Citation:

Van Dingenen, I., L. Vergauwen, A. Haigis, B. Blackwell, E. Stacy, D. Villeneuve, AND D. Knapen. Deiodinase inhibition impairs the formation of the three posterior swim bladder tissue layers during early embryonic development in zebrafish. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, 261:106632, (2023). https://doi.org/10.1016/j.aquatox.2023.106632

Impact/Purpose:

Certain per- and polyfluorinated alkyl substances (PFAS) and other environmental contaminants have potential to disrupt thyroid hormone regulation and signaling through inhibition of deiodinase enzymes that convert thyroid hormones to more or less active forms in various tissues. The current research contributes to characterization of a series of adverse outcome pathways (AOPs) that have link deiodinase inhibition to impaired swimbladder inflation in fish. However, up to now, it was unclear whether deiodinase inhibition caused the effect by impacting the development of the organ, or by impairing the fishes' ability to inflate the organ properly. The current sub-product addresses this question and provides evidence that deiodinase inhibition impairs the formation of the swim bladder itself, not the inflation process. These results add further mechanistic understanding of the previously described AOPs and provide a foundation for designing short term assays with fish embryos suitable for rapidly and sensitively detecting this mode of endocrine disruption.

Description:

Thyroid hormone system disruption (THSD) negatively affects multiple developmental processes and organs. In fish, inhibition of deiodinases, which are enzymes crucial for (in)activating thyroid hormones (THs), leads to impaired swim bladder inflation. Until now, the underlying mechanism has remained largely unknown. Therefore, the objective of this study was to identify the process during swim bladder development that is impacted by deiodinase inhibition. Zebrafish embryos were exposed to 6 mg/L iopanoic acid (IOP), a model deiodinase inhibitor, during 8 different exposure windows (0–60, 60–120, 24–48, 48–72, 72–96, 96–120, 72–120 and 0–120 h post fertilization (hpf)). Exposure windows were chosen based on the three stages of swim bladder development: budding (24–48 hpf), pre-inflation, i.e., the formation of the swim bladder tissue layers (48–72 hpf), and inflation phase (72–120 hpf). Exposures prior to 72 hpf, during either the budding or pre-inflation phase (or both), impaired swim bladder inflation, while exposure during the inflation phase did not. Based on our results, we hypothesize that DIO inhibition before 72 hpf leads to a local decrease in T3 levels in the developing swim bladder. Gene transcript analysis showed that these TH level alterations disturb both Wnt and hedgehog signaling, known to be essential for swim bladder formation, eventually resulting in impaired development of the swim bladder tissue layers. Improper development of the swim bladder impairs swim bladder inflation, leading to reduced swimming performance. This study demonstrates that deiodinase inhibition impacts processes underlying the formation of the swim bladder and not the inflation process, suggesting that these processes primarily rely on maternal rather than endogenously synthetized THs since TH measurements showed that THs were not endogenously synthetized during the sensitive period.

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