GARC�A-G , C; VILLALOBOS, P; JEZIORSKI , MC; VALVERDE-R , C; OROZCO , A*; Universidad Nacional Autonoma de Mexico: 3,5-T2 has thyromimetic effects in killifish.

3,5-T2 has been considered an inactive by-product of T3 deiodination. However, we have shown that supra-physiological doses of 3,5-T2 exert an inhibitory effect upon hepatic iodothyronine deiodinase type 2 (D2) activity and mRNA levels in the killifish in the same manner as T3 and T4, suggesting that 3,5-T2 could be bioactive at least in fish. In this study, we further analyzed this possibility by rendering male killifish hypothyroid by treatment by immersion in 4.5 mM of metimazol (MMI), then adding physiological doses (30 nM) of T4, T3, rT3, or 3,5-T2. Hepatic D2 activity and mRNA levels were measured. Our results showed that 3,5-T2 reversed the increase in D2 caused by the hypothyroid state, as did the classical bioactive iodothyronines T4 and T3. In contrast, the inactive iodothyronine, rT3, showed no effect. Since D2 provides bioactive thyroid hormone to the cell, the fact that 3,5-T2 blocked the up-regulation of D2 during a hypothyroidal state strongly suggests that 3,5-T2 is indeed bioactive. To further test this hypothesis, we osmotically challenged killifish. We had previously observed that a hypoosmotic demand up-regulates hepatic D2 activity 12 h post-exposure in the killifish. We now challenged a group of sea water (SW) adapted male killifish with 50% SW-FW (fresh water) for 12 h and co-administered physiological doses (30 nM) of 3,5-T2, T4, T3, and rT3. Hepatic D2 activity and mRNA levels were measured. Our results showed that 3,5-T2 as well as T4 and T3 reversed the increase in D2 caused by the hypoosmotic challenge, whereas rT3 produced no effect. Together, our results suggest that the regulation of the three iodothyronines upon D2 occurs at the level of transcription, and support the proposal that 3,5-T2 is a bioactive thyroid hormone in the killifish. Supported by PAPIIT IN222405