title: Time- and dose rate-related effects of internal (177)Lu exposure on gene expression in mouse kidney tissue.
abstract: BACKGROUND
  The kidneys are the dose-limiting organs in some radionuclide therapy regimens. However, the biological impact of internal exposure from radionuclides is still not fully understood. The aim of this study was to examine the effects of dose rate and time after i.v. injection of (177)LuCl3 on changes in transcriptional patterns in mouse kidney tissue.
  
  
  METHODS
  To investigate the effect of dose rate, female Balb/c nude mice were i.v. injected with 11, 5.6, 1.6, 0.8, 0.30, and 0 MBq of (177)LuCl3, and killed at 3, 6, 24, 48, 168, and 24 hours after injection, respectively. Furthermore, the effect of time after onset of exposure was analysed using mice injected with 0.26, 2.4, and 8.2 MBq of (177)LuCl3, and killed at 45, 90, and 140 days after injection. Global transcription patterns of irradiated kidney cortex and medulla were assessed and enriched biological processes were determined from the regulated gene sets using Gene Ontology terms.
  
  
  RESULTS
  The average dose rates investigated were 1.6, 0.84, 0.23, 0.11 and 0.028 mGy/min, with an absorbed dose of 0.3 Gy. At 45, 90 and 140 days, the absorbed doses were estimated to 0.3, 3, and 10 Gy. In general, the number of differentially regulated transcripts increased with time after injection, and decreased with absorbed dose for both kidney cortex and medulla. Differentially regulated transcripts were predominantly involved in metabolic and stress response-related processes dependent on dose rate, as well as transcripts associated with metabolic and cellular integrity at later time points.
  
  
  CONCLUSIONS
  The observed transcriptional response in kidney tissue was diverse due to difference in absorbed dose, dose rate and time after exposure. Nevertheless, several transcripts were significantly regulated in all groups despite differences in exposure parameters, which may indicate potential biomarkers for exposure of kidney tissue.
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: emil.schuler@gu.se.
authors.forename: Emil
authors.initials: E
authors.lastname: Schüler
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Rudqvist
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Toshima Z
authors.initials: TZ
authors.lastname: Parris
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Langen
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Spetz
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Khalil
authors.initials: K
authors.lastname: Helou
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Forssell-Aronsson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D004307:Dose-Response Relationship, Radiation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000528:radiation effects*; D008187:Lutetium / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D008187:Lutetium
keywords: Kidney toxicity; Lutetium-177; Microarray; Radiation biology