Science Inventory

OECD Series on Adverse Outcome Pathways No. 26: Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation

Citation:

Vergauwen, L., E. Stinckens, D. Villeneuve, AND D. Knapen. OECD Series on Adverse Outcome Pathways No. 26: Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation. OECD Press, Paris, France, 2022. https://doi.org/10.1787/2415170X

Impact/Purpose:

This Adverse Outcome Pathway (AOP) describes the linkage between Thyroperoxidase inhibition and increased mortality via reduced anterior 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 159 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).

Description:

This AOP describes the sequence of events leading from thyroperoxidase inhibition to increased mortality via reduced anterior swim bladder inflation. The enzyme thyroperoxidase (TPO) is essential for the synthesis of thyroxine (T4) and triiodothyronine (T3) in the thyroid follicles. Inhibition of TPO reduces thyroid hormone (TH) levels. Thyroid hormones are critical in regulating developmental processes and thyroid hormone disruption can interfere with normal development. Swim bladder inflation is known to be under TH control (Brown et al., 1988; Liu and Chan, 2002). Many fish species have a swim bladder which 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. Both the posterior and the anterior chamber have an important role in regulating buoyancy, and the anterior chamber has an additional role in hearing (Robertson et al., 2007). This AOP describes how inhibition of TPO results in decreased synthesis of THs in the thyroid follicles. This reduces the availability of T4 for conversion to the more biologically active T3. Reduced T3 levels prohibit normal inflation of the anterior swim bladder chamber. Due to its role in regulating buoyancy, this results in reduced swimming performance. Since reduced swimming performance results in a decreased ability to forage and avoid predators, this reduces chances of survival. 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 (Nelson et al., 2016; Godfrey et al., 2017; Stinckens et al., 2016, 2020). Additional evidence of a link between reduced TH synthesis and reduced anterior chamber inflation is available from a study where a mutation was inserted in the gene coding for dual oxidase, another enzyme that is important for TH synthesis since it provides hydrogen peroxide for iodide oxidation (Chopra et al., 2019). 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). Apart from the upstream part, the current AOP is identical to the corresponding AOPs leading from DIO1 and DIO2 inhibition to increased mortality via anterior swim bladder inflation (https://aopwiki.org/aops/156, https://aopwiki.org/aops/158).