Tentative Application of a Streamlined Protocol to Determine Organ-Specific Regulations of Deiodinase 1 and Dehalogenase Activities as Readouts of the Hypothalamus-Pituitary-Thyroid-Periphery-Axis

Renko, Kostja; Kerp, Helena; Pape, Janina; Rijntjes, Eddy; Burgdorf, Tanja; Führer, Dagmar; Köhrle, Josef

doi:10.3389/ftox.2022.822993

Cited by 5 publications

(2 citation statements)

References 36 publications

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“…It should be noted that it is difficult to make the distinction between decreased T3 levels caused by outer ring deiodination mediated by DIO2 inhibition or DIO1 inhibition. Renko et al (2022) showed tissue-specific changes in DIO1 activity in hyperand hypothyroid mice. Taxonomic: The overall evidence supporting taxonomic applicability is strong.…”

Section: How It Is Measured or Detectedmentioning

confidence: 90%

Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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This AOP describes the sequence of events leading from deiodinase inhibition to increased mortality via reduced anterior swim bladder inflation. Thyroid hormones (THs) are critical during development and disruption of the TH system can interfere with normal development. 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. While 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), type I deiodinase is capable of both converting T4 into T3 and converting rT3 to the inactive thyroid hormone 3,3' T2. Inhibition of DIO1 thus reduces T3 levels.However, partly because rT3, rather than T4, is the preferred substrate for DIO1, DIO1 inhibition is probably less important in causing reduced T3 levels when compared to DIO2 inhibition. 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., 2017). This AOP describes how inhibition of DIO1 reduces levels of T3, thereby prohibiting proper inflation of the anterior chamber. Due to its role in regulating buoyancy, this results in reduced swimming performance. Since reduced swimming performance resuls in a decreased ability to forage and avoid predators, this reduces chances of survival. The final adverse outcome is a decrease of the population trajectory. 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 (

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Section: How It Is Measured or Detectedmentioning

confidence: 90%

Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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show abstract

Section: How It Is Measured or Detectedmentioning

confidence: 90%

Deiodinase 1 inhibition leading to increased mortality via reduced posterior swim bladder inflation

2022

OECD Series on Adverse Outcome Pathways

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This AOP describes the sequence of events leading from deiodinase inhibition to increased mortality via reduced posterior swim bladder inflation. Thyroid hormones (THs) are critical during embryonic development and disruption of the TH system can interfere with normal development. 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. While 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), type I deiodinase is capable of both converting T4 into T3 and converting rT3 to 3,3' T2. Inhibition of DIO1 thus reduces T3 levels. However, partly because rT3, rather than T4, is the preferred substrate for DIO1, DIO1 inhibition is probably less important in causing reduced T3 levels when compared to DIO2 inhibition. 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;. 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 DIO1 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 trajectory. 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 (

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Neuroendocrine effects of polychlorinated biphenyls (PCBs)

Gore,

Zoeller,

Currás-Collazo

2023

Advances in Neurotoxicology

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Tentative Application of a Streamlined Protocol to Determine Organ-Specific Regulations of Deiodinase 1 and Dehalogenase Activities as Readouts of the Hypothalamus-Pituitary-Thyroid-Periphery-Axis

Cited by 5 publications

References 36 publications

Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation

Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation

Deiodinase 1 inhibition leading to increased mortality via reduced posterior swim bladder inflation

Neuroendocrine effects of polychlorinated biphenyls (PCBs)

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