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Front Pharmacol
2026 Feb 18;17:1746017. doi: 10.3389/fphar.2026.1746017.
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Zebrafish: a key model for unraveling endocrine-disrupting effects on thyroid development and function.
Mezzalira N, Rodrigues VG, Serrano-Nascimento C.
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The zebrafish (Danio rerio) has emerged as a crucial vertebrate model for studying thyroid physiology and toxicology, owing to its high genomic homology with mammals, external embryogenesis, transparent development, and the availability of advanced genetic manipulation techniques. Moreover, this experimental system is widely used for toxicity testing of environmental chemical compounds that affect thyroid function, yielding well-characterized phenotypic and molecular responses. It is well known that thyroid hormones regulate embryonic development in vertebrates, particularly the development of the central nervous system. Moreover, thyroid hormones control energy metabolism, growth, cellular differentiation, and overall homeostasis, physiological processes conserved in both zebrafish and mammal models. Therefore, this mini-review provides a comprehensive analysis of the current literature regarding the use of zebrafish to investigate the effects of endocrine-disrupting chemicals on the hypothalamic-pituitary-thyroid axis and thyroid function, as well as the associated physiological and behavioral responses. This review also discusses the limitations of the zebrafish model, including the challenges of establishing exposure models that are realistic and comparable to those experienced by humans and other animals in the environment. Finally, it discusses the intra- and intergroup variability, technical challenges in molecular analyses at early developmental stages, anatomical differences relative to humans, and difficulties in experimental handling and reproducibility. Nevertheless, zebrafish is an undeniable, versatile, and powerful model for advancing research in thyroid endocrinology and toxicology, especially during critical developmental windows, which are more complex to assess in mammals.
FIGURE 1. Advantages of using zebrafish as an experimental model. The zebrafish (Danio rerio) exhibits a high degree of genetic similarity to humans, supporting its broad applicability in biomedical research. Zebrafish reproduce prolifically (200–300 eggs per week) and reach adulthood in about 3 months. External fertilization and embryo transparency enable direct phenotypic observation and experimental manipulation. Genetic modifications can be efficiently performed through microinjection techniques, allowing functional studies from the earliest developmental stages. Zebrafish is also widely used for behavioral and neurobiological protocols, serving as a versatile model for studying various diseases, toxic compounds, and drugs, while maintaining low maintenance and husbandry costs in comparison to rodent models. Created in BioRender.
FIGURE 2. Schematic representation of the HPT axis, TH synthesis, transport, and action in zebrafish. (A) Hypothalamic TRH and CRH stimulate the pituitary to secrete TSH, which acts on thyroid follicles, stimulating the synthesis and release of T3 and T4, which regulate hypothalamus and pituitary function through negative feedback loops. (B) In the thyrocyte, TSH binds to its receptor (TSHR) and stimulates all the steps involved in the synthesis and secretion of TH. The sodium/iodide symporter (NIS) mediates iodide uptake, driven by the Na+ gradient generated by the Na+/K+-ATPase. Iodide is then transported to the follicular lumen, where the apical machinery, including thyroid peroxidase (TPO), catalyzes the oxidation of iodide to iodine and its incorporation into thyroglobulin (TG). Subsequently, TPO catalyzes the coupling reactions of iodotyrosines to generate T4 and T3. Iodinated TG is endocytosed and hydrolyzed in the cytoplasm, releasing TH, which exit the cell through basolateral membrane transporters and circulate bound to carrier proteins (e.g., transthyretin, TTR). In target tissues, TH are transported across the membrane through specific transporters, and deiodinases such as DIO2 and DIO1 convert T4 into the active T3, whereas DIO3 catalyzes the inactivation of T3 to T2 or T4 to rT3. T3 binds to nuclear TH receptors (THR), modulating gene transcription and eliciting systemic physiological effects. The purple starburst callouts highlight steps within the HPT axis and in TH synthesis, secretion, transport, metabolism, and action that have been reported as targets of endocrine-disrupting chemicals. Created in BioRender.
