Aop: 242

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Inhibition of lysyl oxidase leading to enhanced chronic fish toxicity

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Lysyl oxidase inhibition

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Stefan Scholz, Helmholtz Centre for Environmental Research - UFZ, Department of Bioanalytical Ecotoxicology, Permoserstr. 15, 04318 Leipzig, Germany, T +49 341 235 1080, email stefan.scholz@ufz.de

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Brendan Ferreri-Hanberry   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Stefan Scholz
  • Brendan Ferreri-Hanberry

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for adoption
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Thiol group of chemicals interact with sulfuhydryl groups of proteins to form thiol adducts August 03, 2017 11:25
Inhibition of lysyl oxidase August 03, 2017 11:26
Reduction of collagen crosslinking August 03, 2017 11:27
Weak collagen matrix August 03, 2017 11:28
Notochord distortion or malformations August 03, 2017 11:29
Reduced, Swimming performance September 08, 2021 06:12
Growth, reduction August 03, 2017 11:31
Decreased, survival December 03, 2016 16:37
Thiol protein adducts leads to Inhibition of lysyl oxidase August 03, 2017 11:33
Inhibition of lysyl oxidase leads to Reduction of collagen crosslinking August 03, 2017 11:34
Reduction of collagen crosslinking leads to Weak collagen matrix August 03, 2017 11:35
Weak collagen matrix leads to Notochord malformation August 03, 2017 11:36
Notochord malformation leads to Reduced, Swimming performance August 03, 2017 11:37
Reduced, Swimming performance leads to Growth, reduction August 03, 2017 11:37
Reduced, Swimming performance leads to Decreased, survival August 03, 2017 11:38
Sodium metam August 03, 2017 10:46
Dimethyl dithiocarbamate August 03, 2017 10:49
Thiram August 03, 2017 10:52
Disulfiram August 03, 2017 10:53
Ferbam August 03, 2017 10:54
Dazornet August 03, 2017 10:56
Pyrolidine dithiocarbamate August 03, 2017 10:57
Mancozeb August 03, 2017 10:58
Maneb November 29, 2016 18:42
Nabam-sodium August 03, 2017 11:00
Ziram August 03, 2017 11:15
Zineb August 03, 2017 11:18

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Exposure of fish embryos to various dithiocarbamates elicited specific notochord distortions. Growth inhibitions in the FELS test for thiram, ziram, maneb and NaDTMC were observed in a range of concentrations close to those causing notochord distortions in zebrafish embryos. This notochord distortion appears to be caused by inhibition of the enzyme lysyl oxidase. Notochord malformation are caused by muscle contractions due to the weak resistance of the extracellular matrix. It can be assumed that the notochord distortions affect swimming behaviour and feeding, leading to the observed reduction in survival and growth observed in the FELS test.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
KE 1463 Inhibition of lysyl oxidase Inhibition of lysyl oxidase
KE 1464 Reduction of collagen crosslinking Reduction of collagen crosslinking
KE 1465 Weak collagen matrix Weak collagen matrix
KE 1466 Notochord distortion or malformations Notochord malformation
KE 1005 Reduced, Swimming performance Reduced, Swimming performance
AO 1467 Growth, reduction Growth, reduction
AO 636 Decreased, survival Decreased, survival

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Embryo High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
fish fish Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

The evidence for the link between lysyl oxidase inhibition and enhanced chronic toxicity has been provided only for fish and can be concluded from various publications describing the impact of dithiocarbamate fungicides on lysyl oxidase enzyme inhibition, morpholino knock-down studies and embryonic malformations in zebrafish. The link to chronic toxicity is only provided via a meta-analysis of Fish Early Life Stage (FELS) tests that showed high toxic ratios (TR) and acute-to-chronic ratios (ACR) for dithiocarbamates. There is no study available that has analysed the the whole chain of AOP events within a single study and species, which may weaken the confidence in the AOP. Of particular regulatory relevance is the observations of malformations in fish embryos which may used to infer chronic fish toxicity from short term fish embryo tests.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Fish, embryonic, larvae, juveniles

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

All key events are considered as essential but the weight-of-evidence is weak to mediocre given that MIEs, KEs and AO have been partially investigated in different studies with different experimental set-up.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Strong evidence for individual KER relationships that were however, provided from individual disconnected studies with different experimental setups and species. Therefore, the overall weight of evidence is estimated as weak.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Quantitative data are available from Tilton et al. (2006) which demonstrate a clear concentration - dependency of notochord malformation in zebrafish embryos exposed to diverse dithiocarbamates.No observed effect levels were calculated for the test compounds in this study. Similar malformations were shown for selected concentrations (probably concentration-dependent but not explicitely specified in the original publication) were also observed for rainbow trout (Leeuwen et al. 1986). A concentration dependent inhibition was shown for the enzyme lysyl oxidase in zebrafish by Boxtel et al. (2010). Morpholino injection in zebrafish to confirm that the observed notochord malformation phenotype is caused by interference with lysyl oxidase has been only provided for single selected concentrations and provoke the same phenotype as lysyl oxidase inhibition.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

Haendel, M.A., Tilton, F., Bailey, G.S., Tanguay, R.L., 2004. Developmental Toxicity of the Dithiocarbamate Pesticide Sodium Metam in Zebrafish. Tox. Sci. 81, 390-400.

Scholz, S., Schreiber, R., Armitage, J., Mayer, P., Escher, B., Lidzba, A., Léonard, M., Altenburger, R., Meta-analysis of fish early life stage tests –  association of toxic ratios and acute-to-chronic ratios with modes of action Manuscript in preparation.

Tilton, F., La Du, J.K., Vue, M., Alzarban, N., Tanguay, R.L., 2006. Dithiocarbamates have a common toxic effect on zebrafish body axis formation. Toxicol. Appl. Pharmacol. 216, 55-68.

Van Leeuwen, C.J., Espeldoorn, A., Mol, F., 1986. Aquatic toxicological aspects of dithiocarbamates and related compounds. III. Embryolarval studies with rainbow trout (Salmo gairdneri). Aquat. Toxicol. 9, 129-145.