FMA:61796Nicotinic acetylcholine receptorCHEBI:39124calcium ionPR:000004978calmodulinGO:0015464acetylcholine receptor activityGO:0007612learningGO:0007613memoryD056631colony collapseGO:0060756foraging behaviorGO:0030549acetylcholine receptor activator activityGO:0030545receptor regulator activityGO:0005488bindingGO:0023052signalingGO:0005516calmodulin binding1increased2decreased4abnormal2-Imidazolidinimine, 1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-, (2E)-2016-11-29T18:42:272016-11-29T18:42:27WCS_9606human10116ratWCS_7227fruit flyWCS_7955zebrafishWCS_160004gastropods10090mouseWikiUser_2Honey beeActivation, Nicotinic acetylcholine receptorActivation, Nicotinic acetylcholine receptorMolecular<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"Nicotinic acetylcholine receptors belong to the<br />
cys-loop superfamily of ligand-gated ion channels, responsible for<br />
rapid neurotransmission (Karlin, 2002). In insects nAChR have signaling<br />
roles in nervous systems and neuromuscular junctions and other cells<br />
(Jones and Sattelle, 2010; Lindstrom, 2003). Under normal conditions<br />
the endogenous neurotransmitter, acetylcholine (ACh), attaches to the<br />
ligand binding domains on the extracellular region of the pentameric<br />
nAChR. This initiates a conformation change that promotes the influx<br />
and efflux of calcium (Ca2+) and extracellular sodium and intracellular<br />
potassiumions, respectively, to create the action potential necessary for<br />
synaptic signaling (Jones and Sattelle, 2010). Activation of the nAChR,<br />
by natural or synthetic agonists, and subsequent involvement in neurotransmission<br />
is well established. Although the nAChR is conserved<br />
across vertebrates and invertebrates, the diverse composition and assembly<br />
of α-(containing two adjacent cysteine residues important in<br />
ACh binding) and non α-(lacking the cysteine residues) subunits confer<br />
diverse functional architecture and, therefore, toxicological responses<br />
(Jones and Sattelle, 2010)."</p>
<p>Text fromTable 2 of LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"• Radiolabeled nAChR agonists, (e.g., [3H] imidacloprid) or nAChR subunit specific antibodies to detect location and subunit<br />
composition of nAChR<br />
• Ligand competition studies evaluating [3H] agonist displacement to determine ligand affinities to the nAChR<br />
• Whole-cell voltage clamp electrophysiological measurements with agonists to measure nAChR activation"</p>
CL:0000540neuron<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Karlin, A., 2002. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev.<br />
Neurosci. 3 (2), 102–114.</p>
<p>Jones, A.K., Sattelle, D.B., 2010. Diversity of insect nicotinic acetylcholine receptor subunits.<br />
Adv. Exp. Med. Biol. 683, 25–43.</p>
<p>Lindstrom, J.M., 2003. Nicotinic acetylcholine receptors of muscles and nerves. Ann. N. Y.<br />
Acad. Sci. 998 (1), 41–52.</p>
<p>Tomizawa,M., Casida, J.E., 2003. Selective toxicity of neonictinoids attributable to specificity<br />
of insect and mammalian nicotinic receptors. Annu. Rev. Entomol. 48, 339–364.</p>
<p>Dani, J.A., Bertrand, D.D., 2007. Nicotinic acetylcholine receptors and nicotinic cholinergic<br />
mechanisms of the central nervous system.Annu. Rev. Pharmacol. Toxicol. 47, 699–729.</p>
<p>Matsuda, K., Kanaoka, S., Akamatsu,M., Sattelle, D.B., 2009. Diverse actions and target-site<br />
selectivity of neonicotinoids: structural insights. Mol. Pharmacol. 76 (1), 1–10.</p>
<p>LaLone, C.A., Villeneuve, D.L., Lyons, D., Helgen, H.W., Robinson, S.L., Swintek, J.A., Saari,<br />
T.W., Ankley, G.T., 2016. Sequence alignment to predict across species susceptibility<br />
(SeqAPASS): a web-based tool for addressing the challenges of cross-species extrapolation<br />
of chemical toxicity. Toxicol. Sci. 153 (2), 228–245.</p>
2016-11-29T18:41:252018-06-07T09:33:27Impairment, Learning and memoryImpairment, Learning and memoryIndividual<p> </p>
<p>Learning can be defined as the process by which new information is acquired to establish knowledge by systematic study or by trial and error (Ono, 2009). Two types of learning are considered in neurobehavioral studies: a) associative learning and b) non-associative learning. Associative learning is based on making associations between different events. In associative learning, a subject learns the relationship among two different stimuli or between the stimulus and the subject’s behaviour. On the other hand, non-associative learning can be defined as an alteration in the behavioural response that occurs over time in response to a single type of stimulus. Habituation and sensitization are some examples of non-associative learning.</p>
<p>The memory formation requires acquisition, retention and retrieval of information in the brain, which is characterised by the non-conscious recall of information (Ono, 2009). There are three main categories of memory, including sensory memory, short-term or working memory (up to a few hours) and long-term memory (up to several days or even much longer).</p>
<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. For example, the hippocampus has been shown to be critical for spatial-temporal memory, visio-spatial memory, verbal and narrative memory, and episodic and autobiographical memory (Burgess et al., 2000; Vorhees and Williams, 2014). However, there is substantial evidence that fundamental learning and memory functions are not mediated by the hippocampus alone but require a network that includes, in addition to the hippocampus, anterior thalamic nuclei, mammillary bodies cortex, cerebellum and basal ganglia (Aggleton and Brown, 1999; Doya, 2000; Mitchell et al., 2002, Toscano and Guilarte, 2005; Gilbert et al., 2006, 2016). Thus, damage to variety of brain structures can potentially lead to impairment of learning and memory. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990).While the prefrontal cortex and frontostriatal neuronal circuits have been identified as the primary sites of higher-order cognition in vertebrates, invertebrates utilize paired mushroom bodies, shown to contain ~300,000 neurons in honey bees (Menzel, 2012; Puig et al., 2014).</p>
<p>For the purposes of this KE (AO), impaired learning and memory is defined as an organism’s inability to establish new associative or non-associative relationships, or sensory, short-term or long-term memories which can be measured using different behavioural tests described below.</p>
<p><strong>In laboratory animals:</strong> 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, <span style="color:#3498db">Hebb-Williams maze</span>, passive avoidance and Spontaneous alternation 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>1) RAM, Barnes, MWM, <span style="color:#3498db">Hebb-Williams maze </span>are examples of spatial tasks, 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). The <span style="color:#3498db">Hebb-Williams maze measures an animal’s problem solving abilities by providing no spatial cues to find the target (Pritchett & Mulder, 2004).</span></p>
<p>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 have seen one of these objects before, but not this one (Cohen and Stackman, 2015).</p>
<p>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>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., 2001).</p>
<p><span style="color:#3498db">5) Operant Responding. Performance on operant responding reflects the cortex’ ability to organize processes (Rabin et al., 2002). </span></p>
<p><strong>In humans:</strong> A variety of standardized learning and memory tests have been developed for human neuropsychological testing, including children (Rohlman et al., 2008). These include episodic autobiographical memory, perceptual motor tests, short and long term memory tests, working memory tasks, word pair recognition memory; object location recognition memory. Some have been incorporated in general tests of intelligence (IQ) such as the Wechsler Adult Intelligence Scale (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>1) Rey Osterieth Complex Figure test (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006).</p>
<p>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 1994; Talley, 1986).</p>
<p>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>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>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, 2011).</p>
<p>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><span style="color:#3498db">7) Attentional set-shifting (ATSET) task. Measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015).</span></p>
<p>8. Comprehensive developmental inventory for infants and toddlers (CDIIT). The CDIIT was designed and standardized in 1996, and it measures the global, cognitive, language, motor, gross motor, fine motor, social, self-help and behavioral developmental status of children from 3 to 71 months old (Wang et al., 1998).</p>
<p><strong>In Honey Bees:</strong> For over 50 years an assay for evaluating olfactory conditioning of the proboscis extension reflex (PER) has been used as a reliable method for evaluating appetitive learning and memory in honey bees (Guirfa and Sandoz, 2012; LaLone et al., 2017). These experiments pair a conditioned stimulus (e.g., an odor) with an unconditioned stimulus (e.g., sucrose) provided immediately afterward, which elicits the proboscis extension (Menzel, 2012). After conditioning, the odor alone will lead to the conditioned PER. This methodology has aided in the elucidation of five types of olfactory memory phases in honey bee, which include early short-term memory, late short-term memory, mid-term memory, early long-term memory, and late long-term memory (Guirfa and Sandoz, 2012). These phases are dependent on the type of conditioned stimulus, the intensity of the unconditioned stimulus, the number of conditioning trials, and the time between trials. Where formation of short-term memory occurs minutes after conditioning and decays within minutes, memory consolidation or stabilization of a memory trace after initial acquisition leads to mid-term memory, which lasts 1 d and is characterized by activity of the cAMP-dependent PKA (Guirfa and Sandoz, 2012). Multiple conditioning trials increase the duration of the memory after learning and coincide with increased Ca2+-calmodulin-dependent PKC activity (Guirfa and Sandoz, 2012). Early long-term memory, where a conditioned response can be evoked days to weeks after conditioning requires translation of existing mRNA, whereas late long-term memory requires de novo gene transcription and can last for weeks (Guirfa andSandoz, 2012)."</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. Recently, larval zebrafish has also been suggested as a model for the study of learning and memory (Roberts et al., 2013).</p>
<p><span style="color:#3498db"><strong>Life stage applicability: </strong>This key event is applicable to various life stages such as during brain development and maturity (Hladik & Tapio, 2016). </span></p>
<p><span style="color:#3498db"><strong>Sex applicability:</strong> This key event is not sex specific (Cekanaviciute et al., 2018), although sex-dependent cognitive outcomes have been recently ; Parihar et al., 2020). </span></p>
<p><span style="color:#3498db"><strong>Evidence for perturbation by a prototypic stressor: </strong>Current literature provides ample evidence of impaired learning and memory being induced by ionizing radiation (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). </span></p>
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<p>Guirfa, M., Sandoz, J.C., 2012. Invertebrate learning and memory: fifty years of olfactory conditioning of the proboscis extension response in honeybees. Learn. Mem. 19 (2),<br />
54–66.</p>
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<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
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<p> </p>
2016-11-29T18:41:242023-06-26T12:44:45Death/Failure, ColonyDeath/Failure, ColonyPopulation<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"Colony death/failure is defined as demise of a functional colony. Dramatic losses in the number of managed honey bee colonies have been reported across the globe (Potts et al., 2010) and efforts have been undertaken to survey and identify trends in losses over time, particularly in the US and European Union. Most recent survey results collected in the US have shown that managed honey bee colony losses are significantly higher than those deemed acceptable by beekeepers (Seitz et al., 2015). From surveying commercial (>300 colonies), sideline (25–300 colonies), and small scale <25 colonies) beekeepers, average annual colony losses (both<br />
summer and winter losses) per operation in the US during 2014–2015 were 49%, compared to 18.7% that has been identified by beekeepers as an acceptable loss rate (Seitz et al., 2015). Starvation, poor over-winter survival, and weak colonies, were among the most common perceived causes of loss reported by bee keepers (Seitz et al., 2015). Commercial beekeepers, managing thousands of colonies, self-reported colony collapse disorder and pesticides as third and fourth leading reasons for colony loss, respectively (Seitz et al., 2015)."</p>
<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Potts, S.G., Biesmeijer, J.C., Kremen, C., Neumann, P., Schweiger, O., Kunin, W.E., 2010.<br />
Global pollinator declines: trends, impacts and drivers. Trends Ecol. Evol. 25 (6),<br />
345–353.</p>
<p>Seitz, N., Traynor, K.S., Steinhauer, N., Rennich, K., Wilson, M.E., Ellis, D., Rose, R., Tarpy,<br />
D.R., Sagili, R.R., Caron, D.M., Delaplane, K.S., Rangel, J., Lee, K., Baylis, K., Wilkes, J.T.,<br />
Skinner, J.A., Pettis, J.S., vanEngelsdorp, D., 2015. A national survey of managed<br />
honey bee 2014–2015 annual colony losses in the USA. J. Apic. Res. 54 (4), 1–12.</p>
<p> </p>
2016-11-29T18:41:252018-06-07T11:15:11Abnormal, Foraging activity and behaviorAbnormal, Foraging activity and behaviorIndividual<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"As eusocial insects, honey bees rely on theworker bee caste to forage<br />
for nectar, pollen, andwater. Foraged water can be used for evaporative<br />
cooling of the hive during warm weather (as reviewed by Jones and<br />
Oldroyd, 2006). Nectar and pollen collected by the foragers are the<br />
sole food source for the colony, with nectar providing carbohydrates<br />
and pollen providing lipids, protein, vitamins, and essential minerals<br />
(Brodschneider and Crailsheim, 2010). Upon returning to the hive, forager<br />
bees identify non-foraging, food-storing hive bees and deliver their<br />
collection by regurgitating nectar carried back in their honey stomach<br />
(i.e., foregut of proventriculus; Free, 1959). The hive bees place the nectar<br />
in wax cells for processing into honey. Hive bees also aid foragers in<br />
unloading pollen from the pollen baskets (corbicula) on the forager's<br />
hind legs and place it in cells where it is mixed with nectar to form<br />
bee bread, which is stored for consumption by the colony (Winston,<br />
1987). Foragers consume only small amounts of the food they collect.<br />
Hive bees consume the food they receive in order to produce proteinrich<br />
royal jelly and brood food, which they use to nourish both the<br />
queen and the developing brood (Winston, 1987). During winter, the<br />
colony survives on the pollen and nectar that was stored as bee bread<br />
and honey over the spring, summer, and fall seasons (Seeley and<br />
Visscher, 1985).<br />
The act of foraging is a perilous and metabolically challenging task<br />
that is typically carried out by worker bees in the later stages of life<br />
(Woyciechowski and Moroń, 2009). However, the timing of the role<br />
change from hive bee to forager can vary depending on the needs of<br />
the colony. There are environmental, hormonal, and social cues that determine<br />
when and how often foragers search for food and fluid, includingweather,<br />
abundance or scarcity of food resources, magnitude of food<br />
stockpiled in the hive, health of the colony, and size of the brood<br />
(Dreller and Tarpy, 2000). Such cues initiate physiological changes involved<br />
in the transition of a worker bee to foraging, which include<br />
changes to flight muscles andmetabolic rate. These changes accommodate<br />
the reported 70-fold increase in oxygen consumption needed to<br />
sustain physical and cognitive activities of the forager bee (Kammer<br />
and Heinrich, 1978). It has been documented that the volume of<br />
neuropil in mushroom bodies is increased by approximately 15%, and<br />
the somata of the Kenyon cells decreased by approximately 29% in foragers<br />
compared to day-old bees (Withers et al., 1995). Change in lipid<br />
stores also occurs in forager bees prior to foraging, whereby their abdominal<br />
lipid is reduced to approximately half that of nurse bees<br />
(Chang et al., 2015; Toth and Robinson, 2005). Further, there is lowprotein<br />
content in the forager's fat body cells, and vitellogenin (Vtg; egg</p>
<p>yolk) protein production is significantly reduced, while juvenile hormone<br />
levels are significantly increased (Toth and Robinson, 2005). Another<br />
change which occurs at the stage where worker bees become<br />
foragers is that their flight muscle fiber thickness decreases and diameter<br />
of the myofibrils, which contain the contractile filaments, increases<br />
in preparation for prolonged flight during foraging (Correa-Fernandez<br />
and Cruz-Landim, 2010)."</p>
<p>Text from table 2 in LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"• Radio-frequency identification tagging technology to track the frequency and duration of individual foraging events, flight time,<br />
foragers homing ability, duration of time spent at a feeder, and duration between feeding<br />
• Video tracking software for measures of total distance traveled and time spent in social interaction<br />
• Weigh bee-collected pollen from hive entrance trap<br />
• Pollen load can also be assessed by scoring the size of amount of pollen in the forager’s corbiculae (pollen basket) relative to the<br />
size of the worker bee<br />
• Nectar loads from individual forager bees can be measured with a pocket refractometer after inducing regurgitation<br />
• Video foragers returning to hive and measure waggle dance circuits performed<br />
• Food storage can be measured by visual inspection or digital imaging of the combs with the objective to estimate the percent of<br />
cells filled with nectar (uncapped), honey (capped), or pollen"</p>
<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Brodschneider, R., Crailsheim, K., 2010. Nutrition and health in honey bees. Apidologie 41<br />
(3), 278–294.</p>
<p>Jones, J.C., Oldroyd, B.P., 2006. Nest thermoregulation in social insects. Adv. Insect Physiol.<br />
33, 153–191.</p>
<p>Free, J.B., 1959. The transfer of food between the adult members of a honeybee community.<br />
Bee World 40 (8), 193–201.</p>
<p>Winston, M.L., 1987. The Biology of the Honey Bee. Harvard University Press.</p>
<p>Seeley, T.D., Visscher, P.K., 1985. Survival of honeybees in cold climates: the critical timing<br />
of colony growth and reproduction. Ecol. Entomol. 10 (1), 81–88.</p>
<p>Woyciechowski, M., Moroń, D., 2009. Life expectancy and onset of foraging in the honeybee<br />
(Apis mellifera). Insect. Soc. 56 (2), 193–201.</p>
<p>Dreller, C., Tarpy, D.R., 2000. Perception of the pollen need by foragers in a honeybee colony.<br />
Anim. Behav. 59 (1), 91–96.</p>
<p>Kammer, A.E., Heinrich, B., 1978. Insect flight metabolism. Adv. Insect Physiol. 13,<br />
133–228.</p>
<p>Withers, G.S., Fahrbach, S.E., Robinson, G.E., 1995. Effects of experience and juvenile hormone<br />
on the organization of the mushroom bodies of honey bees. J. Neurobiol. 26<br />
(1), 130–144.</p>
<p>Chang, L.H., Barron, A.B., Cheng, K., 2015. Effects of the juvenile hormone analogue<br />
methoprene on rate of behavioural development, foraging performance and navigation<br />
in honey bees (Apis mellifera). J. Exp. Biol. 218 (11), 1715–1724.</p>
<p>Toth, A.L., Robinson, G.E., 2005. Worker nutrition and division of labour in honeybees.<br />
Anim. Behav. 69, 427–435.</p>
<p>Correa-Fernandez, F., Cruz-Landim, C., 2010. Differential flight muscle development in<br />
workers, queens and males of the eusocial bees, Apis mellifera and Scaptotrigona<br />
postica. J. Insect Sci. 10, 85.</p>
2016-11-29T18:41:252018-06-07T10:51:36Desensitization, Nicotinic acetylcholine receptorDesensitization, Nicotinic acetylcholine receptorMolecular<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"Upon prolonged and repeated exposure to a nAChR agonist, desensitizationmay<br />
occur.Desensitization is characterized by an initial opening<br />
of the ion channel and ion exchange across the cell membrane followed<br />
by rapid channel closure and inactivity, effectively inhibiting neurotransmission<br />
(Quick and Lester, 2002). Further, inhibition of nAChR activity<br />
from desensitization can lead to an up-regulation in nAChR<br />
expression, termed pharmacological chaperoning (Srinivasan et al.,<br />
2012; Flores et al., 1992; Marszalec et al., 2005). Exposure to<br />
imidacloprid and thiamethoxam for 72 or 48 h, respectively was<br />
shown to significantly increase transcriptional abundance of nAChRα1<br />
subunit in the honey bee brain (Christen et al., 2016). In the<br />
desensitized state, nAChR receptors have high affinity for the agonist<br />
and therefore establish a blockade to subsequent agonist binding<br />
(Ochoa et al., 1989). It has been demonstrated that recovery from<br />
nAChR desensitization occurs (though not always complete) upon removal<br />
of the agonist (Ochoa et al., 1989). However, the speed of recovery<br />
is dependent on the concentration and duration of exposure to the<br />
agonist, with longer exposures typically resulting in slower recovery<br />
times (Quick and Lester, 2002). In fact, loss of functional nAChR channels<br />
has been reported in neuronal cell line PC12 (rat adrenal gland<br />
pheochromocytoma tumor) upon prolonged exposure to carbachol, a<br />
cholinergic agonist (Simasko et al., 1986).<br />
Phosphorylation of nAChR subunits is another factor that regulates<br />
the rate of desensitization and subsequent recovery. Nicotinic acetylcholine<br />
receptor subunits possess phosphorylation sites for cAMP-dependent<br />
protein kinase A (PKA), protein kinase C (PKC), calciumcalmodulin-<br />
dependent protein kinase (CaM kinase) and endogenous<br />
protein tyrosine kinase (Hopfield et al., 1988; Thany et al., 2007). Evidence<br />
suggests that phosphorylation of nAChR subunits regulate the<br />
rate of desensitization,with the greater number of phosphotyrosines indicative<br />
of rapid recovery from desensitization (Hopfield et al., 1988;<br />
Thany et al., 2007)."</p>
<p>Text from Table 2 in LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"• Electrophysiological characterization for investigation of desensitization. Patch-clamp, number of channel openings per unit time<br />
• Immunoblotting to determine phosphotyrosine content of purified nAChR"</p>
CL:0000540neuron<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Quick, M.W., Lester, R.A., 2002. Desensitization of neuronal nicotinic receptors.<br />
J. Neurobiol. 53 (4), 457–478.</p>
<p>Srinivasan, R., Richards, C.I., Xiao, C., Rhee, D., Pantoja, R., Dougherty, D.A., Miwa, J.M.,<br />
Lester, H.A., 2012. Pharmacological chaperoning of nicotinic acetylcholine receptors<br />
reduces the endoplasmic reticulumstress response.Mol. Pharmacol. 81 (6), 759–769.</p>
<p>Flores, C.M., Rogers, S.W., Pabreza, L.A.,Wolfe, B.B., Kellar, K.J., 1992. A subtype of nicotinic<br />
cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is upregulated<br />
by chronic nicotine treatment. Mol. Pharmacol. 41 (1), 31–37.</p>
<p>Marszalec, W., Yeh, J.Z., Narahashi, T., 2005. Desensitization of nicotine acetylcholine receptors:<br />
modulation by kinase activation and phosphatase inhibition. Eur.<br />
J. Pharmacol. 514 (2–3), 83–90.</p>
<p>Christen, V., Mittnter, F., Fent, K., 2016. Molecular effects of neonicotinoids in honey bees<br />
(Apis mellifera). Environ. Sci. Technol. 50 (7), 4071–4081.</p>
<p>Ochoa, E.L., Chattopadhyay, A., McNamee, M.G., 1989. Desensitization of the nicotinic acetylcholine<br />
receptor: molecular mechanisms and effect of modulators. Cell. Mol.<br />
Neurobiol. 9 (2), 141–178.</p>
<p>Simasko, S.M., Soares, J.R., Weiland, G.A., 1986. Two components of carbamylcholine-induced<br />
loss of nicotinic acetylcholine receptor function in the neuronal cell line<br />
PC12. Mol. Pharmacol. 30 (1), 6–12.</p>
<p>Hopfield, J.F., Tank, D.W., Greengard, P., Huganir, R.L., 1988. Functional modulation of the<br />
nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336 (6200),<br />
677–680.</p>
<p>Thany, S.H., Lenaers, G., Raymond-Delpech, V., Sattelle, D.B., Lapied, B., 2007. Exploring the<br />
pharmacological properties of insect nicotinic acetylcholine receptors. Trends<br />
Pharmacol. Sci. 28 (1), 14–22.</p>
<p> </p>
2016-11-29T18:41:262018-06-07T09:38:50Weakened, ColonyWeakened, ColonyPopulation<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"The characteristics evaluated to determine the strength/health of honey bee colonies, include adequate numbers of adult bees, presence of sealed and open brood, adequate amounts of stored pollen, nectar and sealed honey, the absence of pests and disease, and the presence of a queen that lays eggs in consistent and tight patterns, with limited eggless cells (Sagili and Burgett, 2011). If the colony is weakened by any one (or a combination) of these factors for an extended period, a critical point can be reached<br />
that will lead to colony failure. Through honey bee population dynamics models, it has been demonstrated that loss of foragers leading to precocious foraging of young bees may restore the overall foraging capacity, but the brood rearing capacity of the colony might be reduced (Khoury et al., 2011). Further, as noted above, precocious foragers are less effective and resilient, causing the forager death rate to increase. The model predicts that sustained forager losses that reduce the force by two-thirds would place a colony at risk for failure (Khoury et al., 2011). Additionally, proper brood rearing is essential to the development of healthy adult bees."</p>
<p>Text from Table 2 in LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"• Count number of adult bees, presence of sealed and open brood, assess amount of food stores by visual method or by weighing,<br />
assess presence/absence of pests and disease, evaluate egg laying patterns of queen<br />
• Brood care behavior can be evaluated by filming the brood nest and then recording nursing frequency, total nursing period per<br />
hour, and average duration of nursing episodes for individual cells<br />
• Cannibalism of brood can be detected by mapping eggs, larvae and pupae present on brood frames and noting developmental<br />
stages for each individual, then inspecting daily for missing larvae<br />
• Assess health of bee: dry weight, muscle development, protein content"</p>
<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Sagili, R.R., Burgett, D.M., 2011. Evaluating honey bee colonies for pollination: a guide for<br />
commercial growers and beekeepers. A Pacific Northwest Extension Publication. vol.<br />
623, pp. 1–8.</p>
<p>Khoury, D.S.,Myerscough,M.R., Barron, A.B., 2011. A quantitativemodel of honey bee colony<br />
population dynamics. PLoS One 6 (4), e18491.</p>
<p> </p>
2016-11-29T18:41:292018-06-07T11:04:32Altered, Ca2+-calmodulin activated signal transductionAltered, Ca2+-calmodulin activated signal transductionCellular<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"Some neuronal nAChR subunit combinations are highly permeable<br />
to Ca2+, which acts as a messenger relaying extracellular information<br />
to intracellular regions and to the nucleus (Uteshev, 2012). Upon influx<br />
of Ca2+ into neurons via nAChR, Ca2+ binds to calmodulin (CaM). This<br />
complex either activates adenylyl cyclase (AC) to catalyze the conversion<br />
of ATP to 3′5′-adenosine monophosphate (cAMP),which then activates<br />
PKA, or interacts with Ca2+-CaM kinase II (CaMKII) (e.g.,<br />
Dajas-Bailador andWonnacott, 2004; Sweatt, 2001). Regardless of signaling<br />
through PKA or CaMKII, both kinases activate the phosphorylation<br />
cascade via extracellular signal-related protein kinase/mitogenactivated<br />
protein kinase (ERK/MAPK), stimulating transcription of<br />
cAMP response element (CRE) binding protein (CREB) mediated<br />
genes (Impey et al., 1999). In neurons, these signaling cascades lead to<br />
the production of proteins that direct synaptic plasticity (i.e., changes<br />
in synaptic strength in response to signaling activity),which is essential<br />
to learning and memory."</p>
<p>Text from Table 2 in LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"• Fluorescent Ca2+ imaging in cells expressing nAChR for evaluation of Ca2+ levels entering individual nAChR-mediated ion<br />
channels<br />
• Western blotting and kinase assays can be used to evaluate ERK1/2 phosphorylation and activity<br />
• Activation of CREB/CRE transcription<br />
• Pharmacological inhibition of pathway"</p>
<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Uteshev, V.V., 2012. alpha7 nicotinic ACh receptors as a ligand-gated source of Ca(2+)<br />
ions: the search for a Ca(2+) optimum. Adv. Exp. Med. Biol. 740, 603–638.</p>
<p>Dajas-Bailador, F., Wonnacott, S., 2004. Nicotinic acetylcholine receptors and the regulation<br />
of neuronal signalling. Trends Pharmacol. Sci. 25 (6), 317–324.</p>
<p>Sweatt, J.D., 2001. The neuronalmap kinase cascade: a biochemical signal integration system<br />
subserving synaptic plasticity and memory. J. Neurochem. 76, 1–10.</p>
<p>Impey, S., Obrietan, K., Storm, D.R., 1999. Making new connections: role of ERK/MAP kinase<br />
signaling in neuronal plasticity. Neuron 23, 11–14.</p>
2016-11-29T18:41:312018-06-07T09:46:42d8d295cd-8c42-4c6a-a481-2be906115fd700a6922c-c1b8-40e6-8495-399dfb3e1645<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"The first draft of the honey bee genome became available through<br />
the efforts of the Honey Bee Genome Sequencing Consortium (2006),</p>
<p>and has provided valuable insights on evolution and comparisons between<br />
species. The honey bee has 11 genes that encode nAChR subunits<br />
- nineα and two β subunits (Jones et al., 2006), consistentwith the condensed<br />
number of genes seen in other insects compared to vertebrates<br />
(Tomizawa and Casida, 2001). The primary location of insect nAChRs is<br />
the brain. In honey bees, nAChRs have been identified in Kenyon cells<br />
located onmushroombodies and antennal lobes, both involved in olfactory<br />
learning (Deglise et al., 2002; Dupuis et al., 2011).</p>
<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"It has been demonstrated in various models that nAChR agonism<br />
does indeed lead to desensitization. For example, upon exposure of<br />
human α7 nAChR expressed in African clawed frog (Xenopus laevis) oocytes<br />
to classical nAChR agonists, including nicotine, Briggs and<br />
McKenna (1998) showed that even weak or low concentrations of an<br />
agonist could act asmore potent inhibitors than activators of the receptor<br />
through desensitization. Further, in another examplemeasuring current<br />
across the neuron and activity of the natural nAChR ligand and ACh<br />
neurotransmitter, Zwart et al. (1994) demonstrated that six nAChR agonists<br />
induced nAChR-mediated inward ionic current, and that their<br />
continued presence significantly blocked ACh-induced inward current<br />
in whole-cell voltage-clamped African locust (Locusta migratoria) thoracic<br />
ganglion neurons. In that study, it was shown that concentrations<br />
of 0.1 μM and 10 μM imidacloprid induced ACh-inward current with<br />
peak amplitudes of 4% and 30%, respectively (Zwart et al., 1994). Continued<br />
exposure to 0.1 μMimidacloprid led to desensitization that reduced<br />
the amplitude of 1 mM ACh-induced inward current by 73%; whereas,<br />
continued exposure to 10 μM imidacloprid completely blocked inward<br />
current indicting that the potency to block the ACh-induced ion current<br />
was greater than the potency to induce inward current (Zwart et al.,<br />
1994).<br />
Specific evidence of desensitization exists in honey bees as well. Exposure<br />
of cultured Kenyon cells from honey bee brains to imidacloprid<br />
yielded partial nAChR agonist activity, eliciting 36% of the ACh-induced<br />
current and causing desensitization of the receptor after prolonged<br />
(16 s) exposure (Deglise et al., 2002). Further, when 10−5 M<br />
imidacloprid was co-applied with ACh, the mean amplitude of ACh-induced<br />
currents was significantly lowered (64%) compared to ACh coapplication<br />
with saline, thereby providing evidence that imidacloprid<br />
antagonized the ACh-induced receptor activation by out-competing<br />
ACh for the same binding site (Deglise et al., 2002). Interestingly, an antagonist<br />
of the nAChR (mecamylamine) demonstrated similar properties,<br />
likely affecting neurotransmission, in that direct injection into the<br />
brain hemolymph of honey bee was shown to not only impair olfactory<br />
learning but, in patch-clamp experiments with cultured Kenyon cells,<br />
completely block the ACh-induced current (Lozano et al., 1996;<br />
Wüstenberg and Grünewald, 2004).<br />
Recovery from desensitization depends on the availability of phosphorylation<br />
sites on the nAChR subunits and the number of<br />
phosphotyrosine residues. Mutation of key PKC phosphorylation sites<br />
on the rat α4 nAChR subunit expressed in Xenopus oocytes resulted in<br />
impaired recovery from deep desensitization (Fenster et al., 1999).<br />
Further inhibition of PKC or knockout of PKC in a mouse model<br />
(Prkce−/−) also led to impaired recovery from desensitization (Lee<br />
et al., 2015a). Phosphorylation sites on nAChR subunits as well as PKC<br />
isozymes continue to be identified. Cross species differences in those<br />
sites may contribute to the differences in sensitivity to various<br />
chemicals that act on the nAChR (Hug and Sarre, 1993). Demonstration<br />
that perturbation to PKC can impact recovery fromdesensitization is an<br />
important piece of evidence, describing a potential feedback loop<br />
linking the downstreamKE of altered Ca2+-calmodulin activated signal<br />
transduction back to desensitization (see Fig. 2; step 6). Kinases phosphorylate<br />
nAChR subunits, indicating that disruption of downstream<br />
signaling could further impact nAChR desensitization status."</p>
<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>Desensitizationis a well-studied biological function that occurs upon activation of ligand-<br />
gated ion channels, such as the nAChR, with prolonged or repeated<br />
exposure to variable concentrations (typically low) of agonist; thus,<br />
biological plausibility of activation leading to desensitization is quite<br />
strong.However, there are relatively significant uncertainties associated<br />
with desensitization of the insect neuronal nAChR, due to incomplete<br />
characterization of the subunit combinations that make-up the nAChR<br />
in neurons of the honey bee (or other invertebrates), which may affect<br />
both chemical binding affinity and available phosphorylation sites involved<br />
in recovery from the desensitized state (Hopfield et al., 1988;<br />
Thany et al., 2007). Although progress has been made in characterizing<br />
the composition of the nAChR subunits, most recombinant hybrid<br />
nAChRs evaluated consist of a combination of both insect and vertebrate<br />
subunits (Ihara et al., 2007). Therefore, the composition and activity of<br />
insect subunits alone have not been elucidated nor evaluated. Further,<br />
concentrations and durations of agonist exposure that would lead to a<br />
prolonged desensitized state of the receptor, effectively inactivating it,<br />
are uncertain. Research focused on characterization of insect nAChR,<br />
with evaluation of temporal and dosimetric concordancewould provide<br />
greater understanding of the mechanism through which activation of<br />
the nAChR can lead to desensitization and subsequent downstream<br />
events.</p>
<p>LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.<em> </em>STOTEN. 584-585, 751-775.</p>
<p>Honey Bee Genome Sequencing Consortium, 2006. Insights into social insects from the<br />
genome of the honeybee Apis mellifera. Nature 443 (7114), 931.</p>
<p>Jones, A.K., Raymond-Delpech, V., Thany, S.H., Gauthier, M., Sattelle, D.B., 2006. The nicotinic<br />
acetylcholine receptor gene family of the honey bee, Apis mellifera. Genome Res.<br />
16 (11), 1422–1430.</p>
<p>Tomizawa, M., Casida, J.E., 2001. Structure and diversity of insect nicotinic acetylcholine<br />
receptors. Pest Manag. Sci. 57 (10), 914–922.</p>
<p>Deglise, P., Grunewald, B., Gauthier, M., 2002. The insecticide imidacloprid is a partial agonist<br />
of the nicotinic receptor of honeybee Kenyon cells. Neurosci. Lett. 321 (1–2),<br />
13–16.</p>
<p>Dupuis, J.P., Gauthier, M., Raymond-Delpech, V., 2011. Expression patterns of nicotinic<br />
subunits alpha2, alpha7, alpha8, and beta1 affect the kinetics and pharmacology of<br />
ACh-induced currents in adult bee olfactory neuropiles. J. Neurophysiol. 106 (4),<br />
1604–1613.</p>
<p>Briggs, C.A., McKenna, D.G., 1998. Activation and inhibition of the human alpha7 nicotinic<br />
acetylcholine receptor by agonists. Neuropharmacology 37 (9), 1095–1102.</p>
<p>Zwart, R., Oortgiesen, M., Vijverberg, H.P., 1994. Nitromethylene heterocycles: selective<br />
agonists of nicotinic receptors in locust neurons compared to mouse N1E-115 and<br />
BC3H1 cells. Pestic. Biochem. Physiol. 48, 202–213.</p>
<p>Lozano, V.C., Bonnard, E., Gauthier, M., Richard, D., 1996.Mecamylamine-induced impairment<br />
of acquisition and retrieval of olfactory conditioning in the honeybee. Behav.<br />
Brain Res. 81 (1–2), 215–222.</p>
<p>Wüstenberg, D.G., Grünewald, B., 2004. Pharmacology of the neuronal nicotinic acetylcholine<br />
receptor of cultured Kenyon cells of the honeybee, Apis mellifera. J. Comp.<br />
Physiol. A. 190 (10), 807–821.</p>
<p>Fenster, C.P., Beckman, M.L., Parker, J.C., Sheffield, E.B., Whitworkth, T.L., Quick, M.W.,<br />
Lester, R.A., 1999. Regulation of alpha4beta2 nicotinic receptor desensitization by calcium<br />
and protein kinase C. Mol. Pharmacol. 55 (3), 432–443.</p>
<p>Lee, A.M., Wu, D.F., Dadgar, J., Wang, D., McMahon, T., Messing, R.O., 2015a. PKCε phosphorylates<br />
α4β2 nicotinic ACh receptors and promotes recovery from desensitization.<br />
Br. J. Pharmacol. 172 (17), 4430–4441.</p>
<p>Hug, H., Sarre, T.F., 1993. Protein kinase C isoenzymes: divergence in signal transduction?<br />
Biochem. J. 291, 329–343.</p>
<p>Hopfield, J.F., Tank, D.W., Greengard, P., Huganir, R.L., 1988. Functional modulation of the<br />
nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336 (6200),<br />
677–680.</p>
<p>Thany, S.H., Lenaers, G., Raymond-Delpech, V., Sattelle, D.B., Lapied, B., 2007. Exploring the<br />
pharmacological properties of insect nicotinic acetylcholine receptors. Trends<br />
Pharmacol. Sci. 28 (1), 14–22.</p>
<p>Ihara, M., Shimomura, M., Ishida, C., Nishiwaki, H., Akamatsu, M., Sattelle, D.B., Matsuda,<br />
K., 2007. A hypothesis to account for the selective and diverse actions of<br />
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catch and release in hydrogen bond networks. Invertebr. Neurosci. 7 (1), 47–51.</p>
<p> </p>
2016-11-29T18:41:342018-06-07T13:04:004ac44146-15cd-4b44-abab-2d5cb3f4a832da41b5bb-e050-4ac3-8fea-6551ba4f7ec02016-11-29T18:41:342016-12-03T16:37:58da41b5bb-e050-4ac3-8fea-6551ba4f7ec0c083e5a2-8ce3-4400-b458-c19ec1b8c4ca2016-11-29T18:41:362016-12-03T16:38:04c083e5a2-8ce3-4400-b458-c19ec1b8c4ca7e6e46ce-16a8-4cd0-9a93-fee1ca5fa65a2016-11-29T18:41:362016-12-03T16:38:04d8d295cd-8c42-4c6a-a481-2be906115fd74ac44146-15cd-4b44-abab-2d5cb3f4a8322016-11-29T18:41:362016-12-03T16:38:0400a6922c-c1b8-40e6-8495-399dfb3e16454beb5ee1-ad90-440d-93e3-b0f5affb27fc2016-11-29T18:41:372016-12-03T16:38:074beb5ee1-ad90-440d-93e3-b0f5affb27fc4ac44146-15cd-4b44-abab-2d5cb3f4a8322016-11-29T18:41:372016-12-03T16:38:07Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony loss/failure via abnormal role change within castenAChR activation - colony loss 6<p>Carlie A. LaLone, U.S. Environmental Protection Agency (LaLone.Carlie@epa.gov)</p>
Open for comment. Do not citeUnder Development1.29<p>Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. <em>Science of the Total Environment</em> 584-585, 751-775:</p>
<p>"The nicotinoids and neonicotinoids are both agonists of the nAChR<br />
(Tomizawa and Casida, 2003); however, neonicotinoids are the primary<br />
chemicals considered in the AOPs relevant to bees.<br />
The potency of a nAChR agonist is dependent on the receptor subunit<br />
composition, structurally important amino acid residues at the<br />
binding site, and the ionization status of the chemical at physiological<br />
pH (Tomizawa and Casida, 2003; Dani and Bertrand, 2007). For example,<br />
nicotine is a classical vertebrate nAChR agonist; however, it has relatively<br />
low affinity (and insecticidal activity) for the invertebrate<br />
nAChR. Due to ionization, nicotine is poor at passing though the ion-impermeable<br />
barrier surrounding the insect central nervous system(CNS;<br />
Tomizawa and Casida, 2003). Conversely, non-ionizable neonicotinoids<br />
readily translocate into the insect CNS and have high affinity for the<br />
nAChR (e.g., Drosophila nAChR IC50 4.6 nM imidacloprid), with limited<br />
or no binding activity to vertebrate nAChR (Tomizawa and Casida,<br />
2003). Various studies have demonstrated that similarities and differences<br />
in key amino acid residues in the ligand binding domain across<br />
species can lead to structural and binding site differences that dictate<br />
chemical interaction with the receptor (Dani and Bertrand, 2007;<br />
Matsuda et al., 2009; Tomizawa and Casida, 2009; Jones and Sattelle,<br />
2010; LaLone et al., 2016). Due to the intended insecticidal action of<br />
neonicotinoids, a growing number of studies have been conducted to</p>
<p>evaluate potential adverse effects in non-target species such as honey<br />
bees exposed to neonicotinoids, particularly imidacloprid, clothianidin,<br />
and thiamethoxam. Some of the results of these studies are included<br />
in subsequent AOP descriptions."</p>
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