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Transcriptional response in normal mouse tissues after i.v. (211)At administration - response related to absorbed dose, dose rate, and time.

Langen B, Rudqvist N, Parris TZ, Schüler E, Spetz J, Helou K, Forssell-Aronsson E - EJNMMI Res (2015)

Bottom Line: Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function.This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after (211)At administration.These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden ; Department of Applied Physics, Chalmers University of Technology, 412 96 Gothenburg, Sweden.

ABSTRACT

Background: In cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after (211)At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from (211)At in normal mouse tissues.

Methods: Female BALB/c nude mice were intravenously injected with 1.7 kBq (211)At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms.

Results: Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions.

Conclusions: This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after (211)At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.

No MeSH data available.


Related in: MedlinePlus

Potential molecular biomarkers in the liver for i.v.211At administration. Differentially regulated genes on the transcriptional level responding at all investigated time points in the liver after injection of 1.7, 7.5, or 105 kBq 211At. Note the difference in scaling of the y-axis compared with Figure 3.
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Fig4: Potential molecular biomarkers in the liver for i.v.211At administration. Differentially regulated genes on the transcriptional level responding at all investigated time points in the liver after injection of 1.7, 7.5, or 105 kBq 211At. Note the difference in scaling of the y-axis compared with Figure 3.

Mentions: The sample cohort was investigated for potential molecular biomarkers with sensitivity in the (very) low absorbed dose range. In addition, the dose rate effect for responses after 1 and 6 h was also analyzed. For the majority of transcripts regulated at all exposure conditions, fold change values were lowest after 7 days (Figures 3 and 4). In kidney cortex, ten genes were significantly regulated at all exposures, including two probe variants for the Per1 gene (Figure 3A), all of which were continuously upregulated. In the lungs and spleen, only two and one gene(s) were significantly regulated at all exposures, respectively (Figure 3B, C). Similar to kidney cortex, neither the lungs nor spleen showed downregulation among commonly regulated genes. Liver tissue showed the highest yield with 32 significantly regulated genes at all exposures, including two probe variants for the Coq10b and Per1 genes (Figure 4). Among these 34 transcripts, 25 were upregulated and all transcripts showed no change in direction of regulation with changing exposure condition. In kidney medulla, no genes were significantly regulated at all exposures within this sample cohort.Figure 3


Transcriptional response in normal mouse tissues after i.v. (211)At administration - response related to absorbed dose, dose rate, and time.

Langen B, Rudqvist N, Parris TZ, Schüler E, Spetz J, Helou K, Forssell-Aronsson E - EJNMMI Res (2015)

Potential molecular biomarkers in the liver for i.v.211At administration. Differentially regulated genes on the transcriptional level responding at all investigated time points in the liver after injection of 1.7, 7.5, or 105 kBq 211At. Note the difference in scaling of the y-axis compared with Figure 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384707&req=5

Fig4: Potential molecular biomarkers in the liver for i.v.211At administration. Differentially regulated genes on the transcriptional level responding at all investigated time points in the liver after injection of 1.7, 7.5, or 105 kBq 211At. Note the difference in scaling of the y-axis compared with Figure 3.
Mentions: The sample cohort was investigated for potential molecular biomarkers with sensitivity in the (very) low absorbed dose range. In addition, the dose rate effect for responses after 1 and 6 h was also analyzed. For the majority of transcripts regulated at all exposure conditions, fold change values were lowest after 7 days (Figures 3 and 4). In kidney cortex, ten genes were significantly regulated at all exposures, including two probe variants for the Per1 gene (Figure 3A), all of which were continuously upregulated. In the lungs and spleen, only two and one gene(s) were significantly regulated at all exposures, respectively (Figure 3B, C). Similar to kidney cortex, neither the lungs nor spleen showed downregulation among commonly regulated genes. Liver tissue showed the highest yield with 32 significantly regulated genes at all exposures, including two probe variants for the Coq10b and Per1 genes (Figure 4). Among these 34 transcripts, 25 were upregulated and all transcripts showed no change in direction of regulation with changing exposure condition. In kidney medulla, no genes were significantly regulated at all exposures within this sample cohort.Figure 3

Bottom Line: Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function.This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after (211)At administration.These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden ; Department of Applied Physics, Chalmers University of Technology, 412 96 Gothenburg, Sweden.

ABSTRACT

Background: In cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after (211)At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from (211)At in normal mouse tissues.

Methods: Female BALB/c nude mice were intravenously injected with 1.7 kBq (211)At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms.

Results: Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions.

Conclusions: This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after (211)At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.

No MeSH data available.


Related in: MedlinePlus