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The effect of aging on the transcriptional profile of female mice exposed to x-ray radiation

ABSTRACT: Background: In the event of an improvised nuclear device or radiological dirty bomb detonation large numbers of people will be exposed to radiation that would require a timely and accurate biodosimetry to identify the highly exposed individuals who would require medical treatment from those who have received low or no radiation (the “worried well”). Gene expression signatures in response to radiation have been derived from mice and human peripheral blood and the impact of a number of variables, such as dose, time, genotype, and gender, on gene expression has been analyzed. However, the impact of aging on radiation gene profiling has not been taken into consideration. Results: Global gene expression was measured in the blood of young (2 mo) and old (24 mo) female C57BL/6J mice 1 day after they were exposed to 4 Gy x-rays or they were sham irradiated (control) using the Agilent Mouse Whole Genome microarrays. Ingenuity Pathway Analysis revealed that “Integrin signaling” was the most overrepresented canonical pathway in both young (p = 1.69E-10) and old (p = 2.93E-10) female mice exposed to x-ray irradiation. In contrast, immune-related processes, such as “Communication between Innate and Adaptive Immune Cells” (p = 2.33E-11), were overrepresented in young but not old irradiated mice. On the other hand, “Molecular Mechanisms of Cancer” processes were significant only in irradiated old mice (p = 5.78E-07). Finally, a number of phagocytosis pathways, involved in apoptotic cell elimination and tissue homeostasis preservation, were enriched in irradiated young, but not old, mice. Conclusions: We show that age is a variable that has the potential to fundamentally alter the transcriptomic profile of irradiated female mouse blood. A number of biological processes, including phagocytosis, are differentially represented in young and old mice exposed to x-ray radiation. Our results highlight the significance of age as a variable that can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency.

ORGANISM(S): Mus musculus

PROVIDER: GSE133451 | GEO | 2021/06/10

REPOSITORIES: GEO

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Project description:Background: In the event of an improvised nuclear device or radiological dirty bomb detonation large numbers of people will be exposed to radiation that would require a timely and accurate biodosimetry to identify the highly exposed individuals who would require medical treatment from those who have received low or no radiation (the “worried well”). Gene expression signatures in response to radiation have been derived from mice and human peripheral blood and the impact of a number of variables, such as dose, time, genotype, and gender, on gene expression has been analyzed. However, the impact of aging on radiation gene profiling has not been taken into consideration. Results: Global gene expression was measured in the blood of young (2 mo) and old (21 mo) male C57BL/6J mice 1 day after they were exposed to 4 Gy x-rays or they were sham irradiated (control) using the Agilent Mouse Whole Genome microarrays. Animals exposed to radiation suppressed expression of DNA repair genes with fold-changes being very similar to the two age groups. A notable exception was Mismatch Repair (MMR) that was significantly enriched among the downregulated genes in irradiated old mice (p = 2.34E-09) compared with irradiated young mice (p = 1.62E-04). Furthermore, cardiac hypertrophy signaling (p < 0.002) and the role of NFAT in cardiac hypertrophy (p = 0.01) were predicted to be enriched among the upregulated differentially expressed genes in irradiated old mice, but not irradiated young mice. In contrast, young mice respond to x-ray exposure by significantly upregulating genes involved in phagosome formation (p = 3.09E-07), phagosome maturation (p = 0.001), and Fcγ receptor-mediated phagocytosis (p = 0.03), all crucial processes that eliminates apoptotic cells and preserve tissue homeostasis. Conclusions: We show that age is a variable that has the potential to fundamentally alter the transcriptomic profile of irradiated mouse blood. A number of biological processes, including phagocytosis, are differentially represented in young and old mice exposed to x-ray radiation. Our results highlight the significance of age as a variable that can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency.

Project description:Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age at exposure and their underlying mechanisms remain unclear. We analyzed the mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). T-cell lymphoma incidence did not show any statistical differences among three irradiated groups; however, the frequency of loss of heterozygosity on chromosomes 11 and 19 showed opposing correlations with age at exposure. Ikaros on chromosome 11 was mutated frequently in the young adultâ??irradiation group (63%; 5/8), frequently incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik11, which lacks two of the four zincâ??finger domains important for DNA binding). Pten on chromosome 19 was mutated more frequently in tumors from infant- (67%; 10/15) compared with young adult-irradiated mice (13%; 1/8, P = 0.041). Despite the presence of homozygous Pten mutations, DNA copy number was unchanged in the infant-irradiation group, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Taken together, our findings demonstrate that while deletions on chromosome 11 affecting the Ikaros locus are a prominent feature of young adult irradiation-induced T-cell lymphoma, tumors arising after infant irradiation suffer a second hit in the Pten gene by chromosome mis-segregation or recombination. This is the first report showing age-at-exposure associated radiation-induced genomic alterations in two key tumor suppressor genes linked to T-cell lymphomagenesis. These data are important for considering the risks associated with childhood exposure to radiation. 38 T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting at different ages (Infant: 1 week old (15 tumors), Adolescent: 4 weeks old (13 tumors), Young adult: 8 weeks old (10 tumors)) were analyzed.

Project description:Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age at exposure and their underlying mechanisms remain unclear. We analyzed the mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). T-cell lymphoma incidence did not show any statistical differences among three irradiated groups; however, the frequency of loss of heterozygosity on chromosomes 11 and 19 showed opposing correlations with age at exposure. Ikaros on chromosome 11 was mutated frequently in the young adult–irradiation group (63%; 5/8), frequently incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik11, which lacks two of the four zinc–finger domains important for DNA binding). Pten on chromosome 19 was mutated more frequently in tumors from infant- (67%; 10/15) compared with young adult-irradiated mice (13%; 1/8, P = 0.041). Despite the presence of homozygous Pten mutations, DNA copy number was unchanged in the infant-irradiation group, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Taken together, our findings demonstrate that while deletions on chromosome 11 affecting the Ikaros locus are a prominent feature of young adult irradiation-induced T-cell lymphoma, tumors arising after infant irradiation suffer a second hit in the Pten gene by chromosome mis-segregation or recombination. This is the first report showing age-at-exposure associated radiation-induced genomic alterations in two key tumor suppressor genes linked to T-cell lymphomagenesis. These data are important for considering the risks associated with childhood exposure to radiation.

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The effect of aging on the transcriptional profile of female mice exposed to x-ray radiation

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