This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 292

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 tyrosinase leads to decreased population in fish

Short name

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

tyrosinase, fish

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.0

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

Kichul Cho (kichul.cho@mabik.re.kr)

Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, Campus E 7.1, 66123 Saarbruecken, Germany

Youngjun Kim (youngjunkim@kist-europe.de)

Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, Campus E 7.1, 66123 Saarbruecken, Germany

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

Young Jun Kim (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

Young Jun Kim

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

Dan Villeneuve

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version
1.78	Under Development

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
Inhibition of tyrosinase	May 03, 2019 08:28
Reduction of L-Dopaquinone	May 03, 2019 08:29
Reduction in melanin level	May 03, 2019 08:30
Reduction of melanosome level	May 03, 2019 08:31
Reduction fo Pigmentation pattern	May 03, 2019 08:31
Decrease, Population growth rate	January 03, 2023 09:09
tyrosinase leads to Reduction of L-Dopaquinone	May 03, 2019 08:33
Reduction of L-Dopaquinone leads to Reduction in melanin level	May 03, 2019 08:33
Reduction in melanin level leads to Reduction of melanosome level	May 03, 2019 08:35
Reduction of melanosome level leads to Reduction fo Pigmentation pattern	May 03, 2019 08:35
Reduction fo Pigmentation pattern leads to Decrease, Population growth rate	May 03, 2019 08:36
1-phenyl 2-thiourea	May 03, 2019 08:37

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

This AOP is designed to estimate changes in population trajectory of fishes resulting from the inhibition of the enzyme tyrosinase (TYR), which is rate-limiting in the control of melanogenesis. Since tyrosinase inhibition leads to the decrease of DOPAquinone synthesis, tyrosinase inhibition by unknown or known chemicals will lead to L DOPA quinone inhibition and decrease of eu - and pheo -melanogenesis. Subsequently, these KEs possibly lead to the decline of teleost population. Hence this AOP could support the use of an in vitro high throughput screening assay for tyrosinase inhibition to identify chemicals that may reduce pigmentation in fish leaving them vulnerable to predation and unable to perform important social behaviors important to their survival and reproduction. Decreased population trajectory resulting from reduced pigmentation patterns in the fish body is a potential endpoint for eco-toxicity. The proposed endpoint will provide useful high throughput risk assessment screening tools for potential chemicals. Consequently, this AOP can be applied to the prediction of eco-toxicity caused by the inhibition of TYR.

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

The present AOP shows a tyrosinase (TYR) inhibition-mediated adverse outcome (AO) in fishes. TYR is the rate-limiting enzyme controlling the induction of melanogenesis in diverse colored patterns in aquatic organisms. The significant reactions of TYR can be considered that the tyrosinase inhibitor-induced depigmentation reduces the trajectory of fishes.

Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)

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

MIE

1627

Inhibition of tyrosinase

tyrosinase

KE	1628	Reduction of L-Dopaquinone	Reduction of L-Dopaquinone
KE	1629	Reduction in melanin level	Reduction in melanin level
KE	1630	Reduction of melanosome level	Reduction of melanosome level
KE	1631	Reduction fo Pigmentation pattern	Reduction fo Pigmentation pattern

360

Decrease, Population growth rate

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

Title	Adjacency	Evidence	Quantitative Understanding

tyrosinase leads to Reduction of L-Dopaquinone	adjacent	High	High
Reduction of L-Dopaquinone leads to Reduction in melanin level	adjacent	High	High
Reduction in melanin level leads to Reduction of melanosome level	adjacent	High	High
Reduction of melanosome level leads to Reduction fo Pigmentation pattern	adjacent	High	High
Reduction fo Pigmentation pattern leads to Decrease, Population growth rate	adjacent	Moderate	Low

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

Name
1-phenyl 2-thiourea

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Not Otherwise Specified

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	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	Moderate

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

To do
Building the AOP frame	Development of KEs
	Production of experimental data
Overall assessment of the AOP	Biological domain of applicability
	Essentiality of all KEs
	Evidence supporting all KERs
	Quantitative WoE considerations
	Quantitative understanding for each KER

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

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

Inhibition of TYR (KER 1627) can be caused by chemical inhibitors such as 1-phenyl 2-thiourea (PTU), sesamol, arbutin, Kojic acid, bis(4-hydroxybenzyl) and etc. (J. Karlsson et al., 2001; W. C. Chen et al., 2015; Baek and Lee, 2015; S. H. Cha et al., 2011).

TYR inhibition as Key event 1891, the MIE for the present AOP, results in reduction of L-Dopaquinone level in the melanocyte via inhibition of L-DOPA oxidation moreover, it results in attenuation of eumelanin and pheomelanin biosynthesis (T. S. Chang, 2012; J. Choi and J. G. Jee, 2015; S. Y. Lee, 2016; A. J. Winder and H. Harris, 1991; W. C. Chen et al., 2015).

There are perhaps a non-adjacent relationship linking event 1629 to event 1631 that the lowered level of melanin biosynthesis by TYR inhibition simultaneously leads to depigmentation in skin tissue and diminished pigmentation pattern in the fish body (L. E. Jao et al., 2013; S. Y. Wu et al., 2015; S. H. Baek and S. H. Lee, 2015; W. C. Chen et al., 2015; D. C. Kim et al., 2017).

Evidence Assessment

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

First, TYR can convert L-tyrosine directly to L-3,4-dihydroxyphenylalanine (L-DOPA) which is a precursor of (2S)-2-Amino-3-(3,4-dioxocyclohexa-1,5-dien-1-yl)propanoic acid (L-Dopaquinone) synthesis; Second, TYR catalyzes the oxidation of L-DOPA to the L-Dopaquinone which is the reactive intermediate for the eumelanin and pheomelanin synthesis. Pigment patterns in common fishes usually play a significant role to communicate within species, intersexual interactions, escape potential in the eyes of predators and finding shoal mate (Price et al., 2008; C. L. Peichel et al., 2004; R. E. Engeszer et al., 2004)

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

It will be come soon,

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

In fish as behavioral ecology, color patterns are often multi-component signals, composed of pigment-based and physiological regulation that can be used to communicate in both inter- and intrasexual interactions in population. This endpoint is essential and useful for screening of pigmentation effects on the photosensitive context for skin toxicity screening and relevant to teratogenic effects.

References

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

References

Karlsson, J., et al. (2001). Generating transparent zebrafish: a refined method to improve detection of gene expression during embryonic development. Marine Biotechnology, 3(6), 522-527.

Chen, W. C., et al. (2015). Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling. Scientific reports, 5, 7995.

Baek, S. H., & Lee, S. H. (2015). Sesamol decreases melanin biosynthesis in melanocyte cells and zebrafish: Possible involvement of MITF via the intracellular cAMP and p38/JNK signalling pathways. Experimental dermatology, 24(10), 761-766.

Cha, S. H., et al. (2011). Screening of marine algae for potential tyrosinase inhibitor: those inhibitors reduced tyrosinase activity and melanin synthesis in zebrafish. The Journal of dermatology, 38(4), 354-363.

Chang, T. S. (2012). Natural melanogenesis inhibitors acting through the down-regulation of tyrosinase activity. Materials, 5(9), 1661-1685.

Choi, J., & Jee, J. G. (2015). Repositioning of thiourea-containing drugs as tyrosinase inhibitors. International journal of molecular sciences, 16(12), 28534-28548.

Lee, S. Y., Baek, N., & Nam, T. G. (2016). Natural, semisynthetic and synthetic tyrosinase inhibitors. Journal of enzyme inhibition and medicinal chemistry, 31(1), 1-13.

Winder, A. J., & Harris, H. (1991). New assays for the tyrosine hydroxylase and dopa oxidase activities of tyrosinase. European journal of biochemistry, 198(2), 317-326.

Chen, W. C., et al. (2015). Discovery highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling. Scientific reports, 5, 7995.

Jao, L. E., et al. (2013). Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proceedings of the National Academy of Sciences, 110(34), 13904-13909.

Wu, S. Y., et al. (2015). 4-(Phenylsulfanyl) butan-2-one suppresses melanin synthesis and melanosome maturation in vitro and in vivo. International journal of molecular sciences, 16(9), 20240-20257.

Kim, D. C., et al. (2017). p-coumaric acid potently down-regulates zebrafish embryo pigmentation: Comparison of in vivo assay and computational molecular modeling with phenylthiourea. Biomedical Science Letters, 23(1), 8-16.

Price, A. C., et al. (2008). Pigments, patterns, and fish behavior. Zebrafish, 5(4), 297-307.

Peichel, C. L. (2004). Social behavior: how do fish find their shoal mate?. Current Biology, 14(13), R503-R504.

Engeszer, R. E., et al. (2004). Learned social preference in zebrafish. Current Biology, 14(10), 881-884.

Slavík, O., et al. (2016). How does agonistic behaviour differ in albino and pigmented fish?. PeerJ, 4, e1937.

Ren, J. Q., et al. (2002). Behavioral visual responses of wild-type and hypopigmented zebrafish. Vision research, 42(3), 293-299.

Slavík, O., et al. (2015). Ostracism of an albino individual by a group of pigmented catfish. Plos one, 10(5), e0128279.

Onyia, U. L., et al. (2016). Growth and survival of normal coloured and albino clarias gariepinus and their reciprocal hybrids. Nigerian Journal of Fisheries and Aquaculture, 4(1), 22-27.

Bondari, K. (1984). Comparative performance of albino and normally pigmented channel catfish in tanks, cages, and ponds. Aquaculture, 37(4), 293-301.

Pérez-Carpinell, J. O. A. Q. U. I. N., et al. (1992). Vision defects in albinism. Optometry and vision science: official publication of the American Academy of Optometry, 69(8), 623-628.

Cho, K., Ryu, C. S., Jeong, S., & Kim, Y. (2020). Potential adverse effect of tyrosinase inhibitors on teleosts: A review. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 228, 108655.

Maki JA, Cavallin JE, Lott KG, Saari TW, Ankley GT, Villeneuve DL. A method for CRISPR/Cas9 mutation of genes in fathead minnow (Pimephales promelas). Aquat Toxicol. 2020;222:105464. doi:10.1016/j.aquatox.2020.105464