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Dries Knapen , [dries.knapen (at)uantwerpen.be]
Lucia Vergauwen , [lucia.vergauwen(at)uantwerpen.be]
Evelyn Stinckens , [evelyn.stinckens(at)uantwerpen.be]
Dan Villeneuve , [villeneuve.dan*(at)epa.gov]
 Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
United States Environmental Protection Agency, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN, USA.
Point of Contact
Dries Knapen (email point of contact)
- Dries Knapen
- Lucia Vergauwen
|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 Do not cite||Under Development||1.35||Included in OECD Work Plan|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
|Inhibition, Deiodinase 2||August 20, 2019 09:52|
|Decreased, Triiodothyronine (T3) in serum||September 26, 2017 11:03|
|Reduced, Posterior swim bladder inflation||February 18, 2019 10:52|
|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||October 31, 2019 04:54|
|Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3) in serum||February 25, 2020 11:02|
|Decreased, Triiodothyronine (T3) in serum leads to Reduced, Posterior swim bladder inflation||February 26, 2020 06:37|
|Reduced, Posterior swim bladder inflation leads to Reduced, Swimming performance||September 17, 2019 11:49|
|Reduced, Swimming performance leads to Reduced, Young of year survival||September 17, 2019 12:00|
|Reduced, Young of year survival leads to Decrease, Population trajectory||December 03, 2016 16:38|
|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||February 25, 2020 12:15|
|Inhibition, Deiodinase 2 leads to Reduced, Posterior swim bladder inflation||August 13, 2019 13:16|
|Reduced, Posterior swim bladder inflation leads to Reduced, Young of year survival||March 08, 2019 08:33|
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 .
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|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)
|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|
Life Stage Applicability
|fathead minnow||Pimephales promelas||NCBI|
Overall Assessment of the AOP
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
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
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.
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.
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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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.
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