Science Inventory

OECD Series on Adverse Outcome Pathways No. 22: Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation

Citation:

Vergauwen, L., E. Stinckens, D. Villeneuve, AND D. Knapen. OECD Series on Adverse Outcome Pathways No. 22: Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation. OECD Press, Paris, France, 2022. https://doi.org/10.1787/dc406014-en

Impact/Purpose:

This Adverse Outcome Pathway (AOP) describes the linkage between Deiodinase 2 inhibition and increased mortality via reduced posterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 155 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).

Description:

This AOP describes the sequence of events leading from deiodinase inhibition to increased mortality via reduced posterior swim bladder inflation. Disruption of the thyroid hormone system is increasingly being recognized as an important toxicity pathway that can cause many adverse outcomes, including developmental abnormalities. Three types of iodothyronine deiodinases (DIO1-3) have been described in vertebrates that activate or inactivate THs and are therefore important mediators of thyroid hormone (TH) action. Type II deiodinase (DIO2) has thyroxine (T4) as a preferred substrate and is mostly important for converting T4 to the more biologically active triiodothyronine (T3). Inhibition of DIO2 therefore reduces T3 levels. As in amphibians, the transition between the different developmental phases in fish, including maturation and inflation of the swim bladder, is mediated by THs (Brown et al., 1988; Liu and Chan, 2002). The swim bladder is a gas-filled organ that typically consists of two chambers (Robertson et al., 2007). The posterior chamber inflates during early development in the embryonic phase, while the anterior chamber inflates during late development in the larval phase. This AOP describes how DIO2 inhibition results in reduced T3 levels, which prohibit normal inflation of the posterior chamber of the swim bladder in the embryonic phase. The posterior chamber is important for regulating buoyancy and thus for swimming performance (Robertson et al., 2007). Reduced swimming performance reduces chances of survival due to a decreased ability to forage and avoid predators. The final adverse outcome is a decrease of the population growth rate. Since many AOPs eventually lead to this more general adverse outcome at the population level, the more specific and informative adverse outcome at the organismal level, increased mortality, is used in the AOP title. Support for this AOP is mainly based on chemical exposures in zebrafish and fathead minnows (Jomaa et al., 2014; Cavallin et al., 2017; Stinckens et al., 2018) and on knockdown/knockout and TH supplementation studies in zebrafish embryos where the DIO2 gene is inactivated (Walpita et al., 2009, 2010; Heijlen et al., 2014; Bagci et al., 2015; Houbrechts et al., 2016). This AOP is part of a larger AOP network describing how decreased synthesis and/or decreased biological activation of THs leads to incomplete or improper inflation of the swim bladder, leading to reduced swimming performance, increased mortality and decreased population trajectory (Knapen et al., 2018; Knapen et al., 2020; Villeneuve et al., 2018).Other than the difference in deiodinase (DIO) isoform, the current AOP is identical to the corresponding AOP leading from DIO1 inhibition to increased mortality via posterior swim bladder inflation (https://aopwiki.org/aops/157). The overall importance of DIO1 versus DIO2 in fish is not exactly clear. DIO2 inhibitors are often also inhibitors of DIO1 (Stinckens et al. 2018). 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. The current state of the art suggests that DIO2 is more important than DIO1 in regulating swim bladder inflation (Stinckens et al., 2018). Therefore the current AOP may be of higher biological relevance compared to AOP 157.