title: ⁹⁹mTcO₄--, auger-mediated thyroid stunning: dosimetric requirements and associated molecular events.
abstract: Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) 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, 99mTc, 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 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4-) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4- required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4--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 99mTc 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.
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Cambien
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Philippe R
authors.initials: PR
authors.lastname: Franken
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lamit
authors.affiliation: UMR 1037 INSERM/UPS, Centre de Recherche en Cancérologie, Toulouse, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mauxion
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Richard-Fiardo
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Guglielmi
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Crescence
authors.affiliation: Université de Nice-Sophia Antipolis, Nice, France; Institut de Pharmacologie Moléculaire et Cellulaire-IPMC, CNRS UMR 7275, Sophia Antipolis, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pourcher
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Darcourt
authors.affiliation: UMR 1037 INSERM/UPS, Centre de Recherche en Cancérologie, Toulouse, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bardiès
authors.affiliation: Laboratoire TIRO, UMRE 4320, iBEB, DSV, CEA, Nice, France; Université de Nice-Sophia Antipolis, Nice, France; Centre Antoine Lacassagne, Department of nuclear medicine, Nice, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Vassaux
mesh_terms: D000818:Animals; D001692:Biological Transport; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004583:Electrons; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011874:Radiometry; D013670:Sodium Pertechnetate Tc 99m / Q000009:adverse effects* / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D000099209:Sodium-Iodide Symporters
chemical_list: D012333:RNA, Messenger; D013670:Sodium Pertechnetate Tc 99m; D027981:Symporters; D000099209:Sodium-Iodide Symporters