To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1028

Relationship: 1028


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

Reduced, Posterior swim bladder inflation leads to Reduced, Swimming performance

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 adjacent Moderate Low Dries Knapen (send email) Under Development: Contributions and Comments Welcome WPHA/WNT Endorsed
Deiodinase 1 inhibition leading to increased mortality via reduced posterior swim bladder inflation adjacent Moderate Low Dries Knapen (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 Moderate NCBI
bluefin tuna Thunnus thynnus Moderate NCBI
Dicentrarchus labrax Dicentrarchus labrax Moderate NCBI
Perca flavescens Perca flavescens Moderate NCBI
Salmo salar Salmo salar Moderate 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

Effects on swim bladder inflation can alter swimming performance and buoyancy of fish, which is essential for predator avoidance, energy sparing, migration, reproduction and feeding behaviour, resulting in increased mortality.

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

The weight of evidence supporting a direct linkage between these two KEs, i.e. reduced posterior swim bladder inflation and reduced swimming performance, is 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

The posterior chamber of the swim bladder has a function in regulating the buoyancy of fish (Roberston et al., 2007). Fish rely on the lipid and gas content in their body to regulate their position within the water column, with the latter being more efficient at increasing body buoyancy. Therefore, fish with functional swim bladders have no problem supporting their body (Brix 2002), while it is highly likely that impaired inflation severely impacts swimming performance, as has been suggested previously (Bagci et al., 2015; Hagenaars et al., 2014). Fish without a functional swim bladder are severely disadvantaged, making the likelihood of surviving smaller. Stoyek et al. (2011) showed that the posterior chamber volume is maintained at a stable level at varying pressures corresponding to varying depths through gas exchange with the anteror chamber.

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

Robertson et al., (2007) reported that the swim bladder only becomes functional as a buoyancy regulator when it is fully developed into a double-chambered swim bladder. This implies that effects on posterior chamber inflation would not directly result in effects on swimming capacity. However, it was also reported that gas in the swim bladder increases the buoyancy of zebrafish larvae already just after initial inflation, while it would be actively controlled only after 28–30 d post hatch. Therefore, an effect on swimming capacity is still likely.

Exposure of zebrafish embryos to 6-propylthiouracil (PTU) resulted in an effect on posterior chamber inflation, but did not result in a direct effect on the swimming distance in the larval stage (Stinckens et al., unpublished). Vergauwen et al. (2015) reported decreased swimming activity as well as impaired posterior chamber inflation after exposure to phenanthrene, a non-polar narcotic, but there was no significant difference between swimming activity of larvae with our without inflated posterior chamber within the same treatment. Possibly, the impact of baseline toxicity on respiration and energy metabolism was more important in decreasing swimming activity compared to impaired inflation of the posterior chamber.

It has been difficult to unambiguously attribute reduced swimming activity to impaired inflation of the posterior chamber, since swimming activity can be altered via different modes of action including altered energy metabolism, altered brain development and thus swimming behaviour. For example, the swimming activity of zebrafish larvae was reduced after 5 days of exposure to 2-mercaptobenzothiazole (MBT), while they had inflated posterior chambers.

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

Relations between reduced swim bladder inflation and reduced swimming performance are currently based on a binary observation of swim bladder inflation. Several studies have shown that larvae with inflated swim bladders have higher swiming activity compared to larvae that failed to inflate the swim bladder. No direct relationship between swim bladder surface (quantitative measure of swim bladder inflation) and swimming performance has been reported yet.

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

The data of Michiels et al. (2017) and Stinckens et al. (unpublished) on swim bladder inflation and swimming activity have been collected on the same day. The process of posterior chamber inflation normally occurs during a specific developmental time frame, resulting in limited flexibility to explore temporal concordance. Based on the biologically plausible direct importance of swim bladder functionality to swimming performance, no lag is expected.

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: Importance of proper functioning of the swim bladder for supporting natural swimming behaviour can be plausibly assumed to be generally applicable to fish possessing a posterior chamber. Evidence exists for a wide variety of freshwater and marine fish species.

Life stage: This KER is only applicable to early embryonic development, which is the period where the posterior swim bladder chamber inflates. To what extent fish can survive and swim with partly inflated swim bladders during later life stages is unknown.

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.


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 earlyzebrafish development affects growth, development, energy metabolism,motility and phototransduction. PLoS One 10, e0123285,

Brix O (2002) The physiology of living in water. In: Hart PJ, Reynolds J (eds) Handbook of Fish Biology and Fisheries, Vol. 1, pp. 70–96. Blackwell Publishing, Malden, USA.

Chatain, B., 1994. Abnormal swimbladder development and lordosis in sea bass (Dicentrarchus labrax) and sea bream (Sparus auratus). Aquaculture 119:371–379.

Czesny, S.J., Graeb, B.D.S., Dettmersn, J.M., 2005. Ecological consequences of swimbladder noninflation for larval yellow perch. Trans. Am. Fish. Soc. 134,1011–1020,

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.

Goodsell, D.S., Morris, G.M., Olsen, A.J. 1996. Automated docking of fleixble ligands. Applications of Autodock. J. Mol. Recogonition, 9:1-5.

Hagenaars, A., Stinckens, E., Vergauwen, L., Bervoets, L., Knapen, D., 2014. PFOS affects posterior swim bladder chamber inflation and swimming performanceof zebrafish larvae. Aquat. Toxicol. 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.

Kurata, M., Ishibashi, Y., Takii, K., Kumai, H., Miyashita, S., Sawada, Y., 2014.Influence of initial swimbladder inflation failure on survival of Pacific bluefintuna, Thuunus orientalis (Temminck and Schlegl) larvae. Aquacult. Res. 45,882–892.

Lindsey, B.W., Smith, F.M., Croll, R.P., 2010. From inflation to flotation: contributionof the swimbladder to whole-body density and swimming depth duringdevelopment of the zebrafish (Danio rerio). Zebrafish 7, 85–96,

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

Massei R et al. (in preparation) Sublethal adverse effects of non-polar narcotics in the zebrafish embryo.

Michiels, E.D.G., Vergauwen, L., Hagenaars, A., Fransen, E., Van Dongen, S., Van Cruchten, S.J., Bervoets, L., Knapen, D., 2017. Evaluating Complex Mixtures in the Zebrafish Embryo by Reconstituting Field Water Samples: A Metal Pollution Case Study. International Journal of Molecular Sciences 18, 539.

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.

Poppe, T.T., Hellberg, H., Griffiths, D., Mendal, H. 1977. Swim bladder abnormality in farmed Atlantic salmon, Salmo salar. Diseases of aquatic organisms 30:73-76.

Roberston, G.N., McGee, C.A.S., Dumbarton, T.C., Croll, R.P., Smith, F.M., 2007.Development of the swim bladder and its innervation in the zebrafish, Danio rerio. J. Morphol. 268, 967–985,

Stewart, D.B., Gee, J.H., 1981. Mechanisms of buoyancy adjustments and effects of water velocity and temperature on ability to maintain buoyancy in fathead minnows, Pimephales promelas, Rafinesque. Comparative Biochemistry and Physiology a-Physiology 68, 337-347.

Stinckens, E., Vergauwen, L., Blackwell, B.R., Anldey, G.T., Villeneuve, D.L., Knapen, D., 2020. Effect of Thyroperoxidase and Deiodinase Inhibition on Anterior Swim Bladder Inflation in the Zebrafish. Environmental Science & Technology 54, 6213-6223.

Stinckens, E., Vergauwen, L., Schroeder, A.L., Maho, W., Blackwell, B., Witter, H.,Blust, R., Ankley, G.T., Covaci, A., Villenueve, D.L., Knapen, D., 2016. Disruption of thyroid hormone balance after 2-mercaptobenzothiazole exposure causes swim bladder inflation impairment—part II: zebrafish. Aquat. Toxicol. 173:204-17.

Stoyek, M.R., Smith, F.M., Croll, R.P., 2011. Effects of altered ambient pressure on the volume and distribution of gas within the swimbladder of the adult zebrafish, Danio rerio. Journal of Experimental Biology 214, 2962-2972.

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.

Vergauwen, L., Schmidt, S.N., Stinckens, E., Maho, W., Blust, R., Mayer, P., Covaci, A., Knapen, D., 2015. A high throughput passive dosing format for the Fish Embryo Acute Toxicity test. Chemosphere 139, 9-17.