TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs

Ichiro Yamauchi; Takuro Hakata; Yohei Ueda; Taku Sugawa; Ryo Omagari; Yasuo Teramoto; Shoji F Nakayama; Daisuke Nakajima; Takuya Kubo; Nobuya Inagaki

doi:10.1016/j.isci.2023.107135

TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs

iScience. 2023 Jun 15;26(7):107135. doi: 10.1016/j.isci.2023.107135. eCollection 2023 Jul 21.

Authors

Ichiro Yamauchi¹, Takuro Hakata¹, Yohei Ueda¹, Taku Sugawa¹, Ryo Omagari², Yasuo Teramoto², Shoji F Nakayama², Daisuke Nakajima^{2

3}, Takuya Kubo⁴, Nobuya Inagaki^{1

5}

Affiliations

¹ Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
² Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan.
³ Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
⁴ Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8530, Japan.
⁵ Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka 530-8480, Japan.

Abstract

As 3,3',5-triiodothyroacetic acid (TRIAC), a metabolite of thyroid hormones (THs), was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC's potential for endocrine disruption. We administered either TRIAC or 3,3',5-triiodo-L-thyronine (LT3) to euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC administration suppressed the hypothalamus-pituitary-thyroid (HPT) axis and upregulated TH-responsive genes in the pituitary gland, the liver, and the heart. We observed that, unlike LT3, TRIAC administration did not upregulate cerebral TH-responsive genes. Measurement of TRIAC contents suggested that TRIAC was not efficiently trafficked into the cerebrum. By analyzing euthyroid mice, we found that cerebral TRIAC content did not increase despite TRIAC administration at higher concentrations, whereas serum levels and cerebral contents of THs were substantially decreased. Disruption by TRIAC is due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogeneous distribution of TRIAC among different organs.

Keywords: Biochemistry; Chemical substance; Endocrine disrupter; Endocrine system physiology.