Time- and dose rate-related effects of internal ¹⁷⁷Lu exposure on gene expression in mouse kidney tissue

Introduction: 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 ¹⁷⁷LuCl₃ 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 0MBq of ¹⁷⁷LuCl₃, and killed at 3, 6, 24, 48, 168, and 24hours after injection, respectively. Furthermore, the effect of time after onset of exposure was analysed using mice injected with 0.26, 2.4, and 8.2MBq of ¹⁷⁷LuCl₃, and killed at 45, 90, and 140days 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. Conclusion: 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.