99mTcO4--, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm(3)) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, Tc-99m, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as Tc-99m may significantly influence thyroid physiology. The aims of this study were to determine whether Tc-99m pertechnetate ((TcO4-)-Tc-99m) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of (TcO4-)-Tc-99m required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that (TcO4-)-Tc-99m-mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by Tc-99m can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.