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Aop: 297

AOP Title

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Inhibition of retinaldehyde dehydrogenase leads to population decline

Short name:

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retinaldehyde dehydrogenase inhibition,population decline

Graphical Representation

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Click to download graphical representation template

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Authors

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Cho,Kichul (kichul.cho@kist-europe.de)

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

Ryu, Chang Seon (changryu@kist-europe.de)

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

Sung, Baekkyung (baeckkyoung@gmail.com)

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

Baik, Seung yun (sbaik@kist-europe.de)

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

Kim, Youngjun (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

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Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on May 22, 2019 05:20

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Revision dates for related pages

Page Revision Date/Time
Retinaldehyde dehydrogenase inhibition May 22, 2019 05:03
Decreased optical elements of the eye May 22, 2019 05:06
Decreased retinoic acid (RA) synthesis May 22, 2019 05:10
Decreased plasma RA level May 22, 2019 05:11
Increased visual impairment May 22, 2019 05:12
Decline, Population December 03, 2016 16:33
Retinaldehyde dehydrogenase leads to retinoic acid May 22, 2019 05:13
Visual impairment leads to Decline, Population May 22, 2019 05:16
retinoic acid leads to plasma retionic acid May 22, 2019 05:14
plasma retionic acid leads to Optical elements of the eye May 22, 2019 05:14
Optical elements of the eye leads to Visual impairment May 22, 2019 05:15
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

Abstract

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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.


Background (optional)

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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).

 

Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1637 Retinaldehyde dehydrogenase inhibition Retinaldehyde dehydrogenase
2 KE 1640 Decreased optical elements of the eye Optical elements of the eye
KE 1641 Decreased retinoic acid (RA) synthesis retinoic acid
KE 1642 Decreased plasma RA level plasma retionic acid
KE 1643 Increased visual impairment Visual impairment
AO 361 Decline, Population Decline, Population

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Retinaldehyde dehydrogenase leads to retinoic acid adjacent High
retinoic acid leads to plasma retionic acid adjacent High
plasma retionic acid leads to Optical elements of the eye adjacent High
Optical elements of the eye leads to Visual impairment adjacent Moderate
Visual impairment leads to Decline, Population non-adjacent Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Birth to < 1 month Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
fish fish Moderate NCBI

Sex Applicability

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Sex Evidence
Mixed Moderate

Overall Assessment of the AOP

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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

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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  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.