This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Inhibition of lysyl oxidase leading to enhanced chronic fish toxicity
- Stefan Scholz
- Brendan Ferreri-Hanberry
|Author status||OECD status||OECD project||SAAOP status|
|Open for adoption|
This AOP was last modified on December 05, 2020 22:08
|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||November 20, 2020 12:57|
|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|
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1462||Thiol group of chemicals interact with sulfuhydryl groups of proteins to form thiol adducts||Thiol protein adducts|
|2||KE||1463||Inhibition of lysyl oxidase||Inhibition of lysyl oxidase|
|3||KE||1464||Reduction of collagen crosslinking||Reduction of collagen crosslinking|
|4||KE||1465||Weak collagen matrix||Weak collagen matrix|
|5||KE||1466||Notochord distortion or malformations||Notochord malformation|
|6||KE||1005||Reduced, Swimming performance||Reduced, Swimming performance|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
Overall Assessment of the AOP
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
Fish, embryonic, larvae, juveniles
Essentiality of the Key Events
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.
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.
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)
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.