.</p>
</li>
<li dir="ltr">
<p dir="ltr">Coulson FR1, 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.</p>
</li>
<li dir="ltr">
<p 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.</p>
</li>
<li dir="ltr">
<p dir="ltr">Stenersen J. 2004. Specific enzyme inhibitors. Chemical Pesticides: Mode of action and toxicology, CRC Press, Boca Raton, FL, USA.</p>
</li>
<li dir="ltr">
<p dir="ltr">Kobayashi, H., Yuyama, A., Kudo, M., and Matsusaka, N. 1983. Effects of Organophosphorus Compounds, O,O-Dimethyl O-(2,2-Dichlorovinyl)Phosphate (DDVP) and O,O-Dimethyl O-(3-Methyl 4-Nitrophenyl)Phosphorothioate (Fenitrothion), on Brain Acetylcholine Content and Acetylcholinesterase Activity in Japanese Quail. Toxicology 28[3], 219-227.</p>
</li>
<li dir="ltr">
<p dir="ltr">Grue CE, Shipley BK. 1984. Sensitivity of nestling and adult starling to dicrotophos, an organophosphate pesticide. Environ Res 35:454–465.</p>
</li>
<li dir="ltr">
<p dir="ltr">Verma, S.R., Tonk, I.P., Gupta, A.K., Dalela, R.C. 1981. In Vivo Enzymatic Alteration in Certain Tissues of Saccobranchus Fossilis Following Exposure to Four Toxic Substances. Environ. Pollut. (Series A). 26(2), 121-127.</p>
</li>
</ul>
2016-11-29T18:41:342019-12-20T09:16:353dba98e7-be4b-4a0c-87b4-a4e3b242be8f0f61d01d-9558-495e-a8a3-1ba6c9c0de9f<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Acetylcholine signaling underlies the specific aspect of cognitive function including learning and memory, simultaneously acetylcholine is regulated by disperse group of cholinergic neurons (</span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Luchicchi A et al., 2014)</span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">. Cholinergic signaling refers to the activation of receptors bound with acetylcholine and here receptors defines as acetylcholine or cholinergic receptors which classify into Muscarinic and Nicotinic receptors (</span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://aopwiki.org/events/39" style="color:blue; text-decoration:underline">https://aopwiki.org/events/39</a></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">). Precious work documented that Acetylcholine (Ach) released from cholinergic input of basal forebrain play important role in supporting neurocognitive function (</span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Berman JA et al., 2007)</span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">. The loss of basal forebrain cholinergic neuron is directly linked to decrease in Ach release in hippocampus and cortex areas and to </span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Alzheimer related cognitive dysfunction (Bekdash, R.A et al., 2021; </span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ballinger EC et al., 2016)</span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">. Thus cholinergic signaling is a key player in mediating cognitive performance. Simultaneously previous worked showed that failure of cholinergic circuit of basal forebrain is accountable for cognitive impairment. Cholinergic signaling from medial septal (MS) and diagonal band (DB) to the hippocampus is certainly important for formation of spatial memories. (</span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ballinger EC et al., 2016)</span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">. Thus the role of cholinergic signaling in cognitive function is preserve. Prior work has also shown that stimulation of cholinergic neurons in the MS controlled via cholinergic basal forebrain - hippocampal projection and cholinergic to GABAergic basal forebrain to hippocampal pathway (</span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ballinger EC et al., 2016)</span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">. Thus this two pathways worked synergistically to maximize hippocampal-firing (Dannenberg et al., 2015).</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">The weight of evidence supporting the relationship between decrease cognitive functions is induced by increased cholinergic signaling is moderate. </span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Cholinergic signaling is determined by the capacity of Ach to bind to respective Ach receptors on target neurons to modulate their excitability (</span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Bekdash, R.A et al., 2021)</span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">. Previous study tested the hypothesis that failures of cholinergic circuitry of the basal forebrain are responsible for the cognitive impairments associated with neurodegenerative disorders (Ballinger EC et al., 2016; Bartus et al., 1982). Study have further connect alterations in cholinergic signaling in disorders of attention and cognitive control (Ballinger EC et al., 2016; Higley and Picciotto, 2014). </span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Ach is formed from choline and Acetyl-CoA upon released at synapses, Ach binds to nicotinic or muscarinic receptors on postsynaptic neurons to control cholinergic signaling in various regions of brain (</span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Bekdash, R.A et al., 2021)</span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">. Cholinergic neurons are extensively dispersed in brain regions that play important task in cognitive functions and normal cholinergic signaling related to learning and memory (</span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Bekdash, R.A et al., 2021). </span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Most of the brain regions that are innervate by cholinergic neurons play important part in learning, memory and cognitive functions (</span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Woolf, N.J et al., 2011)</span>. Several studies demonstrated the contribution of Ach in cognitive functions like learning and memory, attention and thinking abilities (Picciotto, M.R et al., 2012, Hasselmo, M.E et al., 2011). Loss of Cholinergic neuron from the forebrain causes cognitive deficits associated with Parkinson’s and Alzheimer’s disease (Ahmed NY et al., 2019).</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Many experimental studies have recommended that cholinergic neurotransmission dysfunction in the cerebral hippocampus and cortex plays an important role in cognitive impairment [R. Schliebs and T. Arendt et al., 2006].</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">In vertebrates, ACh is released during neurotransmission via cholinergic neurons, are found in the brain and spinal cord, including the basal forebrain. Brain cholinergic systems regulate vital cognitive processes including learning, memory (Rima, M et al., 2020). In human: Patients experiencing cholinergic poisoning constricted or pinpointed pupils are commonly reported in clinical cohort studies casing organophosphate exposure (</span><a href="https://aopwiki.org/events/39" style="color:blue; text-decoration:underline">https://aopwiki.org/events/39</a><span style="color:#333333">, Wadia, 1974, Peter, 2014). </span></span></span></span></span><br />
<span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">In embryonic fish and frogs: Spontaneous movements in developing fish and frog embryos are demarcated as flexing or side-to-side motion of the trunk or tail and free-swimming activity. The number of movements per minute was recorded by embryonic study under a dissection microscope. In zebrafish embryos spontaneous motion were observed at 1 day post fertilization and in Xenopus at 2 day post fertilization (</span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://aopwiki.org/events/39" style="color:blue; text-decoration:underline">https://aopwiki.org/events/39</a></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">, Watson, 2014).</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="background-color:white"><span style="font-family:"Segoe UI",sans-serif"><span style="color:#212121">Ahmed NY, Knowles R, Dehorter N. New Insights Into Cholinergic Neuron Diversity. Front Mol Neurosci. 2019 Aug 27;12:204. doi: 10.3389/fnmol.2019.00204. PMID: 31551706; PMCID: PMC6736589.</span></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ballinger EC, Ananth M, Talmage DA, Role LW. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016 Sep 21;91(6):1199-1218. doi: 10.1016/j.neuron.2016.09.006. PMID: 27657448; PMCID: PMC5036520.</span></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ballinger EC, Ananth M, Talmage DA, Role LW. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016 Sep 21;91(6):1199-1218. doi: 10.1016/j.neuron.2016.09.006. PMID: 27657448; PMCID: PMC5036520.</span></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Bartus RT, Dean RL 3rd, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982; 217:408–414. [PubMed: 7046051].</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Bekdash, R.A. The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease. Int. J. Mol. Sci. 2021, 22, 1273. <a href="https://doi.org/10.3390/ijms22031273" style="color:blue; text-decoration:underline">https://doi.org/10.3390/ijms22031273</a></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Berman JA, Talmage DA, Role LW. Cholinergic circuits and signaling in the pathophysiology of schizophrenia. <em>Int Rev Neurobiol</em>. 2007;78:193-223. doi:10.1016/S0074-7742(06)78007-2</span></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Dannenberg H, Pabst M, Braganza O, Schoch S, Niediek J, Bayraktar M, Mormann F, Beck H. Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks. J Neurosci. 2015 Jun 3;35(22):8394-410. doi: 10.1523/JNEUROSCI.4460-14.2015</span></span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Hasselmo, M.E.; Sarter, M. Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition. Neuropsychopharmacology2011, 36, 52–73. [CrossRef]</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Hayes, W.J.; Jr, & Laws, E.R.; Jr (1991). Organic Phosphorous Pesticides: In Handbook of Pesticide Toxicology. Vol. 3. Acad. Press,1-1189 San Diego, New York, Boston, London, Sydney, Tokyo, Toronto. ISBN-10: 0123341604.</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Higley MJ, Picciotto MR. Neuromodulation by acetylcholine: examples from schizophrenia and depression. Curr Opin Neurobiol. 2014; 29:88–95. [PubMed: 24983212]</span></span></span></span></p>
<p style="margin-left:24px; margin-right:-48px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Luchicchi A, Bloem B, Viaña JNM, Mansvelder HD, Role LW. Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Frontiers in Synaptic Neuroscience. 2014;6(24).</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#212529">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.</span></span><span style="font-size:11.0pt"><a href="https://doi.org/10.4103/0972-5229.144017" style="color:blue; text-decoration:underline"><span style="color:#337ab7"> https://doi.org/10.4103/0972-5229.144017</span></a><span style="color:#212529">.</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Picciotto, M.R.; Higley, M.J.; Mineur, Y.S. Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior. Neuron 2012, 76, 116–129. [CrossRef]</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">R. Schliebs and T. Arendt, “The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease,” Journal of Neural Transmission, vol. 113, no. 11, pp. 1625–1644, 2006.</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Rima, M., Lattouf, Y., Abi Younes, M. et al. Dynamic regulation of the cholinergic system in the spinal central nervous system. Sci Rep 10, 15338 (2020). https://doi.org/10.1038/s41598-020-72524-3</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#212529">Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#212529">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.</span></span><span style="font-size:11.0pt"><a href="https://doi.org/10.1002/etc.2559" style="color:blue; text-decoration:underline"><span style="color:#337ab7"> https://doi.org/10.1002/etc.2559</span></a><span style="color:#212529">.</span></span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Wayne R. Snodgrass, Chapter 60 - Diagnosis and Treatment of Poisoning Due to Pesticides,Editor(s): Robert Krieger, Hayes' Handbook of Pesticide Toxicology (Third Edition), Academic Press, 2010, Pages 1295-1311, ISBN 9780123743671,</span></span></span></span></p>
<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Woolf, N.J.; Butcher, L.L. Cholinergic Systems Mediate Action from Movement to Higher Consciousness. Behav. Brain Res. 2011,221, 488–498.</span></span></span></span></span></p>
2021-06-24T18:36:552021-09-01T13:47:313dba98e7-be4b-4a0c-87b4-a4e3b242be8ff61e4f1a-cebe-4925-b825-4301d3bf1632<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Cholinergic signaling refers to the activation of receptors bound with acetylcholine. Receptors for acetylcholine is either acetylcholine or cholinergic receptors, which further classify into muscarinic and nicotinic (aopwiki.org/events/39). Nicotinic cholinergic signaling is began early in development and spreads throughout the central nervous system via acetylcholine (ACh) and activating a range of ligand-gated ion channels (John D et al., 2015). Nicotinic cholinergic signaling clearly plays important roles in both during development in shaping the neural networks that form and in the adult where it modulates network function in numerous ongoing ways (John D et al., 2015). Recent study by Wang Y et al, (2021) showed that cholinergic signaling controls excitation and inhibition balance of neuronal network in brain. In thalamus <span style="background-color:white"><span style="color:black">neuronal networks are the target of extensive cholinergic projections from the basal forebrain. Upon activation, these cholinergic signals play important role in regulation of neuronal excitability and firing patterns of neuronal networks (</span></span><span style="background-color:white"><span style="color:#212121">Beierlein M et al., 2014)</span></span><span style="background-color:white"><span style="color:black">.</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">The capacity of a neuron to interconnect is based on neural network formation that count on functional synapse establishment by cholinergic neuron (<span style="color:#333333">Anna Bal-Price</span> et al., 2017; Colón-Ramos, 2009). Previous study reported that changes in the activity of cholinergic interneurons can play a vital role in motor control as well as social behavior (Martos et al., 2017). Thus modifications to the cholinergic system can lead to major dysfunction of neuronal network and the loss of cholinergic neuron from the forebrain can cause cognitive deficits associated with Parkinson’s and Alzheimer’s disease (Ahmed NY et al., 2019). Although the aberrant cholinergic signaling linked with several neurological disorder including schizophrenia but exact role is yet to elucidate (Ahmed NY et al., 2019). The ability of ACh to link the response of neuronal networks in brain makes cholinergic signaling a crucial mechanism underlying complex behaviors (Picciotto MR et al., 2012).</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:black">The cholinergic signaling system is deliberately located to exercise neuromodulatory effects on the excitatory and inhibitory balance. Thus endogenous cholinergic signaling regulate the excitatory and inhibitory balance via both nicotinic and muscarinic receptor (Lucas-Meunier E et al., 2009). The loss of cholinergic neurons has a profound effect on cholinergic signaling. Neurological diseases like Alzheimer’s connecting abnormal or loss of cholinergic signaling and excitatory and inhibitory imbalances. </span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Activation of cholinergic receptors has a robust modulatory influence in the hippocampal network via activation of GABAergic interneurons (Jones and Yakel 1997). Activation of <span style="background-color:white"><span style="color:black">neuronal nicotinic ACh receptors</span></span></span></span> excites interneurones which can inhibit large numbers of hippocampal excitatory and inhibitory neurons, thus <span style="background-color:white"><span style="color:black">neuronal nicotinic ACh receptors</span></span> could participate in the cholinergic regulation of hippocampal neuronal activity (<span style="background-color:white"><span style="color:#303030">Jones S et al., 1997</span></span>). Cholinergic signaling, during development is essential for physiological processes essential for the formation of the PNS and CNS including synaptogenesis (<span style="background-color:white"><span style="color:#222222">Dwyer, J. B et al, 2009; Rima, M et al., 2020</span></span>). Neuronal network formation and function are established via the process of synaptogenesis. Cholinergic transmission can facilitate disparate actions through integration of postsynaptic signals (Calabresi et al., 2000). The developmental period of synaptogenesis is critical for the formation of the basic circuitry of the nervous system, although neurons are able to form new synapses throughout life (Rodier, 1995). Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008).</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">The exact mechanism by which increase in cholinergic signaling lead to decrease in neuronal network function has not been fully elucidated.</span></span></p>
HighMixedHighDuring brain developmentHighHighModerateModerateModerate<p><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212529">The main proof of evidence comes from in vivo studies in rodents. However, </span></span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">Rima, M et al., (2020) carried out a thorough spatiotemporal analysis of the cholinergic system in embryonic and larval zebrafish</span></span></span></span>., cholinergic neurons in vertebrates found in the brain and spinal cord including the basal forebrain, brainstem and the habenula (<span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Ahmed NY et al., 2019; Rima M et al., 2020</span></span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">). In rat spinal cord cholinergic propriospinal innervation analysis was done by Sherriff FE and </span></span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Henderson Z. A (1994).</span></span></span></span><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222"> Study by </span></span></span></span><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Eadaim et al. (2020) illustrated that in vivo reduction of cholinergic signaling induced synaptic homeostasis in Drosophila neurons</span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#212121">Ahmed NY, Knowles R, Dehorter N. New Insights into Cholinergic Neuron Diversity. Front Mol Neurosci. 2019 Aug 27; 12:204. doi: 10.3389/fnmol.2019.00204. PMID: 31551706; PMCID: PMC6736589.</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="color:#333333">Anna Bal-Price, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, Marta Barenys, Ellen Fritsche, Magdalini Sachana, M.E. (Bette) Meek. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity, NeuroToxicology, Volume 59, 2017, Pages 240-255, ISSN 0161-813X, https://doi.org/10.1016/j.neuro.2016.05.010.</span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Beierlein M. Synaptic mechanisms underlying cholinergic control of thalamic reticular nucleus neurons. J Physiol. 2014 Oct 1; 592 (19):4137-45. doi: 10.1113/jphysiol.2014.277376. Epub 2014 Jun 27. PMID: 24973413; PMCID: PMC4215766.</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#3e3d40">Calabresi, P., Centonze, D., Gubellini, P., Pisani, A., and Bernardi, G. (2000). Acetylcholine-mediated modulation of striatal function. </span></span></span></span><em>Trends Neurosci.</em> 23, 120–126. doi: 10.1016/s0166-2236(99)01501-5.</span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Cline H, Haas K. (2008). The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis. J Physiol 586: 1509-1517.</span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Colón-Ramos DA. (2009). Synapse formation in developing neural circuits. Curr Top Dev Biol. 87: 53-79.</span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#222222">Dwyer, J. B., McQuown, S. C. & Leslie, F. M. The dynamic effects of nicotine on the developing brain. </span></span></span></span><em>Pharmacol. Ther.</em> <strong>122</strong>, 125–139 (2009). </span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#212121">Eadaim A, Hahm ET, Justice ED, Tsunoda S. Cholinergic Synaptic Homeostasis Is Tuned by an NFAT-Mediated α7 nAChR-K</span></span></span><sub>v</sub>4/Shal Coupled Regulatory System. Cell Rep. 2020 Sep 8; 32(10):108119. doi: 10.1016/j.celrep.2020.108119. PMID: 32905767; PMCID: PMC7521586.</span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">John D, Berg DK. Long-lasting changes in neural networks to compensate for altered nicotinic input. Biochem Pharmacol. 2015 Oct 15; 97 (4):418-424. doi: 10.1016/j.bcp.2015.07.020. Epub 2015 Jul 20.</span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">Jones S, Yakel JL. 1997. Functional nicotinic ACh receptors on interneurones in the rat hippocampus. J Physiol. 504:603—610.</span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:black">Lucas-Meunier E, Monier C, Amar M, Baux G, Fregnac Y, Fossier P. Involvement of nicotinic and muscarinic receptors in the endogenous cholinergic modulation of the balance between excitation and inhibition in the young rat visual cortex. <em>Cereb Cortex. </em>2009 doi:10.1093/cercor/bhn258.</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#3e3d40">Martos, Y. V., Braz, B. Y., Beccaria, J. P., Murer, M. G., and Belforte, J. E. (2017). Compulsive social behavior emerges after selective ablation of striatal cholinergic interneurons. </span></span></span><em>J. Neurosci.</em> 37, 2849–2858. doi: 10.1523/jneurosci.3460-16.2017</span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. </span></span></span></span><em>Neuron</em>. 2012; 76(1):116-129. doi:10.1016/j.neuron.2012.08.036.</span></span></p>
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<p style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="color:#212121">Sherriff FE, Henderson Z. A cholinergic propriospinal innervation of the rat spinal cord. Brain Res. 1994 Jan 14; 634(1):150-4. doi: 10.1016/0006-8993(94)90268-2. PMID: 8156385.</span></span></span></span></span></span></p>
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2021-06-24T18:34:382021-09-01T18:27:26Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive functionOrgano-Phosphate Chemicals leading to impaired cognitive function<p>Saroj Kumar Amar and Kurt A. Gust*</p>
<p><span style="font-size:11pt"><span style="font-family:"Times New Roman",serif">U.S. Army Engineer Research and Development Center, Environmental Laboratory, 3909 Halls Ferry Road, Vicksburg, Mississippi 39180</span></span><br />
<span style="font-size:11pt"><span style="font-family:"Times New Roman",serif">Sarojkumaramar@gmail.com, Saroj.K.Amar@erdc.dren.mil<br />
*Corresponding Author: Kurt.A.Gust@usace.army.mil</span></span></p>
Under development: Not open for comment. Do not cite<p>Organophosphate compounds (OP) are extensively used as pesticides/insecticides including paraoxon, ethyl-parathion, methyl-parathion, but have also been developed as warfare nerve agents such as soman, sarin, tabun and others. OP-induced cognitive deficits were observe not only among farm worker but also among environmentally exposed individual (Corral SA et al., 2017). The present adverse outcome pathways (AOP) describes the risk associated with a molecular initiating event (MIE) characteristic of OP exposure in which inhibition of acetylcholinesterase (AChE) activity causes a series of key events (KEs) that ultimately manifest as the adverse outcome (AO) of cognitive defects. The MIE of inhibited AChE triggers the KEs: accumulation of synaptic AChE (KE 1), increase of cholinergic signaling (KE 2), decrease of neuronal network function (KE 3), and decrease of cognitive function as an adverse outcome. The content of this AOP draws upon content from other AOPs in the AOPwiki page and has expanded interpretation in the interconnected network of AOPs linking the MIE of AChE inhibition to other AOs, including acute mortality. The common threads between this and the other AOPs include common KEs of acetylcholine (ACh) accumulation at the synapses (KE 1), which results in (KE 2) excessive signaling from cholinergic neurons on a broad range of tissues throughout the body. The MIE is engaged when OP binds to AChE causing an irreversible phosphorylation status of the enzyme. AChE is an enzyme responsible for controlling the level of the excitatory neurotransmitter, ACh, at neural synapses and neuromuscular junctions. AChE negatively regulates ACh via hydrolysis to acetic acid and choline (Wilson 2010). Inhibition of AChE (MIE) prevents degradation of ACh, which leads to (KE1) ACh accumulation at neural synapses and neuromuscular junctions in the central and peripheral nervous systems. (<a href="https://aopwiki.org/aops/16">https://aopwiki.org/aops/16</a>, <a href="https://aopwiki.org/aops/312">https://aopwiki.org/aops/312</a>, Soreq and Seidman, 2001; Lushington 2006, Prado, 2017). ACh is generated in presynaptic neurons and released into the synaptic cleft where it can bind to both pre- and postsynaptic receptors. ACh availability is decreased when this neurotransmitter is degraded by AChE and by negative feedback loops controlled by muscarinic M2 receptors on the presynaptic neuron within the synapse (Soreq and Seidman, 2001). Affinity of ACh for metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs), as well as rates of synaptic clearance (mediated through AChE activity) and local concentration of ACh in and outside the synapse, is critical for the control and specificity of cholinergic signaling (KE 2) (Sarter M et al., 2009, Picciotto MR, et al., 2012). Excessive accumulation of ACh at neural synapses (KE 1) and at neural-muscular junctions results in increased cholinergic signaling (KE 2) (AOP 16, https://aopwiki.org/aops/16). Endogenously released ACh regulates cognitive functions (AO), by acting as a neuromodulator and/or acting as a direct transmitter via nicotinic and muscarinic receptors in CNS by cholinergic signaling (KE 2) (Luchicchi A et al., 2014), which is evidence of direct relationship between KE2 and AO. The ability of a neuron to communicate is based on neural network formation (KE 3) that relies on functional synapse establishment by cholinergic neurons (KE 2) (Colón-Ramos, 2009) this is evidence that KE 2 leads to KE3. Muscarinic cholinergic activity influences sensory processing by facilitating or depressing neuronal responses to specific stimuli, and by modulating connection strength and neural synchronization: this results in the fine-tuning of cellular and network properties of neurons during developmental processes, the execution of attention tasks and perceptual learning (Colangelo C et al., 2019, Groleau et al., 2015). Damage or destruction of neurons during development when they are in the process of synapse formation, integration, and formation of neural networks, disrupts the organization and function of these networks (KE3), thereby setting the stage for subsequent impairment of learning and memory as sign of cognitive defects (AO), thus evident that KE 3 leads to AO. (AOP 13, https://aopwiki.org/aops/13). Therefore, if exposure to OP occurs during neuronal differentiation and synaptogenesis processes, there is potential to initiate KE3, functional neuronal network damage, leading to the cognitive defects AO. Thus, this AOP provides a needed link to between chronic AChE inhibition and detrimental long-term impacts on cognitive function, which is relevant for understanding the impacts of long-term environmental and occupational OP pesticide exposures.</p>
<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>
<p>A prime example of impairments in cognitive function as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). In addition, testing for the impact of chemical expsoures on cognitive function, often including spatially-mediated behaviors, is an intergral part of both EPA and OECD developmental neurotoxicity guidelines (USEPA, 1998; OECD, 2007).</p>
adjacentModerateHighadjacentLowHighadjacentModerateModeratenon-adjacentModerateModeratenon-adjacentModerateModerate<ul>
<li>MIE: <strong>Inhibition, AChE</strong>: AChE is a serine hydrolase that terminates the action of the neurotransmitter ACh by hydrolyzing it into acetic acid and choline. (McHardy SF et al., 2017) The AChE inhibitors (pesticides) bind to the enzyme and interfere with the breakdown of ACh, leading to the deposition of ACh (KE1) in the nerve synapses and causing disrupted neurotransmission (Thapa S et al.,2017, <a href="https://aopwiki.org/aops/16">https://aopwiki.org/aops/16</a>, <a href="https://aopwiki.org/aops/312">https://aopwiki.org/aops/312</a>). Previous studies with vertebrate and invertebrate validate the dependence of AChE activity to the dose of OP and increasing inhibition of AChE in dose dependent manner with OP as reported in fish, birds, nematodes, rodents and mollusk (https://aopwiki.org/events/12).</li>
<li>Key Event 1: <strong>Accumulation, synaptic ACh:</strong> ACh is stored in nerve endings at cholinergic synapses in the central and peripheral nervous systems (Soreq and Seidman, 2001; Lushington 2006). OP anticholinesterases potentially have a mechanism of toxicity in common, that is, phosphorylation of AChE causing accumulation of ACh (KE 1), overstimulation of cholinergic receptors, and consequent clinical signs of cholinergic toxicity. However, some OP pesticides appear capable of altering noncholinergic neurochemical processes. These additional actions may contribute to qualitative and quantitative differences in toxicity sometimes noted in the presence of similar levels of AChE inhibition induced by different OP pesticides (Pope CN., 1999). Epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides and neurological deficits that range from cognitive impairments to tremors in childhood (Burke RD et al., 2017). Excessive accumulation of ACh at neural synapses (KE 1) and at neural-muscular junctions results in increased cholinergic signaling (KE 2) (AOP 16, <a href="https://aopwiki.org/aops/16,AOP">https://aopwiki.org/aops/16,AOP</a> 312 <a href="https://aopwiki.org/aops/312">https://aopwiki.org/aops/312</a>).</li>
<li>Key Event 2: <strong>Increase, Cholinergic signaling</strong>: Acetylcholine is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to. ACh facilitates central and peripheral functions as well as somatic and autonomic functions. Excessive accumulation of acetylcholine at neural synapses and at neural-muscular junctions results in increased cholinergic signaling (https://aopwiki.org/relationships/456). The complexity of CNS cholinergic circuits and signaling mechanisms produces a system in which origins and end results may be easier to conclude than intervening intermediate steps. It is well reported that ACh, releases from the cholinergic inputs of the basal forebrain and striatal and from pontomesencephalic (PM) areas is supporting neurocognitive and motivational functions (Cragg, 2006; Sarter et al., 2005). Endogenously released ACh regulates cognitive functions (AO), by acting as a neuromodulator or acting as a direct transmitter via nicotinic and muscarinic receptors in CNS by cholinergic signaling (KE 2) (Luchicchi A et al., 2014), which is evidence of direct relationship between KE2 and AO. The capability of a neuron to communicate is centered on neural network formation (KE 3) that depend on functional synapse formation through cholinergic neurons (KE 2) (Colón-Ramos, 2009) this is evidence that KE 2 leads to KE3. The capacity of a neuron to communicate is dependent to neural network formation (KE 3) that depend on functional synapse formation by cholinergic neurons (KE 2) (Colón-Ramos, 2009) this is evidence that KE 2 leads to KE3.</li>
<li>Key Event 3 <strong>Decrease, neuronal network function</strong>: Exposure to the potential developmental toxicants and OP during neuronal differentiation and synaptogenesis will increase the risk of functional neuronal network damage (KE3) leading to cognitive defects (AO), (<a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/13</a>). Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to (AO) deficits in cognitive function (AOP 13, <a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/13</a>). Damage or destruction of neurons during development when they are in the process of synapse formation, integration, and formation of neural networks, disrupts the organization and function of these networks (KE3), thereby setting the stage for subsequent impairment of learning and memory as sign of cognitive defects (AO), thus evident that KE 3 leads to AO. (AOP 13, https://aopwiki.org/aops/13) Neuronal network formation and function are established via the process of synaptogenesis. The initial period of synaptogenesis is important for the formation of the basic circuitry of the nervous system, though neurons can form new synapses throughout life (Rodier, 1995). Proper neuronal communication is dependent to brain electrical activity and synapse formation. The main roles of synapses are responsible for the regulation of intercellular communication in nervous system as well as the information flow among neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed (Colón-Ramos, 2009). So, the decreased synapse formation during the process of synaptogenesis is vital and resulting to the decrease of neural network formation.</li>
</ul>
ModerateFemaleHighMaleHighNursing ChildModerateAdultsModerateAll life stagesModerateHighHigh<p>Acute and chronic exposure to organophosphate, act by inhibiting cholinesterases which is widely associated with cognitive and motor impairments that can be observed even several months post-intoxication (Roldán-Tapia et al., 2006). Previous studies reported that the cognitive deficits were frequently observed not only in agricultural workers that directly manipulate pesticides but also individuals indirectly exposed during environmental applications (Corral SA et al., 2017). The multifactorial nature of pesticide-related cognitive impairment is consistent with experimental results showing distinct roles for pesticide exposure, duration of exposure and age of exposed individuals. The extent to which each of the aforementioned factors contributes to cognitive deficits remains under-explored (Aloizou AM et al., 2020). AChE inhibition is initiated by electrostatic interaction at the anionic site of the enzyme and binding with the serine hydroxyl radicals at the esteratic site of AChE (Wilson 2010; Fukuto 1990). This irreversible binding between AChE and OP pesticides is due to phosphorylation of enzyme. ACh is crucial for a number of important task including normal function of CNS, learning and memory, cognitive function as well as emotional and behavioral functions (Kilgard and Merzenich, 1998), reward (Leslie et al., 2013) and attention (Klinkenberg et al., 2011; Picciotto et al., 2012). This AChE inhibition (MIE) leads directly to the KE1 where ACh has unmitigated accumulation in neuronal synapses. This KER is directly supported the given observations demonstrating that AChE catalyzes degradation of ACh into choline and acetate (Wilson 2010). For goal-directed behavior, an appropriate levels of ACh are require to stimulate relevant sensory information (Sarter et al., 2009). An increase in cholinergic tone (KE 2) appears to be sufficient to induce depression-like symptoms in humans (Piccioto et al., 2012) and increasing ACh levels (KE 1) increases symptoms of depression (Overstreet, 1993). ACh can induce heterogeneous effects in different brain areas that appear to have opposite behavioral consequences depending on the specific anatomical location (Piccioto et al., 2012). Regardless, the predominant response of excessive accumulation of ACh at neural synapses (KE 1) and at neural-muscular junctions results in increased cholinergic signaling (KE 2) (AOP 16, https://aopwiki.org/aops/16).<br />
The ability of Ach (KE1) to induce synaptic plasticity through actions on pre- and post-synaptic nAChRs and mAChRs is likely to modulate learning and memory – symptoms of cognitive defects (AO), including memory of stressful events (Piccioto et al., 2012, Nijholt et al., 2004), and a role for ACh in regulation of hippocampal excitability (responsible for cognitive task) through presynaptic release of glutamate and GABA has also been well-characterized (Alkondon et al., 1997). It is clear that ACh (KE1), released from the cholinergic inputs (KE 2) of the basal forebrain, striatal, and the pontomesencephalic (PM) areas, plays an important role in supporting neurocognitive (AO) and motivational functions of the prefrontal cortical, hippocampal, and ventral tegmental projections to the striatum (Berman JA et al., 2007, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377023/#R27">Cragg, 2006</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377023/#R119">Sarter <em>et al</em>., 2005</a>; Wonnacott <em>et al</em>., 2005). The integrated-information processing and communication role of neurons is dependent to neural network formation (KE 3) that count on functional synapse formation by cholinergic neurons (KE 2) (Colón-Ramos, 2009) which is influential in KE 2 leading to KE3. Still, the most difficult remaining gap for neuroscientific investigation of OP effects center on connecting the impacts on neuronal network function (KE3) to (AO) cognition, including learning and memory. It is unknown which alterations in neuronal circuits are essential to change motor behavior as per learning and memory test record (Mayford et al., 2012), meaning that there is no clear understanding about how this KE and AO are connected (AOP 13, https://aopwiki.org/aops/13). It’s difficult to establish the relationship between alteration of neural network function and cognitive deficits due to complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have been made across simple monosynaptic connections and largely focused on the hippocampus (AOP 13, https://aopwiki.org/aops/13). There is very limited information on the degree of quantitative change in neural network function (KE 3) required to alter cognitive behaviors (AO). This is a result of the diversity of methods for measuring both neuronal network function and learning and memory deficits, which hamper cross-study analysis (AOP 13, https://aopwiki.org/aops/13). In humans, the hippocampus is involved in recollection of an event’s rich spatial-temporal contexts and distinguished from simple semantic memory, which is memory of a list of facts (<a href="https://aopwiki.org/events/402">https://aopwiki.org/events/402</a>, Burgess et al., 2002).</p>
<p><span style="font-size:12.0pt"><span style="font-family:Cambria,serif"><em><span style="font-family:"Times New Roman",serif"><span style="color:#262626">Life Stage Applicability</span></span></em></span></span></p>
<p><span style="font-size:12.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">The key molecular target is the AChE enzyme, which appears to be available in all life stages of different species </span></span></span></span><em><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#262626"><u><span style="color:teal"><ins>(https://aopwiki.org/aops/16)</ins></span></u></span></span></span></em><span style="font-size:12.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">.</span></span></span></span></p>
<p> </p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Life Stage </span></span></span></span></p>
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<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:283px">
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Evidence</span></span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif">Child</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif">High</span></span></span></p>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif">Adult</span></span></span></p>
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<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:283px">
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif">Moderate</span></span></span></p>
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<p><span style="font-size:12.0pt"><span style="font-family:Cambria,serif"><em><span style="font-family:"Times New Roman",serif"><span style="color:#262626">Taxonomic Applicability</span></span></em></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">Though AChE enzyme can be traced in all vertebrate and invertebrate but the activity among taxa differs </span></span></span></span></span><em><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#262626"><u><span style="color:teal"><ins>(https://aopwiki.org/aops/16)</ins></span></u></span></span></span></em></p>
<p><span style="font-size:12.0pt"><span style="font-family:Cambria,serif"><em><span style="font-family:"Times New Roman",serif"><span style="color:#262626">Sex Applicability</span></span></em></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif"><span style="color:#262626">Study with 44 children for scanning the OP pesticide exposure risk witnessed differences for sex of the child, with male levels higher than female levels (Loewenherz C et al., 1997).</span></span></span></span></p>
<ul>
<li>MIE: <strong>Inhibition, AChE</strong>: AChE is a serine hydrolase that terminates the action of the neurotransmitter ACh by hydrolyzing it into acetic acid and choline. (McHardy SF et al., 2017) The AChE inhibitors (pesticides) bind to the enzyme and interfere with the breakdown of ACh, leading to the deposition of ACh (KE1) in the nerve synapses and causing disrupted neurotransmission (Thapa S et al.,2017, <a href="https://aopwiki.org/aops/16">https://aopwiki.org/aops/16</a>, <a href="https://aopwiki.org/aops/312">https://aopwiki.org/aops/312</a>). Previous studies with vertebrate and invertebrate validate the dependence of AChE activity to the dose of OP and increasing inhibition of AChE in dose dependent manner with OP as reported in fish, birds, nematodes, rodents and mollusk (https://aopwiki.org/events/12).</li>
<li>Key Event 1: <strong>Accumulation, synaptic ACh:</strong> ACh is stored in nerve endings at cholinergic synapses in the central and peripheral nervous systems (Soreq and Seidman, 2001; Lushington 2006). OP anticholinesterases potentially have a mechanism of toxicity in common, that is, phosphorylation of AChE causing accumulation of ACh (KE 1), overstimulation of cholinergic receptors, and consequent clinical signs of cholinergic toxicity. However, some OP pesticides appear capable of altering noncholinergic neurochemical processes. These additional actions may contribute to qualitative and quantitative differences in toxicity sometimes noted in the presence of similar levels of AChE inhibition induced by different OP pesticides (Pope CN., 1999). Epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides and neurological deficits that range from cognitive impairments to tremors in childhood (Burke RD et al., 2017). Excessive accumulation of ACh at neural synapses (KE 1) and at neural-muscular junctions results in increased cholinergic signaling (KE 2) (AOP 16, <a href="https://aopwiki.org/aops/16,AOP">https://aopwiki.org/aops/16,AOP</a> 312 <a href="https://aopwiki.org/aops/312">https://aopwiki.org/aops/312</a>).</li>
<li>Key Event 2: <strong>Increase, Cholinergic signaling</strong>: Acetylcholine is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to. ACh facilitates central and peripheral functions as well as somatic and autonomic functions. Excessive accumulation of acetylcholine at neural synapses and at neural-muscular junctions results in increased cholinergic signaling (https://aopwiki.org/relationships/456). The complexity of CNS cholinergic circuits and signaling mechanisms produces a system in which origins and end results may be easier to conclude than intervening intermediate steps. It is well reported that ACh, releases from the cholinergic inputs of the basal forebrain and striatal and from pontomesencephalic (PM) areas is supporting neurocognitive and motivational functions (Cragg, 2006; Sarter et al., 2005). Endogenously released ACh regulates cognitive functions (AO), by acting as a neuromodulator or acting as a direct transmitter via nicotinic and muscarinic receptors in CNS by cholinergic signaling (KE 2) (Luchicchi A et al., 2014), which is evidence of direct relationship between KE2 and AO. The capability of a neuron to communicate is centered on neural network formation (KE 3) that depend on functional synapse formation through cholinergic neurons (KE 2) (Colón-Ramos, 2009) this is evidence that KE 2 leads to KE3. The capacity of a neuron to communicate is dependent to neural network formation (KE 3) that depend on functional synapse formation by cholinergic neurons (KE 2) (Colón-Ramos, 2009) this is evidence that KE 2 leads to KE3.</li>
<li>Key Event 3 <strong>Decrease, neuronal network function</strong>: Exposure to the potential developmental toxicants and OP during neuronal differentiation and synaptogenesis will increase the risk of functional neuronal network damage (KE3) leading to cognitive defects (AO), (<a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/13</a>). Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to (AO) deficits in cognitive function (AOP 13, <a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/13</a>). Damage or destruction of neurons during development when they are in the process of synapse formation, integration, and formation of neural networks, disrupts the organization and function of these networks (KE3), thereby setting the stage for subsequent impairment of learning and memory as sign of cognitive defects (AO), thus evident that KE 3 leads to AO. (AOP 13, https://aopwiki.org/aops/13) Neuronal network formation and function are established via the process of synaptogenesis. The initial period of synaptogenesis is important for the formation of the basic circuitry of the nervous system, though neurons can form new synapses throughout life (Rodier, 1995). Proper neuronal communication is dependent to brain electrical activity and synapse formation. The main roles of synapses are responsible for the regulation of intercellular communication in nervous system as well as the information flow among neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed (Colón-Ramos, 2009). So, the decreased synapse formation during the process of synaptogenesis is vital and resulting to the decrease of neural network formation.</li>
</ul>
<ul>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">The overall weight of evidence supporting the indirect relationship between AChE inhibition and cognitive defects is very strong and there are many physiological activities associated with ACh neurotransmission that are plausibly linked with organism survival.</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Based on the current information assembled for this AOP, the essentiality of the key events downstream of ACh accumulation is less clear. While there are several key events that correspond with </span></span><span style="font-family:"Times New Roman",serif">well-known</span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"> symptoms of AChE inhibition, it is presently unclear which of these </span></span><span style="font-family:"Times New Roman",serif">the major driver of cognitive defects are</span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"> across different species. Given the abundance of literature on ACh signaling and adverse effects associated with AChE inhibition, this is an area of the AOP that warrants further development.</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Biological Plausibility</span></span></strong></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">ACh is a critical neurotransmitter localized to neuronal synapses. Biological plausibility to support the relationship between AChE inhibition and accumulation of ACh is rooted in evidence demonstrating that AChE catalyzes degradation of ACh into choline and acetate. Therefore, inhibition of the AChE leads to ACh accumulation.</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Biological plausibility for ACh accumulation at the synapse leading to nervous system dysfunction is rooted in the well-established understanding of ACh’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 ACh at neurological synapses will lead to systemic dysfunctions, which are often freely evident and assessable in clinical and research settings.</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">Neuronal network formation and function are established via the process of synaptogenesis. The initial period of synaptogenesis is vital for the formation of the elementary circuitry of the nervous system, while neurons can form new synapses throughout their life (Rodier, 1995). The brain electrical activity dependence on synapse formation is critical for proper neuronal communication (https://aopwiki.org/wiki/index.php/Relationship:358).</span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Learning-induced enhancement in neuronal excitability, a measurement of neural network function, has also been shown in hippocampal neurons following classical conditioning in several e</span></span><span style="font-family:"Times New Roman",serif">xperimental approaches (</span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Saar and Barkai, 2003).</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Previous study with Morris water maze (MWM) test to investigate spatial learning and memory in laboratory rats also indicated that the interruption between neuronal networks rather than the brain damage of certain regions is accountable for the impairment of MWM presentation. Functional integrated neural networks that involve the coordination action of different brain regions are consequently important for spatial learning and MWM performance (<a href="https://aopwiki.org/wiki/index.php/Relationship:359" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/wiki/index.php/Relationship:359</a>, D'Hooge and De Deyn, 2001).</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Concordance of dose-response relationships:</span></span></strong></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">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) (<a href="https://aopwiki.org/relationships/11" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/11</a>, Ray, 2009). In that study, ACh 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 association among AChE inhibition and ACh accumulation at the synapse can be detected within 30 minutes after application of AChE inhibitor (Ray, 2009).</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">The main proof of evidence comes from <em>in vivo</em> studies in rodents. Though, Colón-Ramos (2009) has recently showed that the initial developmental events that during the course of synaptogenesis in invertebrates, indicating the significance of this process in neural network formation and function. </span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity (Johnston et al., 2009). Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine-tuning of synaptic connectivity (Johnston et al., 2009). </span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Temporal concordance among the key events and adverse effect:</span></span></strong></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Strong evidence based on measured AChE inhibition and statistically derived acute endpoints (e.g., LC/LD50) demonstrate a correlation of increase in enzyme inhibition and decrease cognitive function. </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">The literature includes many studies linking increases in ACh in brain tissues after exposure to an OP or carbamate pesticide with increased AChE inhibition in various taxa. As previous 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) revealed. </span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">ACh is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to (Picciotto, 2012). ACh mediates central and peripheral functions, including somatic and autonomic functions (Picciotto, 2012). Excessive accumulation of ACh at neural synapses and at neural-muscular junctions results in increased cholinergic signaling. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of AChE, the enzyme that hydrolyzes the neurotransmitter ACh (Burke RD et al., 2017).</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">ACh is considered to be the most important neurotransmitter involved in the regulation of cognitive functions. Once releasing from the presynaptic neuron, ACh accumulated into the synaptic cleft, followed by binding to the ACh receptors on the postsynaptic membrane, and the signal from the nerve was transmitted during the process (Schliebs R and Arendt T, 2011, Gold P. E., 2003, </span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#212121">Wang XC, 2018</span></span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">). Study showed the cholinergic overstimulation once pigs exposed to dichlorvos (the AChE inhibitor), symptoms may include miosis, cyanosis, tremor, excess secretions and fasciculations. Estimation of AChE levels established that dichlorvos treatment inhibited AChE activity. (Cui, 2013).</span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">There is strong empirical evidence linking the key events, beginning with the molecular initiating event; AChE inhibition, followed by an increase in the ACh at synapses of muscarinic and nicotinic receptors, and subsequent physiological and biochemical response resulting in cholinergic activity (<a href="https://aopwiki.org/aops/16" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/16</a>) , </span></span><span style="font-size:12.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">Picciotto MR </span></span></span></span><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">et al</span></span></span><span style="font-size:12.0pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="color:#303030">, 2012</span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">. </span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Consistency:</span></span></strong></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(<a href="https://aopwiki.org/relationships/11" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/11</a>) Previous study showed female ICR (Institute of Cancer Research) mice exposed to either fenobucarb or propoxur, reported a major increase in ACh in brain tissue 10 minutes after injection, simultaneously major elevation in AChE inhibition (Kobayashi et al., 1985). Sub lethal exposure to methyl parathion conclude that AChE levels in brain tissue in fish (Oreochromis mossambicus) were highly inhibited during 12-48 hrs</span></span><span style="font-family:"Times New Roman",serif">,</span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"> with inhibition increasing from 36-62% as in comparison to controls over the time elapse (Rao and Rao, 1984). The researchers found a significant increase in ACh</span></span><span style="font-family:"Times New Roman",serif"> at all-time</span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"> courses measured (12-48hr) with ACh levels increasing from 33-83% as compared to controls over the same time span (Rao and Rao, 1984). 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 ACh, and major inhibition of AChE in-comparison to controls (Kobayashi et al., 1983). Measurements (in vitro) of AChE inhibition, ACh 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 ACh, and a decrease in the electrophysiological response (Oyama et al., 1989). Wister rats injected with a sublethal concentration of dichlorvos found a significant decrease in AChE activity, increased ACh concentrations, and enhanced contractile responses in jejunum muscle. At sublethal concentrations (56% of the LD50), researchers found a significant (18%) increase in the amount of ACh in brain tissue of Charles River rats exposed to disulfoton for 3 days and resulted in AChE inhibition of 68% with respect to controls (Stavinoha et al., 1969). 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 ACh, and significant influences to motor activity (Karanth et al., 2006). Tadpoles of 20 days were treated with single sub</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">lethal</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">dose of the methyl parathion for 24 hrs and analysis of brain tissue found a significant inhibition in AChE activity and a concurrent increase in ACh levels, as compared to controls (<a href="https://aopwiki.org/relationships/11" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/11</a>, Nayeemunnisa and Yasmeen 1986). Study of fourth instar Ailanthus silkworm exposed to malathion for 5 days found increased mortality, decreased AChE, and increases in ACh as compared to controls (Pant and Katiyar 1983).</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">The relationship between excess ACh at synapses and nervous system dysfunction has been reviewed in Molecular Cell Biology, 4th Edition (<a href="https://aopwiki.org/relationships/456" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/456</a>, Lodish, 2000). ACh is a neurotransmitter in most vertebrate and invertebrate species, but the mechanism of activity may differ. For example in insects, ACh acts as a neurotransmitter between sensory neurons and the central nervous system but glutamate acts as a neurotransmitter between motor neurons and skeletal muscles (<a href="https://aopwiki.org/relationships/456" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/456</a>, Stenersen, 2004). 8-14 weeks old male quail were exposed to a single dose of either dichlorvos or fenitrothion by subcutaneous injection and brain tissue showed an 80% reduction of AChE, and a simultaneous major increase in ACh as compared to controls. With maximum doses, mortality was headed by symptoms including vigorous tremors, lacrimation, salivation, ataxia, and respiratory distress (Kobayashi, 1985). Previous study with male and female starlings of three age groups (5 days to >1 year) showed that the LD50 for nestlings was around half of the LD50 for adult birds exposed to dicrotophos. Simultaneously all birds exposed, showing impaired coordination and tremors. AChE inhibition increased in dose dependent manner for all three-age groups. There is no sex differences in LC50 or AChE inhibition were reported (Grue and Shipley, 1984). Asian stinging catfish (Heteropneustes fossilis) exposed for 40 days to sublethal concentrations of oxydemeton-methyl, had a >71% inhibition of AChe in the brain and a concurrent increase of ACh in brain (>200%) and muscles (>188%), with fish displaying violent body movements (tremors) followed by loss of equilibrium (Verma 1981). </span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:10pt"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-size:12.0pt"><span style="color:#333333">Single injection of methylmercury (8 mg/kg by gavage) at gestational day 15. Offsprings examined at the age of 14, 21, and 60 days showed a reduction in the number of muscarinic receptors at 14 and 21 days and a decline in avoidance latency at 60 days, demonstrating learning and memory deficits (<strong>Zanoli et al., 1994), </strong>(<a href="https://aopwiki.org/relationships/359" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/relationships/359</a>, <strong>Rice, 1992)</strong>.</span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Uncertainties, inconsistencies, and data gaps:</span></span></strong></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">No known qualitative inconsistencies or uncertainties associated </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">between AChE inhibition and ACh accumulation at the synapse as well as ACh accumulation at the synapse to cholinergic signaling.</span></span></span></span></span></span></li>
<li style="text-align:justify"><span style="font-size:11pt"><span style="background-color:white"><span style="color:#333333"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">The exact mechanism by which a change in cell number, reduced dendritric arborization and synaptogenesis may lead to decreased neuronal network function has not been fully elucidated. </span></span></span></span></span></span></li>
</ul>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">The direct relationship of alterations in neural network function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memo</span></span></span><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:#333333">ry processes have</span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333"> been made across simple monosynaptic connections and largely focused on the hippocampus. Changes in synaptic function have been noticed even in the lack of any behavioral losses. (https://aopwiki.org/relationships/359).</span></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Exposure to organophosphate (OP) pesticides, which inhibit acetylcholinesterase, increases the risk of neurological disorders (Voorhees, J.R. et al., 2019). Recent study suggested that organophosphate pesticides may cause cognitive impairment. Mild cognitive impairment are dominating with symptoms like decreased attention or vigilance, narrowed information processing speed and memory impairment (Zhang HY et al., 2021). Mild cognitive impairment is largely being ignored for a long periods of time. Though, it might have huge impact on patients' life and work, and even progress to irreversible neurodegenerative disorder (Zhang HY et al., 2021). On cognitive tasks of learning and memory, male TgF344-AD rats displayed chlorpyrifos- an OP pesticide dependent deficits that were not seen in WT males or females of either genotype (Voorhees, J.R. et al., 2019). Previous study suggested that lower cognitive performances with huge decline in performances in vine workers is linked with pesticides exposure (Audrey Blanc-Lapierre et al., 2013). Thus this AOP attempt to establish the quantitative relationship between organophosphate pesticides and cognitive defects. Understanding the underlying mechanisms, this AOP can provide new means to avoid or neutralize the pesticide exposure risk. The stepwise relationships between consecutive key events is as follow. Existing key event relationship number 11, define </span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">inhibition of acetylcholinesterase (MIE) leads to synaptic accumulation of acetylcholine (KE1). Simultaneously key event relationship number 456 explained synaptic accumulation of acetylcholine (KE1) increases cholinergic signaling (KE2). Although the exact mechanism for increase cholinergic signaling </span></span><span style="font-size:12.0pt"><span style="font-family:"Cambria",serif">lead to decreased neuronal network function (KE 3) has not been fully elucidated. But it’s well-known that the ability of a neuron to communicate is based on neural network formation that relies on functional synapse establishment by cholinergic neuron (Colón-Ramos, 2009). </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">The direct relationship of alterations in neural network function (KE 3) and specific cognitive deficits (AO) is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit (</span></span></span><span style="font-size:12.0pt"><span style="font-family:"Cambria",serif"><span style="color:#333333"><a href="https://aopwiki.org/relationships/359" style="color:blue; text-decoration:underline">https://aopwiki.org/relationships/359</a></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#333333">).</span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"> Though the AOP 13 advocate that, <span style="color:black">damage of neurons during development when they are in the process of formation of neural networks (KE3), setting the stage for subsequent impairment of learning and memory as sign of cognitive defects (AO). Thus above evidence supporting the development of this AOP.</span></span></span></p>
<p><span style="font-size:12.0pt"><span style="background-color:white"><span style="font-family:"Segoe UI",sans-serif"><span style="color:#212529">Although the present AOP may require supplementary conditions to fully establish the neurotoxicity potential of OP pesticide and their mode of action. This AOP is an attempt to establish the mechanism of organophosphorus (OP) pesticides induced cognitive defects via cholinergic signaling. It can also be applied to risk assessment in predictive modeling of OP pesticide toxicity.</span></span></span></span></p>
HighHighModerateModerateModerate<p style="margin-left:24px; text-align:justify"><span style="font-size:12pt"><span style="font-family:Cambria,serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Agency for Toxic Substances and Disease Registry (ATSDR). 2001. Toxicological profile for methyl parathion. Update. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.</span></span></span></span></p>
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