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Effect of 90Sr internal emitter on gene expression in mouse blood.

Ghandhi SA, Weber W, Melo D, Doyle-Eisele M, Chowdhury M, Guilmette R, Amundson SA - BMC Genomics (2015)

Bottom Line: We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4.The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance.These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University Medical Center, VC11-215, 630 West 168th Street, New York, NY, 10032, USA. sg2423@cumc.columbia.edu.

ABSTRACT

Background: The radioactive isotope Strontium-90 ((90)Sr) may be released as a component of fallout from nuclear accidents, or in the event of a radiological incident such as detonation of an improvised nuclear device, and if ingested poses a significant health risk to exposed individuals. In order to better understand the response to (90)Sr, using an easily attainable and standard biodosimetry sample fluid, we analyzed the global transcriptomic response of blood cells in an in vivo model system.

Results: We injected C57BL/6 mice with a solution of 90SrCl2 and followed them over a 30-day period. At days 4, 7, 9, 25 and 30, we collected blood and isolated RNA for microarray analyses. These days corresponded to target doses in a range from 1-5 Gy. We investigated changes in mRNA levels using microarrays, and changes in specific microRNA (miRNA) predicted to be involved in the response using qRT-PCR. We identified 8082 differentially expressed genes in the blood of mice exposed to (90)Sr compared with controls. Common biological functions were affected throughout the study, including apoptosis of B and T lymphocytes, and atrophy of lymphoid organs. Cellular functions such as RNA degradation and lipid metabolism were also affected during the study. The broad down regulation of genes observed in our study suggested a potential role for miRNA in gene regulation. We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4.

Conclusions: Our study is the first to report the transcriptomic response of blood cells to the internal emitter (90)Sr in mouse and a possible role for microRNA in gene regulation after (90)Sr exposure. The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance. These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone.

No MeSH data available.


Related in: MedlinePlus

IPA based enrichment of biological functions; the heatmap shows the top scoring biological functions across the study. Each column indicates z-scores corresponding to enriched biological terms for the set of differentially expressed genes at the time indicated after 90Sr injection. Columns were sorted by significant processes from early (day 4, group I) to late (day 30, group V), in the study. Group I included processes that were affected across the study. Group II processes were affected starting on day 7; Group III processes, on day 9; Group IV, started at day 25, and Group V were significant only at day 30 in the study. The colors of the cells indicate z-scores, potentially activated/promoted processes (varying shades of orange) and potentially inhibited/suppressed processes (varying shades of blue); in each case increasing darkness of color represents increasing significance. Processes that did not appear in the core analysis result are shown in gray. The complete table with scores is in Additional file 4
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Fig3: IPA based enrichment of biological functions; the heatmap shows the top scoring biological functions across the study. Each column indicates z-scores corresponding to enriched biological terms for the set of differentially expressed genes at the time indicated after 90Sr injection. Columns were sorted by significant processes from early (day 4, group I) to late (day 30, group V), in the study. Group I included processes that were affected across the study. Group II processes were affected starting on day 7; Group III processes, on day 9; Group IV, started at day 25, and Group V were significant only at day 30 in the study. The colors of the cells indicate z-scores, potentially activated/promoted processes (varying shades of orange) and potentially inhibited/suppressed processes (varying shades of blue); in each case increasing darkness of color represents increasing significance. Processes that did not appear in the core analysis result are shown in gray. The complete table with scores is in Additional file 4

Mentions: We then analyzed all genes affected at the 5 time points of this study using the IPA biological functions tool to assess and compare categories of biological processes activated or inhibited in the course of the study, as predicted from gene expression changes. These are shown in Fig. 3. The heat map shows the scale of predicted activation (shades of orange) and inhibition (shades of blue) states for each biological function across the 5 times measured in this study. There were many processes predicted to be significantly affected across all times in the study, with most showing similar activation or inhibition across the study. These processes are sorted by decreasing z-scores and time point, shown in Fig. 3. There were many processes that were significant starting at day 4 and then mostly significant at other time points (group I); in which the top activated processes were atrophy of lymphatic systems, apoptosis of B and T cells, activation of lysosomal storage and autoimmune disease. Top inhibited processes within this group affected cell survival, cell viability, infection and migration of cells. More specifically, the gene expression changes belonged to potentially inhibited functions centered on apoptosis of B-cells, cell death of leukocytes and atrophy of lymph glands. Within group II, processes emerging as significant on day 7 included activation of hyperplasia of spleen and inhibition of antiviral response. Starting on day 9, (group III) biological processes affected included activation of anemia, inflammation of the body, and inhibition of B cell activation and lipid metabolism. Towards the end of the study at day 25 (group IV), new biological processes affected included activation of protein translation and inhibition of differentiation of lymphocytes. At day 30 (group V) biological processes involving activation of lymphoid cancer and inhibition of NK cell development were included. Further details are described in the legend for Fig. 3 and listed in the table in Additional file 4.Fig. 3


Effect of 90Sr internal emitter on gene expression in mouse blood.

Ghandhi SA, Weber W, Melo D, Doyle-Eisele M, Chowdhury M, Guilmette R, Amundson SA - BMC Genomics (2015)

IPA based enrichment of biological functions; the heatmap shows the top scoring biological functions across the study. Each column indicates z-scores corresponding to enriched biological terms for the set of differentially expressed genes at the time indicated after 90Sr injection. Columns were sorted by significant processes from early (day 4, group I) to late (day 30, group V), in the study. Group I included processes that were affected across the study. Group II processes were affected starting on day 7; Group III processes, on day 9; Group IV, started at day 25, and Group V were significant only at day 30 in the study. The colors of the cells indicate z-scores, potentially activated/promoted processes (varying shades of orange) and potentially inhibited/suppressed processes (varying shades of blue); in each case increasing darkness of color represents increasing significance. Processes that did not appear in the core analysis result are shown in gray. The complete table with scores is in Additional file 4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528784&req=5

Fig3: IPA based enrichment of biological functions; the heatmap shows the top scoring biological functions across the study. Each column indicates z-scores corresponding to enriched biological terms for the set of differentially expressed genes at the time indicated after 90Sr injection. Columns were sorted by significant processes from early (day 4, group I) to late (day 30, group V), in the study. Group I included processes that were affected across the study. Group II processes were affected starting on day 7; Group III processes, on day 9; Group IV, started at day 25, and Group V were significant only at day 30 in the study. The colors of the cells indicate z-scores, potentially activated/promoted processes (varying shades of orange) and potentially inhibited/suppressed processes (varying shades of blue); in each case increasing darkness of color represents increasing significance. Processes that did not appear in the core analysis result are shown in gray. The complete table with scores is in Additional file 4
Mentions: We then analyzed all genes affected at the 5 time points of this study using the IPA biological functions tool to assess and compare categories of biological processes activated or inhibited in the course of the study, as predicted from gene expression changes. These are shown in Fig. 3. The heat map shows the scale of predicted activation (shades of orange) and inhibition (shades of blue) states for each biological function across the 5 times measured in this study. There were many processes predicted to be significantly affected across all times in the study, with most showing similar activation or inhibition across the study. These processes are sorted by decreasing z-scores and time point, shown in Fig. 3. There were many processes that were significant starting at day 4 and then mostly significant at other time points (group I); in which the top activated processes were atrophy of lymphatic systems, apoptosis of B and T cells, activation of lysosomal storage and autoimmune disease. Top inhibited processes within this group affected cell survival, cell viability, infection and migration of cells. More specifically, the gene expression changes belonged to potentially inhibited functions centered on apoptosis of B-cells, cell death of leukocytes and atrophy of lymph glands. Within group II, processes emerging as significant on day 7 included activation of hyperplasia of spleen and inhibition of antiviral response. Starting on day 9, (group III) biological processes affected included activation of anemia, inflammation of the body, and inhibition of B cell activation and lipid metabolism. Towards the end of the study at day 25 (group IV), new biological processes affected included activation of protein translation and inhibition of differentiation of lymphocytes. At day 30 (group V) biological processes involving activation of lymphoid cancer and inhibition of NK cell development were included. Further details are described in the legend for Fig. 3 and listed in the table in Additional file 4.Fig. 3

Bottom Line: We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4.The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance.These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University Medical Center, VC11-215, 630 West 168th Street, New York, NY, 10032, USA. sg2423@cumc.columbia.edu.

ABSTRACT

Background: The radioactive isotope Strontium-90 ((90)Sr) may be released as a component of fallout from nuclear accidents, or in the event of a radiological incident such as detonation of an improvised nuclear device, and if ingested poses a significant health risk to exposed individuals. In order to better understand the response to (90)Sr, using an easily attainable and standard biodosimetry sample fluid, we analyzed the global transcriptomic response of blood cells in an in vivo model system.

Results: We injected C57BL/6 mice with a solution of 90SrCl2 and followed them over a 30-day period. At days 4, 7, 9, 25 and 30, we collected blood and isolated RNA for microarray analyses. These days corresponded to target doses in a range from 1-5 Gy. We investigated changes in mRNA levels using microarrays, and changes in specific microRNA (miRNA) predicted to be involved in the response using qRT-PCR. We identified 8082 differentially expressed genes in the blood of mice exposed to (90)Sr compared with controls. Common biological functions were affected throughout the study, including apoptosis of B and T lymphocytes, and atrophy of lymphoid organs. Cellular functions such as RNA degradation and lipid metabolism were also affected during the study. The broad down regulation of genes observed in our study suggested a potential role for miRNA in gene regulation. We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4.

Conclusions: Our study is the first to report the transcriptomic response of blood cells to the internal emitter (90)Sr in mouse and a possible role for microRNA in gene regulation after (90)Sr exposure. The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance. These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone.

No MeSH data available.


Related in: MedlinePlus