Biological consequences and HPT-axis dysregulation under extreme iodine exposure in zebrafish: Implications for thyroid function, behaviour and pathophysiology

Background Iodine deficiency-related thyroid dysfunction has been widely addressed via universal salt iodization; however, the effect of excessive iodine exposure remains unexamined. Recent clinical studies have linked high-dose iodine intake to thyroid dysfunction. Objective This study investigated the effects of extreme iodine exposure on zebrafish thyroid function and development across multiple life stages. Methods Zebrafish were exposed to iodine concentrations of 2.5, 5, 10, and 20 mM across developmental stages: 4–96 h post-fertilization (hpf), 4 hpf to 15 days post-fertilization (dpf), 30 dpf to 60 dpf (30 days post-treatment (dpt)), 90 dpf (60 dpt), and 60-day recovery up to 150 dpf. Toxicity was assessed via lethality (LC50), physiological changes (heartbeat, swim bladder, growth, pigmentation, and thyroid morphology), gene expression in the hypothalamic-pituitary-thyroid (HPT) axis (CRH, TSH, TG, DIO2, THRα, and THRβ), thyroid hormone levels (T3), and behavioral alterations. Results The LC50 of iodine was 12.58 mM. Concentrations of 10 and 20 mM caused changes in heartbeat and swim bladder volume at 96 hpt, with significant mortality observed at 15 dpt. Growth retardation and altered HPT axis gene expression (CRH, TSH, and DIO2) occurred at 30 dpt, escalating at 60 dpt to severe growth retardation, pale pigmentation, thyroid enlargement, broader HPT gene dysregulation, elevated T3 levels, and behavioral changes. Physiology normalized after 60-day recovery, although elevated mortality persisted at lower doses. Conclusion Extreme iodine exposure is associated with significant alterations in HPT axis-related gene expression under conditions of severe systemic toxicity.