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Relationship: 1042

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, Deiodinase 2 leads to Reduced, Posterior swim bladder inflation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Inhibition, Deiodinase 2

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Reduced, Posterior swim bladder inflation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation	non-adjacent	Moderate	Low	Brendan Ferreri-Hanberry (send email)	Under Development: Contributions and Comments Welcome	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Embryo	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The two major thyroid hormones are thyroxine (T4) and the more biologically active triiodothyronine (T3), both iodinated derivatives of tyrosine. Active and inactive THs are tightly regulated by enzymes called iodothyronine deiodinases (DIO). The activation occurs via outer ring deiodination (ORD), i.e. removing iodine from the outer, phenolic ring of T4 to form T3, while inactivation occurs via inner ring deiodination (IRD), i.e. removing iodine from the inner tyrosol ring of T4 or T3.

Three types of iodothyronine deiodinases (DIO1-3) have been described in vertebrates that activate or inactivate THs and are therefore important mediators of TH action. All deiodinases are integral membrane proteins of the thioredoxin superfamily that contain selenocysteine in their catalytic centre. Type I deiodinase is capable of converting T4 into T3, as well as to convert rT3 to the inactive thyroid hormone 3,3’ T2, through outer ring deiodination. rT3, rather than T4, is the preferred substrate for DIO1. furthermore, DIO1 has a very high Km (µM range, compared to nM range for DIO2) (Darras and Van Herck, 2012). Type II deiodinase (DIO2) is only capable of ORD activity with T4 as a preferred substrate (i.e., activation of T4 tot T3). DIO3 can inner ring deiodinate T4 and T3 to the inactive forms of THs, reverse T3, (rT3) and 3,3’-T2 respectively. (Darras and Van Herck, 2012)

Inhibition of DIO2 therefore results in decreased T3 levels. Since swim bladder development and/or inflation is regulated by thyroid hormones, this results in impaired posterior chamber inflation.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

There is convincing evidence that inhibition of DIO activity, either through specific knockdown or through chemical exposure, results in impaired posterior chamber inflation, but the underlying mechanisms are not completely understood, including the relative importance of DIO1 and DIO2. Based on current evidence, it seems that DIO2 is more important in regulating posterior chamber inflation. Due to the difficulty of measuring DIO activity in small fish embryos, quantitative linkages and temporal concordance have been difficult to establish. The quantitative understanding is currently based on a relationship between the classification of chemicals according to their in chemico DIO inhibitory potential (using a threshold and uncertainty zone) on the one hand, and occurence of in vivo effects on posterior chamber inflation on the other hand. Predictions based on this relationship have been proven highly successful. Therefore the evidence supporting this KER can be considered moderate.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Inhibition of DIO 2 activity is widely accepted to reduce the conversion of T4 to the more biologically active T3. Thyroid hormones are known to be involved in development, especially in metamorphosis in amphibians and in embryonic-to-larval transition and larval-to-juvenile transition in fish. Inflation of the posterior swim bladder chamber is part of the embryonic-to-larval transition in fish, together with structural and functional maturation of the mouth and gastrointestinal tract, and resorption of the yolk sac. Together with empirical evidence, it is plausible to assume that posterior swim bladder inflation is under thyroid hormone regulation but scientific understanding is incomplete. It follows that disrupted conversion of T4 to T3 is likely to interfere with normal inflation of the posterior swim bladder chamber.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Deiodinases are criticial for normal development. Several defects have already been reported in cases where the TH hormone balance is disturbed. Winata et al. (2009, 2010) reported reduced pigmentation, otic vesicle length and head-trunk angle in DIO1+2 and DIO2 knockdown fish. These effects were rescued after T3 supplementation, indicating the importance of T4 to T3 conversion by deiodinases.

Substantial evidence for the link between deiodinase inhibition and impaired posterior chamber inflation is available:

Chang et al., (2012) established a base-line for TH levels during zebrafish development and observed peaks in whole-body T3 content at 5 dpf when the posterior chamber of the swim bladder inflates.
Bagci et al. (2015) and Heijlen et al. (2013, 2014) reported that knockdown of DIO1+2 in zebrafish resulted in impairment of the inflation of the posterior chamber of the swim bladder.
Permanent DIO 2 deficiency in zebrafish was shown to result in reduced posterior chamber inflation (Houbrechts et al., 2016).
DIO1 and DIO2 mRNA has also been shown to be present in zebrafish swim bladder tissue at 96 hpf using whole mount in situ hybridization (Heijlen et al., 2013; Dong et al., 2013), suggesting a tissue-specific role of T3 in the inflation process of the posterior chamber.
Propylthiouracil (PTU) decreased serum T3 levels in the rat (Frumess and Larsen, 1975) and resulted in effects on posterior chamber inflation in zebrafish (Jomaa et al., 2014; Stinckens et al., 2018). It should be noted that there are some uncertainties related to the species-specific susceptibility of DIO1 to inhibition by PTU, as teleostean DIO1 seems to be less sensitive to inhibition by PTU (Orozco and Valverde, 2005; Kuiper et al., 2006; Orozco et al., 2012).
Stinckens et al. (2018) showed that effects on posterior chamber inflation in zebrafish could be predicted based on in chemico DIO2 inhibition potential with only few false positives and false negatives.
After exposure of fathead minnows (Pimephales promelas) to the non-specific deiodinase inhibitor IOP from 1-6 dpf, Incidence and length of inflated posterior swim bladders were significantly reduced (Cavallin et al., 2017).
While DIO1 has a high Km and rT3 is its preferred substrate, DIO2 has a low Km and T4 is its preferred substrate, indicating that DIO2 is more important than DIO1 in converting T4 to T3 in a physiological situation (Darras and Van Herck, 2012). It follows that DIO2 inhibition is likely more important than DIO1 inhibition in reducing posterior chamber inflation.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The mechanism through which altered TH levels result in impaired posterior chamber inflation still needs to be elucidated.

It is currently unclear which aspect of swim bladder development and inflation is affected by TH disruption. Based on the developmental stages of the posterior chamber, several hypotheses could explain effects on posterior chamber inflation due to disrupted TH levels. A first hypothesis includes effects on the budding of the posterior chamber inflation. Secondly, the effect on posterior chamber inflation could also be caused by disturbing the formation and growth of the three tissue layers of this organ. It has been reported that the Hedgehog signalling pathway plays an essential role in swim bladder development and is required for growth and differentiation of cells of the swim bladder. The Wnt/β-catenin signalling pathway is required for the organization and growth of all three tissue layers (Yin et al., 2011, 2012, Winata 2009, Kress et al., 2009). Both signalling pathways have been related to THs in amphibian and rodent species (Kress et al., 2009; Plateroti et al., 2006; Stolow and Shi, 1995). Several other hypotheses include effects on the successful initial inflation of the posterior chamber, effects on lactic acid production that is required for the maintenance of the swim bladder volume, or effects on the production of surfactant that is crucial to maintain the surface tension necessary for swim bladder inflation.

Another uncertainty lies in the relative importance of the different T4 activating iodothyronine deiodinases (DIO1, DIO2) in regulating swim bladder inflation. Stinckens et al. (2018) showed that when exposing zebrafish embryos to seven strong DIO1 inhibitors (measured using in chemico enzyme inhibition assays), six out of seven compounds impaired posterior chamber inflation, but almost all of these compounds also inhibit DIO2. Tetrachlorobisphenol A (TCBPA), the only compound that inhibits DIO1 and not DIO2, had no effect on the posterior swim bladder. Exposure to strong DIO2 inhibitors on the other hand affected posterior chamber inflation and/or surface area in all cases. These results suggest that DIO2 enzymes may play a more important role in swim bladder inflation compared to DIO1 enzymes. In the ToxCast DIO2 inhibition single concentration assay, 304 out of 1820 chemicals were positive and 177 of these were also positive for DIO1 inhibition (viewed on 5/7/2022). This complicates the distinction between the relative contribution of DIO1 and DIO2 inhibition to reduced swim bladder inflation. It has been previously suggested that DIO2 is the major contributor to TH activation in developing zebrafish embryos (Darras et al., 2015; Walpita et al., 2010). It has been shown that a morpholino knockdown targeting DIO1 mRNA alone did not affect embryonic development in zebrafish, while knockdown of DIO2 delayed progression of otic vesicle length, head-trunk angle and pigmentation index (Houbrechts et al., 2016; Walpita et al., 2010, 2009). DIO1 inhibition may only become essential in hypothyroidal circumstances, for example when DIO2 is inhibited or in case of iodine deficiency, in zebrafish (Walpita et al., 2010) and mice (Galton et al., 2009; Schneider et al., 2006).

Heijlen et al. (2015) reported histologically abnormal tissue layers in the swim bladder of DIO3 knockdown zebrafish. As reported in Bagci et al. (2015) and Heijlen et al. (2014), posterior chamber inflation was impaired in DIO3 knockdown zebrafish. DIO3 is a thyroid hormone inactivating enzyme, which would result in higher levels of T3. This indicates that not only too low, but also too high T3 levels, impact posterior chamber inflation. The underlying mechanism is currently unknown.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

In chemico DIO2 inhibition assays were performed using potential thyroid disrupting compounds (Stinckens et al., 2018). Using dose-response curves, the IC50 values were determined and used to caterogize the chemicals according to their potency (strong, weak, uncertainty zone). For DIO2, 6 potent DIO2 inhibitors were selected, all of which caused an effect on posterior chamber inflation in zebrafish embryos. Two out of five compounds in the uncertainty zone impaired posterior chamber inflation. Finally, 1 out of 3 weak DIO2 inhibitors caused impaired posterior chamber inflation, resulting in 1 false negative prediction. The latter false negative prediction is potentially due to the fact that multiple AOPs can result in impaired swim bladder inflation.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic: Teleost fish can be divided in two groups according to swim bladder morphology: physoclistous (e.g., yellow perch, sea bass, striped bass) and physostomous (e.g., zebrafish and fathead minnow). Physostomous fish retain a duct between the digestive tract and the swim bladder during adulthood allowing them to gulp air at the surface to fill the swim bladder. In contrast, in physoclistous fish, once initial inflation by gulping atmospheric air at the water surface has occurred, the swim bladder is closed off from the digestive tract and swim bladder volume is regulated by gas secretion into the swim bladder (Woolley and Qin, 2010). Much of the evidence for impaired posterior chamber of the swim bladder currently comes from work on zebrafish and fathead minnow (Stinckens et al., 2018; Cavallin et al., 2017; Wang et al., 2020), but this KE is plausibly applicable across fish species with swim bladders, both physostomous and physoclistous.

Sex: This KE/KER is plausibly applicable to both sexes. Sex differences are not often investigated in tests using early life stages of fish. In Medaka, sex can be morphologically distinguished as soon as 10 days post fertilization. Females appear more susceptible to thyroid‐induced swim bladder dysfunction compared with males (Godfrey et al., 2019). In zebrafish and fathead minnow, it is currently unclear whether sex-related differences are important in determining the magnitude of the changes in this KE/KER. 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 in zebrafish, when sex differentiation has not started yet, sex differences are expected to play a minor role. Fathead minnow gonad differentiation also occurs during larval development. Fathead minnows utilize a XY sex determination strategy and markers can be used to genotype sex in life stages where the sex is not yet clearly defined morphologically (Olmstead et al., 2011). Ovarian differentiation starts at 10 dph followed by rapid development (Van Aerle et al., 2004). At 25 dph germ cells of all stages up to the primary oocytes stage were present and at 120 dph, vitellogenic oocytes were present. The germ cells (spermatogonia) of the developing testes only entered meiosis around 90–120 dph. Mature testes with spermatozoa are present around 150 dph. Since the posterior chamber inflates around 6 days post fertilization (1 dph) in fathead minnows, sex differences are expected to play a minor role in the current AOP.

Life stage: This KER is only applicable to early embryonic development, which is the period where the posterior swim bladder chamber inflates.

References

List of the literature that was cited for this KER description. More help

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, http://dx.doi.org/10.1371/journal.pone.0123285.

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.

Chang, J., Wang, M., Gui, W., Zhao, Y., Yu, L., Zhu, G., 2012. Changes in thyroidhormone levels during zebrafish development. Zool. Sci. 29, 181–184, http://dx.doi.org/10.2108/zsj.29.181.

Darras, V.M., Houbrechts, A.M., Van Herck, S.L.J., 2015. Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor-mediated impact on vertebrate development. Biochimica Et Biophysica Acta-Gene Regulatory Mechanisms 1849, 130-141.

Degitz, S.J., Holcombe, G.W., Flynn, K.M., Kosian, P.A., Korte, J.J., Tietge, J.E., 2005.Progress towards development of an amphibian-based screening assay usinXenopus laevis. Organismal and thyroidal responses to the model compounds6-propylthiouracil, methimazole, and thyroxine. Toxicol. Sci. 87, 353–364.

Dong, W., Macaulay, L., Kwok, K.W.H., Hinton, D.E., Stapleton, H.M., 2013. Using whole mount in situ hydridization to examine thyroid hormone deiodinase expression in embryonic and larval zebrafish: a tool for examining OH-BDE toxicity to early life stages. Aquat. Toxicol. 132–133, 190–199, http://dx.doi.org/10.1016/j.biotechadv.2011.08.021.Secreted.

Frumess, R.D., Larsen, P.R. 1975. Correlation of serum triiodothyronine (T3) and thyroxine (T4) with biological effects of thyroid hormone replacement in propylthiouracil-treated rats. Metabolism 24:4.

Galton, V.A., Schneider, M.J., Clark, A.S., St Germain, D.L., 2009. Life without thyroxine to 3,5,3'-triiodothyronine conversion: studies in mice devoid of the 5'-deiodinases. Endocrinology 150, 2957-2963.

Godfrey A, Hooser B, Abdelmoneim A, Sepulveda MS. 2019. Sex-specific endocrine-disrupting effects of three halogenated chemicals in japanese medaka. Journal of Applied Toxicology. 39(8):1215-1223.

Heijlen, M., Houbrechts, A.M., Bagci, E., Van Herck, S.L.J., Kersseboom, S., Esguerra,C.V., Blust, R., Visser, T.J., Knapen, D., Darras, V.M., 2014. Knockdown of type 3iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. Endocrinology 155, 1547–1559, http://dx.doi.org/10.1210/en.2013-1660.

Heijlen, M., Houbrechts, A.M., Darras, V.M., 2013. Zebrafish as a model to study peripheral thyroid hormone metabolism in vertebrate development. Gen.Comp. Endocrinol. 188, 289–296, http://dx.doi.org/10.1016/j.ygcen.2013.04.004.

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 31,303–317, http://dx.doi.org/10.14573/altex.1402011.

Kress, E., Rezza, A., Nadjar, J., Samarut, J., Plateroti, M., 2009. The frizzled-relatedsFRP2 gene is a target of thyroid hormone receptor alfa1 and activates beta-catenin signaling in mouse intestine. J. Biol. Chem. 284, 1234–1241, http://dx.doi.org/10.1074/jbc.M806548200.

Kuiper, G., Klootwijk, W., Dubois, G.M., Destree, O., Darras, V.M., Van der Geyten, S., Demeneix, B., Visser, T.J., 2006. Characterization of recombinant Xenopus laevis type I iodothyronine deiodinase: substitution of a proline residue in the catalytic center by serine (Pro132Ser) restores sensitivity to 6-propyl-2-thiouracil. Endocrinology 147, 3519-3529.

Mol, K.A., Van der Geyten, S., Burel, C., Kuhn, E.R., Boujard, T., Darras, V.M., 1998. Comparative study of iodothyronine outer ring and inner ring deiodinase activities in five teleostean fishes. Fish Physiology and Biochemistry 18, 253-266.

Nagabhushana A, Mishra RK. 2016. Finding clues to the riddle of sex determination in zebrafish. Journal of Biosciences. 41(1):145-155.

Olmstead AW, Villeneuve DL, Ankley GT, Cavallin JE, Lindberg-Livingston A, Wehmas LC, Degitz SJ. 2011. A method for the determination of genetic sex in the fathead minnow, pimephales promelas, to support testing of endocrine-active chemicals. Environmental Science & Technology. 45(7):3090-3095.

Orozco, A., Valverde, C., Olvera, A., Garcia, C., 2012. Iodothyronine deiodinases: a functional and evolutionary perspective. Journal of Endocrinology 215, 207-219.

Orozco, A., Valverde, R.C., 2005. Thyroid hormone deiodination in fish. Thyroid 15, 799-813.

Plateroti, M., Kress, E., Mori, J.I., Samarut, J., 2006. Thyroid hormone receptor alpha1 directly controls transcription of the beta-catenin gene in intestinal epithelial cells. Mol. Cell. Biol. 26, 3204–3214, http://dx.doi.org/10.1128/MCB.26.8.3204.

Schneider, M.J., Fiering, S.N., Thai, B., Wu, S.Y., St Germain, E., Parlow, A.F., St Germain, D.L., Galton, V.A., 2006. Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 147, 580-589.

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. 10.1016/j.aquatox.2018.04.009.

Stolow, M.A., Shi, Y.B., 1995. Xenopus sonic hedgehog as a potential morphogen during embryogenesis and thyroid hormone-dependent metamorphosis.Nucleic Acids Res. 23, 2555–2562, http://dx.doi.org/10.1093/nar/23.13.2555.

Uchida, D., Yamashita, M., Kitano, T., Iguchi, T., 2002. Oocyte apoptosis during the transition from ovary-like tissue to testes during sex differentiation of juvenile zebrafish. Journal of Experimental Biology 205, 711-718.

van Aerle R, Runnalls TJ, Tyler CR. 2004. Ontogeny of gonadal sex development relative to growth in fathead minnow. Journal of Fish Biology. 64(2):355-369.

Walpita, C.N., Crawford, A.D., Darras, V.M., 2010. Combined antisense knockdown of type 1 and type 2 iodothyronine deiodinases disrupts embryonic development in zebrafish (Danio rerio). General and Comparative Endocrinology 166, 134-141.

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.

Wang JX, Shi GH, Yao JZ, Sheng N, Cui RN, Su ZB, Guo Y, Dai JY. 2020. Perfluoropolyether carboxylic acids (novel alternatives to pfoa) impair zebrafish posterior swim bladder development via thyroid hormone disruption. Environment International. 134.

Winata, C.L., Korzh, S., Kondrychyn, I., Korzh, V., Gong, Z. 2010. The role of vasulature and blood circulation in zebrafish swim bladder development. Dev. Biol. 10:3.

Winata, C.L., Korzh, S., Kondrychyn, I., Zheng, W., Korzh, V., Gong, Z. 2009. Development of zebrafish swimbladder: the requirement of Hedgehog signaling in specification and organization of the three tissue layers. Dev. Biol.331, 222–236, http://dx.doi.org/10.1016/j.ydbio.2009.04.035.

Woolley LD, Qin JG. 2010. Swimbladder inflation and its implication to the culture of marine finfish larvae. Reviews in Aquaculture. 2(4):181-190.

Yin, A., Korzh, S., Winata, C.L., Korzh, V., Gong, Z., 2011. Wnt signaling is required for early development of zebrafish swimbladder. PLoS One 6, http://dx.doi.org/10.1371/journal.pone.0018431.

Yin, A., Korzh, V., Gong, Z., 2012. Perturbation of zebrafish swim bladder development by enhancing Wnt signaling in Wif1 morphants. Biochim.Biophys. Acta—Mol. Cell Res. 1823, 236–244, http://dx.doi.org/10.1016/j.bbamcr.2011.09.018