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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

Number of significantly regulated transcripts. Comparison of the total number (no.) of significantly upregulated (positive numbers) and downregulated (negative numbers) transcripts in the kidney cortex and medulla, liver, lungs, and spleen. (A) shows responses at various time points after i.v. administration of 1.7 kBq 211At. (B) shows total transcript regulation at early time points dependent on dose rate, i.e., effects from 1.7 kBq compared to either 105 kBq 211At after 1 h or to 7.5 kBq 211At after 6 h.
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Fig2: Number of significantly regulated transcripts. Comparison of the total number (no.) of significantly upregulated (positive numbers) and downregulated (negative numbers) transcripts in the kidney cortex and medulla, liver, lungs, and spleen. (A) shows responses at various time points after i.v. administration of 1.7 kBq 211At. (B) shows total transcript regulation at early time points dependent on dose rate, i.e., effects from 1.7 kBq compared to either 105 kBq 211At after 1 h or to 7.5 kBq 211At after 6 h.

Mentions: The number of significantly upregulated transcripts from 1 h to 7 days in response to 1.7 kBq 211At varied between 1 and 133 in the tissues (Figure 2A). Between 0 and 122 transcripts were downregulated. Upregulation dominated over downregulation in two-thirds of all instances. The lowest number of regulated transcripts was observed in the kidney cortex after 6 h and in the other tissues after 7 days. In most tissues, an increased number of regulated transcripts - although marginal for some instances - could be seen with increased absorbed dose (rate) at 1 and 6 h (Figure 2B). However, spleen tissue showed an inverse response with a distinctly reduced number of significantly regulated transcripts at the higher absorbed dose (rate) at both time points (Figure 2B). Moreover, kidney medulla and spleen showed an increased transcript regulation at the higher dose rate (105 kBq administration, 1 h) than at the lower dose rate (7.5 kBq administration, 6 h). In contrast, the kidney cortex, liver, and lungs responded more strongly to the lower dose rate.Figure 2


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)

Number of significantly regulated transcripts. Comparison of the total number (no.) of significantly upregulated (positive numbers) and downregulated (negative numbers) transcripts in the kidney cortex and medulla, liver, lungs, and spleen. (A) shows responses at various time points after i.v. administration of 1.7 kBq 211At. (B) shows total transcript regulation at early time points dependent on dose rate, i.e., effects from 1.7 kBq compared to either 105 kBq 211At after 1 h or to 7.5 kBq 211At after 6 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Number of significantly regulated transcripts. Comparison of the total number (no.) of significantly upregulated (positive numbers) and downregulated (negative numbers) transcripts in the kidney cortex and medulla, liver, lungs, and spleen. (A) shows responses at various time points after i.v. administration of 1.7 kBq 211At. (B) shows total transcript regulation at early time points dependent on dose rate, i.e., effects from 1.7 kBq compared to either 105 kBq 211At after 1 h or to 7.5 kBq 211At after 6 h.
Mentions: The number of significantly upregulated transcripts from 1 h to 7 days in response to 1.7 kBq 211At varied between 1 and 133 in the tissues (Figure 2A). Between 0 and 122 transcripts were downregulated. Upregulation dominated over downregulation in two-thirds of all instances. The lowest number of regulated transcripts was observed in the kidney cortex after 6 h and in the other tissues after 7 days. In most tissues, an increased number of regulated transcripts - although marginal for some instances - could be seen with increased absorbed dose (rate) at 1 and 6 h (Figure 2B). However, spleen tissue showed an inverse response with a distinctly reduced number of significantly regulated transcripts at the higher absorbed dose (rate) at both time points (Figure 2B). Moreover, kidney medulla and spleen showed an increased transcript regulation at the higher dose rate (105 kBq administration, 1 h) than at the lower dose rate (7.5 kBq administration, 6 h). In contrast, the kidney cortex, liver, and lungs responded more strongly to the lower dose rate.Figure 2

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