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AOP: 297


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 retinaldehyde dehydrogenase leads to population decline

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
retinaldehyde dehydrogenase inhibition,population decline
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


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

Cho,Kichul ( )

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

Ryu, Chang Seon (

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

Sung, Baeckkyoung (

Park Chang-Beom, Korea Institute of Toxicology JRC-APT (Joint Research Center for Alternative and Predictive Toxicology)

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

Baik, Seung yun (

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

Kim, Youngjun (

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
Arthur Author   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Young Jun Kim
  • Arthur Author


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
1.77 Under Development
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Retinaldehyde dehydrogenase inhibition May 22, 2019 05:03
Altered, Photoreceptor patterning June 16, 2021 06:56
Decreased retinoic acid (RA) synthesis May 22, 2019 05:10
Decreased plasma RA level May 22, 2019 05:11
Altered, Visual function July 08, 2022 07:30
Decrease, Population growth rate January 03, 2023 09:09
Retinaldehyde dehydrogenase leads to retinoic acid May 22, 2019 05:13
retinoic acid leads to plasma retionic acid May 22, 2019 05:14
plasma retionic acid leads to Altered, Photoreceptor patterning May 22, 2019 05:14
Altered, Photoreceptor patterning leads to Altered, Visual function June 16, 2021 07:24
Altered, Visual function leads to Decrease, Population growth rate May 25, 2020 10:50
Disulphiram May 22, 2019 05:17
Diethylaminobenzaldehyde May 22, 2019 05:17
Citral May 22, 2019 05:18
Paclobutrazol May 22, 2019 05:18
nitrofen May 22, 2019 05:18
4-biphenyl carboxylic acid May 22, 2019 05:18
Bisdiamine May 22, 2019 05:19
SB-210661 May 22, 2019 05:19


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

The present AOP is designed to estimate potential AO of fishes results from the retinaldehyde dehydrogenase (RALDH) inhibition.  Visual impairment results from eye development of an embryonic cell might lead to population decline which is the potential endpoint. This AOP will provide a useful risk assessment tool for the toxic assessment of chemicals. Furthermore, this AOP can be applied to the prediction of eco-toxicity caused by the inhibition of RALDH.

AOP Development Strategy


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

This adverse outcome pathway (AOP) represents the potential causative adverse outcomes (AOs) by inhibition of retinaldehyde dehydrogenase (RALDH), which is one of the crucial enzymes participating in retinol metabolism. The role of RALDH in retinol metabolism is to catalyze the chemical reaction converting retinal to retinoic acid (RA). The synthesized RA is associated with the cellular RA-binding protein (CRABP) and enters into the nucleus, and then bind to retinoic acid receptors (RARs) along with retinoid X receptors (RXRs) (Vilhais-Neto and Pourquié, 2008). The activated RARs and RXRs can act as target gene transcription factors regulating embryonic development in fishes (Perz-Edwards et al., 2011). Inhibition of RALDH can be caused by chemical inhibitors such as Disulphiram, Citral, Paclobutrazol, Diethylaminobenzaldehyde, Nitrofen, 4-biphenyl carboxylic acid, Bisdiamine, SB-210661 and etc. (Marsh-Armstrong et al., 1994; Chawla et al., 2018; Wang et al., 2017; Le et al., 2012; Mey et al., 2003). RALDH inhibition, the molecular initiating event (MIE) for this AOP, leads to decreased RA synthesis blocking the reaction converting retinal to RA in embryonic cells (Hyatt and Dowling, 1997; Molotkov et al., 2002; Le et al., 2012; Duester, 2009). Since RA is an essential activator for the RARs and RXRs-mediated gene transcription, low level of plasma RA leads to abnormal development in embryonic cells. A number of previous studies well-elucidated the abnormal developments by RA inhibition including visual function and eye development (Duester et al., 2009; Hyatt and Dowling, 1997; Hyatt et al., 1996; Kam et al., 2012; Le et al., 2012; Luo et al., 2006; Marsh-Armstrong et al., 1994; Matt et al., 2005; Wang et al., 2017), intestinal development (Nadauld et al., 2005), brain patterning and neurogenesis (Begemann et al., 2004; Niederreither and Dollé, 2008; Samarut et al., 2015), and heart development (Niederreither and Dollé, 2008; Samarut et al., 2015). The development of early embryonic cells of fishes plays an essential role in the organism’s young of year survival and adaptation in fluctuated environmental condition. The impact of the development of the optical elements of the eye by RALDH inhibition in fish population trajectory has not been clarified yet, although the importance of the visual function of fishes previously mentioned by previous studies (Fernald, 1984; Sandström, 1999).

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)



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


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 1637 Retinaldehyde dehydrogenase inhibition Retinaldehyde dehydrogenase
KE 1640 Altered, Photoreceptor patterning Altered, Photoreceptor patterning
KE 1641 Decreased retinoic acid (RA) synthesis retinoic acid
KE 1642 Decreased plasma RA level plasma retionic acid
KE 1643 Altered, Visual function Altered, Visual function
AO 360 Decrease, Population growth rate 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

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
Birth to < 1 month Moderate

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 Moderate 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

This AOP is under development supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe) and  P11911.

To do

Expected duration

Building the AOP frame

Development of KEs

3 month

Production of experimental data

18 month

Overall assessment of the AOP

Biological domain of applicability

3 month

Essentiality of all KEs

3 month

Evidence supporting all KERs

5 month

Quantitative WoE considerations

5 month

Quantitative understanding for each KER

6 month

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

Evidence Assessment

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

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

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

The roles of RALDH play in sensory perception of fish mating opportunities via their presence in the visual functions. Significantly, the AO (population decline) can apply to IATA by dysfunction of the retinoid in reproduction in the aquatic environment. It can be applied to retinoid effects on a central nervous system within the OECD EDTA


List of the literature that was cited for this AOP. More help
  1. Chawla, B., Swain, W., Williams, A. L., & Bohnsack, B. L. (2018). Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish. Investigative ophthalmology & visual science, 59(5), 1924-1935.
  2. Duester, G. (2009). Keeping an eye on retinoic acid signaling during eye development. Chemico-biological interactions, 178(1-3), 178-181.
  3. Fernald, R. D. (1984). Vision and Behavior in an African Cichlid fish: Combining behavioral and physiological analyses reveals how good vision is maintained during rapid growth of the eyes. American Scientist, 72(1), 58-65.
  4. Hyatt, G. A., Schmitt, E. A., Marsh-Armstrong, N., McCaffery, P., Drager, U. C., & Dowling, J. E. (1996). Retinoic acid establishes ventral retinal characteristics. Development, 122(1), 195-204.
  5. Hyatt, G. A., & Dowling, J. E. (1997). Retinoic acid. A key molecule for eye and photoreceptor development. Investigative ophthalmology & visual science, 38(8), 1471-1475.
  6. Kam, R. K. T., Deng, Y., Chen, Y., & Zhao, H. (2012). Retinoic acid synthesis and functions in early embryonic development. Cell & bioscience, 2(1), 11.
  7. Le, H. G. T., Dowling, J. E., & Cameron, D. J. (2012). Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Visual neuroscience, 29(4-5), 219-228.
  8. Luo, T., Sakai, Y., Wagner, E., & Dräger, U. C. (2006). Retinoids, eye development, and maturation of visual function. Journal of neurobiology, 66(7), 677-686.
  9. Marsh-Armstrong, N., McCaffery, P., Gilbert, W., Dowling, J. E., & Dräger, U. C. (1994). Retinoic acid is necessary for development of the ventral retina in zebrafish. Proceedings of the National Academy of Sciences, 91(15), 7286-7290.
  10. Matt, N., Dupé, V., Garnier, J. M., Dennefeld, C., Chambon, P., Mark, M., & Ghyselinck, N. B. (2005). Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Development, 132(21), 4789-4800.
  11. Mey, J., Babiuk, R. P., Clugston, R., Zhang, W., & Greer, J. J. (2003). Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents. The American journal of pathology, 162(2), 673-679.
  12. Molotkov, A., et al. (2002). Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proceedings of the National Academy of Sciences, 99(8), 5337-5342.
  13. Perz-Edwards, A., Hardison, N. L., & Linney, E. (2001). Retinoic acid-mediated gene expression in transgenic reporter zebrafish. Developmental biology, 229(1), 89-101.
  14. Sandström, A. (1999). Visual ecology of fish–a review with special reference to percids. Fiskeriverket rapport, 2, 45-80.
  15. Vilhais-Neto, G. C., & Pourquié, O. (2008). Retinoic acid. Current Biology, 18(5), R191-R192.
  16. Wang, W. D., Hsu, H. J., Li, Y. F., & Wu, C. Y. (2017). Retinoic acid protects and rescues the development of zebrafish embryonic retinal photoreceptor cells from exposure to paclobutrazol. International journal of molecular sciences, 18(1), 130.