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Relationship: 1744

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Premature molting leads to Increase, Mortality

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Premature molting

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Mortality

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
S-adenosylmethionine depletion leading to population decline (2)	adjacent			You Song (send email)	Under development: Not open for comment. Do not cite
S-adenosylmethionine depletion leading to population decline (1)	adjacent			You Song (send email)	Under development: Not open for comment. Do not cite
Chitinase inhibition leading to mortality	adjacent	Moderate	Low	Simon Schmid (send email)	Under development: Not open for comment. Do not cite	Under Development
Chitobiase inhibition leading to mortality	adjacent	Moderate	Low	Simon Schmid (send email)	Under development: Not open for comment. Do not cite	Under Development
Chitin synthase 1 inhibition leading to mortality	adjacent	Moderate	Low	Simon Schmid (send email)	Open for citation & comment	WPHA/WNT Endorsed
Sulfonylureareceptor binding leading to mortality	adjacent	High	High	Simon Schmid (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
crustaceans	Daphnia magna	Moderate	NCBI
insects	insects	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Larvae	High
Juvenile	Moderate
Adult	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

During molting, arthropods pause food uptake and in certain cases also respiration (Camp et al. 2014; Song et al. 2017a). If molting is disrupted and the organism is not able to shed the old exoskeleton, the organism may eventually die of starvation, suffocation or the rupture of the exoskeleton.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

In order to grow and develop, arthropods need to molt periodically (Heming 2018). Since molting is a determining point in arthropod development, the disruption of molting leads to increased mortality (Arakawa et al. 2008; Merzendorfer et al. 2012; Song et al. 2017a; Song et al. 2017b). During ecdysis, arthropods pause food intake and respiration (Camp et al. 2014; Song et al. 2017a). Therefore, if the molt cannot be completed, the organism may die of starvation or suffocation. Additionally, if the cuticle is immature, it may not withstand the stresses associated with ecdysis (Clarke 1957; Lee 1961; Dall et al. 1978; deFur et al. 1985), and the organism may die of desiccation or increased susceptibility to pathogens. Given the well understood biological processes, the biological plausibility of this KER was rated as high.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The event of premature molting is not well characterized. It gets mentioned as cause of death in studies with Pieris brassicae, Spodoptera litura, Bombyx mori and Lucilia cuprina after treatment with polyoxin D, polyoxin B, polyoxin AL (a mixture of polyoxins) and nikkomycin Z (Gijswijt et al. 1979; Tellam et al. 2000; Arakawa et al. 2008). The increase in mortality was reported in studies with Lucilia cuprina, Spodoptera litura and Bombyx mori (Tellam et al. 2000; Tellam and Eisemann 2000; Arakawa et al. 2008). Evidence from studies which assess and link both endpoints, and therefore would support dose concordance, is lacking. However, results from studies where CHS-1 was knocked down by RNA interference support temporal concordance of the KER (Arakane et al. 2005, Li et al. 2017, Chen et al., 2008; Mohammed et al., 2017; Shang et al., 2016; Wang et al., 2012, 2019; Yang et al., 2013; Ye et al., 2019; Zhai et al., 2017; Zhang et al., 2010). Given the support for temporal concordance and the lack of studies showing dose concordance, the empirical evidence for this KER was judged as moderate.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The absence of studies (quantitatively) assessing premature molting constitutes a major data gap. A further data gap is the absence of studies which assess both, increase in premature molting and the increase in mortality are lacking.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Due to the lack of studies linking the increase in premature molting with the increase in mortality, it is not possible to describe the nature of the response-response relationship.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Death occurs after premature molting. However, an exact time frame in which death occurs cannot be defined yet.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic: Likely, this KER is applicable to the whole phylum of arthropods as they all depend on molting in order to develop.

Life stage: This KER is applicable for organisms molting in order to grow and develop, namely larval stages of insects and all life stages of crustaceans and arachnids.

Sex: This KER is applicable to all sexes.

Chemical: Occurrence of premature molting and an increase in mortality observed after treatment with the pyrimidine nucleosides ( e.g. polyoxin D, polyoxin B and nikkomycin Z) (Gijswijt et al. 1979; Tellam et al. 2000; Tellam and Eisemann 2000; Arakawa et al. 2008; New Zealand Environmental Protection Authority 2015). However, studies causally linking both endpoints are lacking.

References

List of the literature that was cited for this KER description. More help

Arakawa T, Yukuhiro F, Noda H. 2008. Insecticidal effect of a fungicide containing polyoxin B on the larvae of Bombyx mori (Lepidoptera: Bombycidae), Mamestra brassicae, Mythimna separata, and Spodoptera litura (Lepidoptera: Noctuidae). Appl Entomol Zool. 43(2):173–181. doi:10.1303/aez.2008.173.

Camp AA, Funk DH, Buchwalter DB. 2014. A stressful shortness of breath: Molting disrupts breathing in the mayfly Cloeon dipterum. Freshw Sci. 33(3):695–699. doi:10.1086/677899.

Chen, X.; Tian, H.; Zou, L.; Tang, B.; Hu, J.; Zhang, W. Disruption of Spodoptera Exigua Larval Development by Silencing Chitin Synthase Gene A with RNA Interference. Bull. Entomol. Res. 2008, 98 (6), 613–619. https://doi.org/10.1017/S0007485308005932.

Mohammed, A. M. A.; DIab, M. R.; Abdelsattar, M.; Khalil, S. M. S. Characterization and RNAi-Mediated Knockdown of Chitin Synthase A in the Potato Tuber Moth, Phthorimaea Operculella. Sci. Rep. 2017, 7 (1), 1–12. https://doi.org/10.1038/s41598-017-09858-y.

Clarke KU. 1957. On the Increase in Linear Size During Growth in Locusta Migratoria L. Proc R Entomol Soc London Ser A, Gen Entomol. 32(1–3):35–39. doi:10.1111/j.1365-3032.1957.tb00361.x.

Dall W, Smith DM, Press B. 1978. Water uptake at ecdysis in the western rock lobster. J Exp Mar Bio Ecol. 35(1960). doi:10.1016/0022-0981(78)90074-6.

deFur PL, Mangum CP, McMahon BR. 1985. Cardiovascular and Ventilatory Changes During Ecdysis in the Blue Crab Callinectes Sapidus Rathbun. J Crustac Biol. 5(2):207–215. doi:10.2307/1547867.

Gijswijt MJ, Deul DH, de Jong BJ. 1979. Inhibition of chitin synthesis by benzoyl-phenylurea insecticides, III. Similarity in action in Pieris brassicae (L.) with Polyoxin D. Pestic Biochem Physiol. 12(1):87–94. doi:10.1016/0048-3575(79)90098-1.

Heming BS. 2018. Insect development and evolution. Ithaca: Cornell University Press.

Lee RM. 1961. The variation of blood volume with age in the desert locust (Schistocerca gregaria Forsk.). J Insect Physiol. 6(1):36–51. doi:10.1016/0022-1910(61)90090-7.

Merzendorfer H, Kim HS, Chaudhari SS, Kumari M, Specht CA, Butcher S, Brown SJ, Robert Manak J, Beeman RW, Kramer KJ, et al. 2012. Genomic and proteomic studies on the effects of the insect growth regulator diflubenzuron in the model beetle species Tribolium castaneum. Insect Biochem Mol Biol. 42(4):264–276. doi:10.1016/j.ibmb.2011.12.008. http://dx.doi.org/10.1016/j.ibmb.2011.12.008.

New Zealand Environmental Protection Authority. 2015. Application for approval to import ESTEEM for release. https://www.epa.govt.nz/assets/FileAPI/hsno-ar/APP202334/fbce9a39e6/APP202334-APP202334-Staff-Report-Final-updated.pdf.

Shang, F.; Xiong, Y.; Xia, W. K.; Wei, D. D.; Wei, D.; Wang, J. J. Identification, Characterization and Functional Analysis of a Chitin Synthase Gene in the Brown Citrus Aphid, Toxoptera Citricida (Hemiptera, Aphididae). Insect Mol. Biol. 2016, 25 (4), 422–430. https://doi.org/10.1111/imb.12228.

Song Y, Evenseth LM, Iguchi T, Tollefsen KE. 2017b. Release of chitobiase as an indicator of potential molting disruption in juvenile Daphnia magna exposed to the ecdysone receptor agonist 20-hydroxyecdysone. J Toxicol Environ Heal - Part A Curr Issues. 80(16–18):954–962. doi:10.1080/15287394.2017.1352215. https://doi.org/10.1080/15287394.2017.1352215.

Song Y, Villeneuve DL, Toyota K, Iguchi T, Tollefsen KE. 2017a. Ecdysone Receptor Agonism Leading to Lethal Molting Disruption in Arthropods: Review and Adverse Outcome Pathway Development. Environ Sci Technol. 51(8):4142–4157. doi:10.1021/acs.est.7b00480.

Tellam RL, Eisemann C. 2000. Chitin is only a minor component of the peritrophic matrix from larvae of Lucilia cuprina. Insect Biochem Mol Biol. 30(12):1189–1201. doi:10.1016/S0965-1748(00)00097-7.

Tellam RL, Vuocolo T, Johnson SE, Jarmey J, Pearson RD. 2000. Insect chitin synthase. cDNA sequence, gene organization and expression. Eur J Biochem. 267(19):6025–6043. doi:10.1046/j.1432-1327.2000.01679.x.

Wang, Z.; Yang, H.; Zhou, C.; Yang, W. J.; Jin, D. C.; Long, G. Y. Molecular Cloning, Expression, and Functional Analysis of the Chitin Synthase 1 Gene and Its Two Alternative Splicing Variants in the White-Backed Planthopper, Sogatella Furcifera (Hemiptera: Delphacidae). Sci. Rep. 2019, 9 (1), 1–14. https://doi.org/10.1038/s41598-018-37488-5.

Wang, Y.; Fan, H. W.; Huang, H. J.; Xue, J.; Wu, W. J.; Bao, Y. Y.; Xu, H. J.; Zhu, Z. R.; Cheng, J. A.; Zhang, C. X. Chitin Synthase 1 Gene and Its Two Alternative Splicing Variants from Two Sap-Sucking Insects, Nilaparvata Lugens and Laodelphax Striatellus (Hemiptera: Delphacidae). Insect Biochem. Mol. Biol. 2012, 42 (9), 637–646. https://doi.org/10.1016/j.ibmb.2012.04.009.

Yang, W. J.; Xu, K. K.; Cong, L.; Wang, J. J. Identification, mRNA Expression, and Functional Analysis of Chitin Synthase 1 Gene and Its Two Alternative Splicing Variants in Oriental Fruit Fly, Bactrocera Dorsalis. Int. J. Biol. Sci. 2013, 9 (4), 331–342. https://doi.org/10.7150/ijbs.6022.

Ye, C.; Jiang, Y. Di; An, X.; Yang, L.; Shang, F.; Niu, J.; Wang, J. J. Effects of RNAi-Based Silencing of Chitin Synthase Gene on Moulting and Fecundity in Pea Aphids (Acyrthosiphon Pisum). Sci. Rep. 2019, 9 (1), 1–10. https://doi.org/10.1038/s41598-019-39837-4.

Zhai, Y.; Fan, X.; Yin, Z.; Yue, X.; Men, X.; Zheng, L.; Zhang, W. Identification and Functional Analysis of Chitin Synthase A in Oriental Armyworm, Mythimna Separata. Proteomics 2017, 17 (21), 1–11. https://doi.org/10.1002/pmic.201700165.

Zhang, J. et al. Silencing of two alternative splicing-derived mRNA variants of chitin synthase 1 gene by RNAi is lethal to the oriental migratory locust, Locusta migratoria manilensis (Meyen). Insect Biochem. Mol. Biol. 40, 824–833 (2010).