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
Affiliations
Ichiro Yamauchi
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; Corresponding author
Takuro Hakata
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Yohei Ueda
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Taku Sugawa
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Ryo Omagari
Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
Yasuo Teramoto
Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
Shoji F. Nakayama
Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
Daisuke Nakajima
Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan; Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
Takuya Kubo
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8530, Japan
Nobuya Inagaki
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka 530-8480, Japan
Summary: 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.
