title: Comparative analysis of transcriptional gene regulation indicates similar physiologic response in mouse tissues at low absorbed doses from intravenously administered 211At.
abstract: (211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted α-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy.
  
  
  METHODS
  Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles.
  
  
  RESULTS
  A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue-specific. The regulatory profiles of categorized biological processes were tissue-specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories.
  
  
  CONCLUSIONS
  The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation-induced damage to, for example, the (211)At-accumulating thyroid gland. The presented results demonstrate the complexity of responses to radionuclides in vivo and highlight the need for further research to also consider physiology in ionizing radiation-induced responses.
authors: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. britta.langen@gu.se
authors: Britta
authors: B
authors: Langen
authors: Nils
authors: N
authors: Rudqvist
authors: Toshima Z
authors: TZ
authors: Parris
authors: Emil
authors: E
authors: Schüler
authors: Khalil
authors: K
authors: Helou
authors: Eva
authors: E
authors: Forssell-Aronsson
mesh_terms: D061605:Administration, Intravenous; D000512:Alpha Particles / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D001246:Astatine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects*; D051379:Mice; D009928:Organ Specificity; D011835:Radiation Protection; D014158:Transcription, Genetic / Q000528:radiation effects*
chemical_list: D001246:Astatine
keywords: 211At; biological processes; normal tissue response; radionuclide therapy; transcriptional gene regulation