Kohei Wada, Keiko Ogata, Hitoshi Tanaka
Thyroid hormone (TH) system disruption in aquatic organisms is a major global concern, yet links between laboratory toxicity data and population-level impacts remain unclear. Here, we investigated the effects of chemically induced TH deficiency on population-relevant apical endpoints-growth, development, and reproduction-in Japanese medaka (Oryzias latipes). Medaka were exposed to propylthiouracil (PTU), a TH synthesis inhibitor, in a 21-day short-term reproduction assay and a 47-day partial life-cycle test. This approach enabled the evaluation of effects across multiple life stages and generations. PTU exposure led to reduced TH levels, thyroid histopathological changes, and upregulation of TH-related genes, confirming the sensitivity of these endpoints in medaka. In offspring from the TH-deficient group, delayed hatching and reduced growth were detected. However, investigation of larval-juvenile metamorphosis and development of the swim bladder and retina showed limited or no effects, despite their established association with TH. While reproductive output and vitellogenin levels were unaffected even under TH depletion, reduced secondary sexual characteristics in adult males and delayed testicular development in offspring were observed. These results suggest possible crosstalk between thyroid and reproductive axes, although non-specific systemic toxicity cannot be excluded. These findings indicate that TH-responsive molecular and organ-/tissue-level endpoints are not necessarily directly relevant to population-level adverse outcomes and should be interpreted carefully. Overall, this study supports the utility of medaka as a model for evaluating thyroid active substances and highlights the importance of a weight-of-evidence approach integrating diverse endpoints for the assessment of endocrine-disrupting chemicals in aquatic environments.