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Aop: 334

AOP Title

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Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration

Short name:

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GR Agonism Leading to Impaired Fin Regeneration

Graphical Representation

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Click to download graphical representation template

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Authors

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Alexander R. Cole, Oak Ridge Institute for Science and Education, U.S. Environmental Protection Agency, Great Lakes Ecology Divison, Duluth, MN

Point of Contact

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Alexander Cole   (email point of contact)

Contributors

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  • Alexander Cole
  • Dan Villeneuve

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 Do not cite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 July 27, 2020 12:54

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Revision dates for related pages

Page Revision Date/Time
Activation, Glucocorticoid Receptor July 07, 2020 12:19
Increase, Cripto-1 expression July 10, 2020 15:26
Inhibition, Activin signaling July 10, 2020 15:36
Inhibition, Fin regeneration July 10, 2020 13:05
Reduced, Swimming performance April 24, 2020 15:05
Decrease, Population trajectory September 26, 2017 11:33
Activation, Glucocorticoid Receptor leads to Increase, Cripto-1 expression July 10, 2020 15:28
Increase, Cripto-1 expression leads to Inhibition, Fin regeneration July 10, 2020 15:53
Increase, Cripto-1 expression leads to Inhibition, Activin signaling July 07, 2020 15:08
Inhibition, Activin signaling leads to Inhibition, Fin regeneration July 10, 2020 15:41
Inhibition, Fin regeneration leads to Reduced, Swimming performance July 10, 2020 15:45
Reduced, Swimming performance leads to Decrease, Population trajectory June 04, 2020 13:09
Beclomethasone dipropionate monohydrate July 07, 2020 15:19

Abstract

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This adverse outcome pathway specifies the relationship between activation of the glucocorticoid receptor in fish species and impaired fin regeneration. Glucocorticoid receptor agonists are used in a variety of over the counter and prescribed medications. Though beneficial in many ways, the adverse effects associated with the use of exposure to GR agonists have not been well documented as those for other endocrine modes of action such as estrogen receptor agonism or inhibition of steroid biosynthesis. More recently, GR activity has been detected in wastewaters and wastewater impacted surface waters (van der Linden et al., 2008). Unlike mammals, fish can regenerate damaged or amputated limbs (fins). Damage to fins is a common throughout a fish’s life cycle (Wehner & Weidinger, 2015), and impaired or delayed ability to regenerate fins following damage can plausibly reduce ecological fitness making affected fish less capable of obtaining food, avoiding predation, and/or migrating within their range. This AOP will help to understand the potential ecological significance of being exposed to environmental GR agonists.


Background (optional)

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Pending


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
MIE 122 Activation, Glucocorticoid Receptor Activation, Glucocorticoid Receptor
KE 1759 Increase, Cripto-1 expression Increase, Cripto-1 expression
KE 1760 Inhibition, Activin signaling Inhibition, Activin signaling
KE 1761 Inhibition, Fin regeneration Inhibition, Fin regeneration
KE 1005 Reduced, Swimming performance Reduced, Swimming performance
AO 360 Decrease, Population trajectory Decrease, Population trajectory

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Activation, Glucocorticoid Receptor leads to Increase, Cripto-1 expression adjacent Moderate
Increase, Cripto-1 expression leads to Inhibition, Activin signaling adjacent Moderate
Inhibition, Activin signaling leads to Inhibition, Fin regeneration adjacent High
Inhibition, Fin regeneration leads to Reduced, Swimming performance adjacent High
Reduced, Swimming performance leads to Decrease, Population trajectory adjacent High
Increase, Cripto-1 expression leads to Inhibition, Fin regeneration non-adjacent Moderate

Network View

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Stressors

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Name Evidence Term
Beclomethasone dipropionate monohydrate Moderate

Life Stage Applicability

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Life stage Evidence
larvae High
Adult, reproductively mature High
Juvenile High

Taxonomic Applicability

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Term Scientific Term Evidence Link
teleost fish teleost fish High NCBI

Sex Applicability

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Sex Evidence
Mixed High

Overall Assessment of the AOP

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Domain of Applicability

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Domain Evidence Reasoning

Taxa

High
  • Biological plausibility suggests that fin regeneration occurs throughout the teleost class (Fu et al., 2013; Wehner & Weidinger, 2015).
Sex High
  • Biological plausibility suggests that fin regeneration is not sex specific
  • Empirical evidence shows fin regeneration occurs in both sex (Sengupta et al., 2012; Garland et al., 2019).
Lifestage High
  • Biological plausibility suggests that fin regeneration is universal to a fish's life; excluding embryonic stage.
  • Empirical evidence shows fin regeneration can occur ineven during larval stage.

 


Essentiality of the Key Events

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Essentiallity has beeen determined in the evidence assesment.


Evidence Assessment

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Key Event Evidence Reasoning
Relationship 2077: GR agonism -> Cripto-1 Expression Moderate
  • Empirical evidence for GR agonism leading to an increase in cripto-1 transcription is prevelant and has been replicated (Sengupta et al., 2012; Garland et al., 2019).
  • The biological pathway regarding GR regulation of Cripto-1 is currently lacking. 

Relationship 2078: Cripto-1 Expression -> Activin inhibition

Moderate
  • Empirical evidence has shown how the mechanism of cripto-1 inhibiting activin receptors occurs (Gray et al., 2003).
  • Biological plausibility suggests cripto-1 is capable of binding with the ALK-4 subunit of the Activin receptor (Gray et al., 2003).

Relationship 2079: Activin Inhibition -> Inibition Fin Regeneration

High
  • Currently there is no emprical evidence measuring activin signalling, or lack there of, during the fin regeneration process.
  • Biological plausibility suggests that activin signalling plays a strong and crucial roll in the fin regeneration process (Wehner & Weidinger, 2015). 

Relationship 2080: Inhibition Fin Regeneration -> Decreased Swim Performance

High
  • Empirical evidence has shown that different fish species with amputated fins have a significant decrease in swim performance (Fu et al., 2013).
  • Biological plausibility suggests that without a main source of locomotion, i.e. fins, locomotion itself will decrease (Fu et al., 2013).
Relationship 2081: Decreased Swim Performance -> Population Decrease High
  • Biological plausibility suggests that without the ability to swim, fish will lack the mobility needed for predator avoidance, obtaining food, or migration (Fu et al., 2013).

Relationship 2082: Cripto-1 Expression -> Inhibition Fin Regeneration

Moderate
  • Empircal evidence showing the relationship between an increase in cripto-1 expression and an inhibition of fin regeneration is prevalent and has been replicated. This indicates an essentiality for cripto-1 expression for inhibition of fin regeneration to occur (Sengupta et al., 2012; Garland et al., 2019).

 


Quantitative Understanding

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Pending


Considerations for Potential Applications of the AOP (optional)

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By collecting surface water samples, a screening for pharmaceuticals, personal care products and other known glucocorticoid agonists could provide insight to the potential risks of the afformentioned. A better understanding of the quantitative AOP would be an advantageous tool for risk assessors.


References

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Ellis T, Hoyle I, Oidtmann B, Turnbull JF, Jacklin TE, Knowles TG. 2009. Further development of the “Fin Index” method for quantifying fin erosion in rainbow trout. Aquaculture 289: 283-288. doi:10.1016/j.aquaculture.2009.01.022

Fu C, Cao ZD, Fu SJ. 2013. The effects of caudal fin loss and regeneration on the swimming performance of three cyprinid fish species with different swimming capacities. The Journal of Experimental Biology 216:3164-3174. doi:10.1242/jeb.084244

Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013

Gray PC, Harrison CA, Vale W. 2003. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proceedings of the National Academy of Sciences of the United States of America 100(9):5193-5198. www.pnas.org/cgi/doi/10.1073/pnas.0531290100

Kaneko H, 2016. Handbook of Hormones: Pages 295-297, e33B-2.

Jaźwińska A, Badakov R, Keating MT. 2007. Activin-βA Signaling is Required for Zebrafish Fin Regeneration. Current Biology 17:1390-1395. DOI 10.1016/j.cub.2007.07.019

Kang HY, Shyr CR. 2011. Activins and Cell Migration. Vitamins and Hormons 85: 129-48. doi: 10.1016/B978-0-12-385961-7.00007-X.

Poss KD, Shen J, Keating MT, Nechiporuk A. 2003. Tales of Regeneration in Zebrafish. Developmental Dynamics 226:202-210. DOI 10.1002/dvdy.10220

Sengupta S, Bisson WH, Mathew LK, Kolluri SK, Tanguay RL. 2012. Alternative glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comparative Biochemistry and Physiology, Part C 156:121-129. doi:10.1016/j.cbpc.2012.05.003

van der Linden SC, Heringa MB, Man HY, Sonneveld Edwin, Puijker LM, Brouwer A, van der Burg B. 2008. Detection of Multiple Hormonal Activities in Wastewater Effluents and Surface Water, Using a Panel of Steroid Receptor CALUX Bioassays. Envionmental Science & Technology 42(15):5814-5820. https://doi.org/10.1021/es702897y

Voesenek CJ, Muijres FT, van Leeuwen JL. 2018. Biomechanics of Swimming in Developing Larval Fish. Journal of Experimental Biology 221:jeb149583. doi: 10.1242/jeb.149583.

Wehner D, Weidinger G. 2015. Signaling networks organizing regenerative growth of the zebrafish fin. Trends in Genetics 31 (6):336-343. http://dx.doi.org/10.1016/j.tig.2015.03.012