SAT-399 Evaluation of Thyroid Hormone Action: Development of a Novel Mouse Model

Abstract Disclosure: I. Yamauchi: None. S. Kimura: None. T. Sugawa: None. T. Hakata: None. D. Kosugi: None. K. Okamoto: None. Y. Ueda: None. D. Taura: None. D. Nakajima: None. T. Kubo: None. D. Yabe: None. Objective: Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with normal hormonal functions. The disruption of thyroid hormone (TH) actions by EDCs is gaining attention, as TH activity has been detected in environmental water across multiple countries. This study aims to develop a mouse model to elucidate the mechanisms by which EDCs disrupt TH function. Methods: We administered 3,3',5-triiodo-L-thyronine (LT3) via drinking water to C57BL/6J mice treated with 6-propyl-2-thiouracil (PTU) to induce hypothyroidism and euthyroid controls. TH actions were assessed using growth curves and TH-responsive gene expression profiles. Additionally, we visualized alterations in the hypothalamus-pituitary-thyroid (HPT) axis, including thyroid gland enlargement and follicular dysmorphology, confirmed by thyroid function tests. Results: Euthyroid mice received 0.1 µg/mL or 1 µg/mL of LT3 for 4 weeks. However, only slight phenotypic changes were observed. To enhance sensitivity, hypothyroid mice treated with PTU for 4 weeks were used. Co-administration of 0.1 µg/mL LT3 significantly restored growth retardation, alterations in the HPT axis, and changes in TH-responsive gene expressions. Detailed analyses in these hypothyroid mice enabled us to evaluate TH actions across various organs. Further improvements to the model included the use of sodium iodide combined with PTU for 1 or 2 weeks, which reduced the hypothyroidism induction period. As a result, PTU monotreatment for 2 weeks was sufficient to induce hypothyroidism and significant phenotypic changes. To identify more sensitive TH-responsive genes, RNA sequencing was conducted on the liver, heart, cerebrum, and gastrocnemius muscle of hypothyroid mice generated by PTU monotreatment for 2 weeks. Conclusions: We established a robust in vivo model to evaluate TH actions. This model has provided valuable insights into the endocrine-disrupting potential of 3,3',5-triiodothyroacetic acid (TRIAC). Our previous study identified its disruptive mechanism as cooperation of depletion of circulating endogenous THs via negative feedback and heterogenous distribution of TRIAC among different organs (iScience. 2023; 26: 107135). The improved model and comprehensive analysis of TH-responsive genes offer a promising approach for further research into the effects of EDCs on TH action. Presentation: Saturday, July 12, 2025