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Aop: 155

AOP Title

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Deiodinase 2 inhibition leading to reduced young of year survival via posterior swim bladder inflation

Short name:

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DIO2i posterior swim bladder

Graphical Representation

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Click to download graphical representation template

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Authors

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Dries Knapen [1], [dries.knapen (at)uantwerpen.be]

Lucia Vergauwen [1], [lucia.vergauwen(at)uantwerpen.be]

Evelyn Stinckens [1], [evelyn.stinckens(at)uantwerpen.be]

Dan Villeneuve [2], [villeneuve.dan*(at)epa.gov]

[1] Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium

[2]United States Environmental Protection Agency, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN, USA.

Point of Contact

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Dries Knapen   (email point of contact)

Contributors

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  • Dries Knapen
  • Lucia Vergauwen

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.35 Included in OECD Work Plan


This AOP was last modified on June 09, 2020 12:24

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Deiodinase 2 August 20, 2019 09:52
Decreased, Triiodothyronine (T3) in serum September 26, 2017 11:03
Reduced, Posterior swim bladder inflation August 26, 2020 11:52
Reduced, Swimming performance April 24, 2020 15:05
Reduced, Young of year survival November 29, 2016 19:36
Decrease, Population trajectory September 26, 2017 11:33
Reduced, Anterior swim bladder inflation August 26, 2020 11:53
Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3) in serum August 26, 2020 08:43
Decreased, Triiodothyronine (T3) in serum leads to Reduced, Posterior swim bladder inflation August 28, 2020 04:39
Reduced, Posterior swim bladder inflation leads to Reduced, Swimming performance August 27, 2020 04:31
Reduced, Swimming performance leads to Reduced, Young of year survival August 28, 2020 05:11
Reduced, Young of year survival leads to Decrease, Population trajectory August 25, 2020 06:21
Reduced, Posterior swim bladder inflation leads to Reduced, Anterior swim bladder inflation October 31, 2019 05:14
Reduced, Anterior swim bladder inflation leads to Reduced, Swimming performance August 28, 2020 05:04
Inhibition, Deiodinase 2 leads to Reduced, Posterior swim bladder inflation August 26, 2020 12:55
Reduced, Posterior swim bladder inflation leads to Reduced, Young of year survival September 08, 2020 10:23

Abstract

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The AOP describes the effects of inhibition of iodothyronine deiodinase 2 (DIO2) on posterior swim bladder inflation in fish leading to reduced young of year survival and population trajectory decline. DIO1 and DIO2 are thryoid hormone (TH) activating deiodinases that convert thyroxin (T4) to the more biologically active 3,5,3′-triiodothyronine (T3). The inhibition of DIO2 results in decreased circulating concentrations of T3 in serum. Disruption of the TH system is increasingly being recognized as an important mode of action that can lead to adverse outcomes, especially during embryonic development. In fish, many different adverse effects during early development resulting from disruption of the TH endocrine system have been reported (e.g., effects on body and eye size, head-to-trunk angle, heartbeat, otolith formation, pigmentation index, swim bladder inflation, hatching time, somite formation, escape response and photoreceptor development). As in amphibians, the transition in fish between the different developmental phases, including maturation and inflation of the swim bladder, have been shown to be mediated by THs. Chemicals interfering with the conversion of T4 to T3 by inhibiting DI21 have the potential to inhibit posterior chamber inflation which may result in reduced swimming capacity of the fish, a relevant adverse outcome that can affect feeding behaviour and predator avoidance, resulting in lower survival probability and ultimately population trajectory decline. The current state of the art suggests that DIO2 is more important than DIO1 in regulating posterior chamber inflation. Therefore the AOP that is described here may be more biologically relevant than the corresponding AOP leading from DIO1 inhibition to reduced young of year survival via posterior swim bladder inflation .


Background (optional)

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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 1002 Inhibition, Deiodinase 2 Inhibition, Deiodinase 2
2 KE 1003 Decreased, Triiodothyronine (T3) in serum Decreased, Triiodothyronine (T3) in serum
3 KE 1004 Reduced, Posterior swim bladder inflation Reduced, Posterior swim bladder inflation
4 KE 1005 Reduced, Swimming performance Reduced, Swimming performance
5 KE 1006 Reduced, Young of year survival Reduced, Young of year survival
6 KE 1007 Reduced, Anterior swim bladder inflation Reduced, Anterior swim bladder inflation
8 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
Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3) in serum adjacent
Decreased, Triiodothyronine (T3) in serum leads to Reduced, Posterior swim bladder inflation adjacent
Reduced, Posterior swim bladder inflation leads to Reduced, Swimming performance adjacent Low
Reduced, Swimming performance leads to Reduced, Young of year survival adjacent
Reduced, Young of year survival leads to Decrease, Population trajectory adjacent
Reduced, Posterior swim bladder inflation leads to Reduced, Anterior swim bladder inflation adjacent
Reduced, Anterior swim bladder inflation leads to Reduced, Swimming performance adjacent
Inhibition, Deiodinase 2 leads to Reduced, Posterior swim bladder inflation non-adjacent Moderate Low
Reduced, Posterior swim bladder inflation leads to Reduced, Young of year survival non-adjacent High Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Embryo High

Taxonomic Applicability

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Term Scientific Term Evidence Link
fathead minnow Pimephales promelas NCBI
zebrafish Danio rerio NCBI

Sex Applicability

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Sex Evidence
Unspecific

Overall Assessment of the AOP

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Overall, the weight of evidence for the sequence of key events laid out in the AOP is moderate to high. Nonetheless, the exact underlying mechanism of TH disruption leading to impaired swim bladder inflation is not understood. The current domain of applicability is larval life stages of zebrafish and fathead minnow pending future research in other fish species such as medaka.

Domain of Applicability

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Sex differences are typically not investigated in tests using early life stages of fish and it is currently unclear whether sex-related differences are important in this AOP. Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Since the posterior chamber inflates around 5 days post fertilization, when sex differentiation has not started yet, sex differences are expected to play a minor role in the current AOP. 


Essentiality of the Key Events

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Overall, the confidence in the supporting data for essentiality of KEs within the AOP is high since there is direct evidence from specifically designed experimental studies (knockdown and knockout studies) illustrating that the impact on downstream KEs corresponds to what is predicted by the AOP.


Evidence Assessment

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Overall, the weight of evidence for the biological plausibility of the KERs in the AOP is moderate since there is empirical support for an association between the sets of KEs and the KERs are plausible based on analogy to accepted biological relationships, but scientific understanding is not completely established. Especially for some of the upstream KERs biological plausibility is high.

Overall, the empirical support for the KERs in the AOP is moderate since dependent changes in sets of KEs following exposure to a small number of specific stressors has been demonstrated, but there are still some data gaps.


Quantitative Understanding

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There is some level of quantitative understanding that can form the basis for development of a quantitative AOP. Quantitative relationships between reduced T4 and reduced T3, and between reduced T3 and reduced anterior chamber inflation were established. The latter is particularly critical for linking impaired swim bladder inflation to TH disruption.


Considerations for Potential Applications of the AOP (optional)

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References

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Bagci, E., Heijlen, M., Vergauwen, L., Hagenaars, A., Houbrechts, A.M., Esguerra, C.V., Blust, R., Darras, V.M., Knapen, D., 2015. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLOS One 10, e0123285.

Brown, C.L., Doroshov, S.I., Nunez, J.M., Hadley, C., Vaneenennaam, J., Nishioka, R.S., Bern, H.A., 1988. MATERNAL TRIIODOTHYRONINE INJECTIONS CAUSE INCREASES IN SWIMBLADDER INFLATION AND SURVIVAL RATES IN LARVAL STRIPED BASS, MORONE-SAXATILIS. Journal of Experimental Zoology 248, 168-176.

Cavallin, J.E., Ankley, G.T., Blackwell, B.R., Blanksma, C.A., Fay, K.A., Jensen, K.M., Kahl, M.D., Knapen, D., Kosian, P.A., Poole, S.T., Randolph, E.C., Schroeder, A.L., Vergauwen, L., Villeneuve, D.L., 2017. Impaired swim bladder inflation in early life stage fathead minnows exposed to a deiodinase inhibitor, iopanoic acid. Environmental Toxicology and Chemistry 36, 2942-2952.

Chopra, K., Ishibashi, S., Amaya, E., 2019. Zebrafish duox mutations provide a model for human congenital hypothyroidism. Biology Open 8.

Czesny, S.J., Graeb, B.D.S., Dettmers, J.M., 2005. Ecological consequences of swim bladder noninflation for larval yellow perch. Transactions of the American Fisheries Society 134, 1011-1020.

Godfrey, A., Hooser, B., Abdelmoneim, A., Horzmann, K.A., Freemanc, J.L., Sepulveda, M.S., 2017. Thyroid disrupting effects of halogenated and next generation chemicals on the swim bladder development of zebrafish. Aquatic Toxicology 193, 228-235.

Hagenaars, A., Stinckens, E., Vergauwen, L., Bervoets, L., Knapen, D., 2014. PFOS affects posterior swim bladder chamber inflation and swimming performance of zebrafish larvae. Aquatic Toxicology 157, 225-235.

Heijlen, M., Houbrechts, A., Bagci, E., Van Herck, S., Kersseboom, S., Esguerra, C., Blust, R., Visser, T., Knapen, D., Darras, V., 2014. Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and  early larval development in zebrafish. Endocrinology 155, 1547-1559.

Houbrechts, A.M., Delarue, J., Gabriels, I.J., Sourbron, J., Darras, V.M., 2016. Permanent Deiodinase Type 2 Deficiency Strongly Perturbs Zebrafish Development, Growth, and Fertility. Endocrinology 157, 3668-3681.

Jomaa, B., Hermsen, S.A.B., Kessels, M.Y., van den Berg, J.H.J., Peijnenburg, A.A.C.M., Aarts, J.M.M.J.G., Piersma, A.H., Rietjens, I.M.C.M., 2014. Developmental Toxicity of Thyroid-Active Compounds in a Zebrafish Embryotoxicity Test. Altex-Alternatives to Animal Experimentation 31, 303-317.

Knapen, D., Angrish, M.M., Fortin, M.C., Katsiadaki, I., Leonard, M., Margiotta-Casaluci, L., Munn, S., O'Brien, J.M., Pollesch, N., Smith, L.C., Zhang, X.W., Villeneuve, D.L., 2018. Adverse outcome pathway networks I: Development and applications. Environmental Toxicology and Chemistry 37, 1723-1733.

Liu, Y.W., Chan, W.K., 2002. Thyroid hormones are important for embryonic to larval transitory phase in zebrafish. Differentiation 70, 36-45.

Maack, G., Segner, H., 2003. Morphological development of the gonads in zebrafish. Journal of Fish Biology 62, 895-906.

Nelson, K., Schroeder, A., Ankley, G., Blackwell, B., Blanksma, C., Degitz, S., Flynn, K., Jensen, K., Johnson, R., Kahl, M., Knapen, D., Kosian, P., Milsk, R., Randolph, E., Saari, T., Stinckens, E., Vergauwen, L., Villeneuve, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquatic Toxicology 173, 192-203.

Power, D.M., Llewellyn, L., Faustino, M., Nowell, M.A., Bjornsson, B.T., Einarsdottir, I.E., Canario, A.V., Sweeney, G.E., 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol 130, 447-459.

Robertson, G.N., McGee, C.A.S., Dumbarton, T.C., Croll, R.P., Smith, F.M., 2007. Development of the swimbladder and its innervation in the zebrafish, Danio rerio. Journal of Morphology 268, 967-985.

Stinckens, E., Vergauwen, L., Ankley, G.T., Blust, R., Darras, V.M., Villeneuve, D.L., Witters, H., Volz, D.C., Knapen, D., 2018. An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish. Aquatic Toxicology 200, 1-12.

Stinckens, E., Vergauwen, L., Blackwell, B.R., Ankley, G.T., Villeneuve, D.L., Knapen, D., The effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology submitted.

Stinckens, E., Vergauwen, L., Schroeder, A., Maho, W., Blackwell, B., Witters, H., Blust, R., Ankley, G., Covaci, A., Villeneuve, D., Knapen, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part II: Zebrafish. Aquatic Toxicology 173, 204-217.

Villeneuve, D., Angrish, M., Fortin, M., Katsiadaki, I., Leonard, M., Margiotta-Casaluci, L., Munn, S., O'Brien, J., Pollesch, N., Smith, L., Zhang, X., Knapen, D., 2018. Adverse Outcome Pathway Networks II: Network Analytics. Environ Toxicol Chem doi: 10.1002/etc.4124.

Villeneuve, D., Volz, D.C., Embry, M.R., Ankley, G.T., Belanger, S.E., Leonard, M., Schirmer, K., Tanguay, R., Truong, L., Wehmas, L., 2014. Investigating alternatives to the fish early-life stage test: a strategy for discovering and annotating adverse outcome pathways for early fish development. Environmental Toxicology and Chemistry 33, 158-169.

Walpita, C.N., Crawford, A.D., Janssens, E.D., Van der Geyten, S., Darras, V.M., 2009. Type 2 iodothyronine deiodinase is essential for thyroid hormone-dependent embryonic development and pigmentation in zebrafish. Endocrinology 150, 530-539.

Woolley, L.D., Qin, J.G., 2010. Swimbladder inflation and its implication to the culture of marine finfish larvae. Reviews in Aquaculture 2, 181-190.