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

Abstract

3,3,5-triiodothyroacetic acid (TRIAC) is a metabolite of endogenous thyroid hormones (THs) that can bind to and activate TH receptors. As TRIAC was previously detected in sewage effluent, we aimed to investigate exogenous TRIACs potential for endocrine disruption. We administered either TRIAC or 3,3,5-triiodo-L-thyronine (LT3) to both euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC alleviated growth retardation, suppressed the hypothalamus-pituitary-thyroid (HPT) axis, and upregulated TH-responsive genes in the pituitary gland, liver, and heart. We observed that, unlike LT3, TRIAC does not upregulate the expression of TH-responsive genes in the cerebrum. Measurement of organ-specific TRIAC levels suggested that TRIAC was not efficiently trafficked into the cerebrum. Furthermore, by analyzing euthyroid mice, we found that cerebral TRIAC levels did not increase despite TRIAC administration at higher concentrations, whereas serum and cerebral TH levels were substantially decreased. Hence, TH-responsive genes in the cerebrum appear to be downregulated by TRIAC. In summary, TRIAC administration decreases circulating TH levels by suppressing the HPT axis, while the consequent attenuation of TH actions was compensated by TRIAC in peripheral tissues but not in the cerebrum due to the relative impermeability of the blood-brain barrier towards TRIAC. We verified that exogenous TRIAC disrupts TH actions in the cerebrum. This disruption is apparently due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogenous distribution of TRIAC among different organs. Our findings indicate that environmental TRIAC poses a potential neurodevelopmental risk.