Abstract
Background131I and 211At are used in nuclear medicine and accumulate in the thyroid gland and may impact normal thyroid function. The aim of this study was to determine transcriptional profile variations, assess the impact on cellular activity, and identify genes with biomarker properties in thyroid tissue after 131I and 211At administration in mice.MethodsTo further investigate thyroid tissue transcriptional responses to 131I and 211At administration, we generated a new transcriptional dataset that includes re-evaluated raw intensity values from our previous 131I and 211At studies. Differential transcriptional profiles were identified by comparing treated and mock-treated samples using Nexus Expression 3.0 software. Further data analysis was performed using R/Bioconductor and IPA.ResultsA total of 1144 genes were regulated. Hierarchical clustering subdivided the groups into two clusters containing the lowest and highest absorbed dose levels, respectively, and revealed similar transcriptional regulation patterns for many kallikrein-related genes. Twenty-seven of the 1144 genes were recurrently regulated after 131I and 211At exposure and divided into six clusters. Several signalling pathways were affected, including calcium, integrin-linked kinase, and thyroid cancer signalling, and the peroxisomal proliferator-activated receptor network.ConclusionsSubstantial changes in transcriptional regulation were shown in 131I and 211At-treated samples, and 27 genes were identified as potential biomarkers for 131I and 211At exposure. Clustering revealed distinct differences between transcriptional profiles of both similar and different exposures, demonstrating the necessity for better understanding of radiation-induced effects on cellular activity. Additionally, ionizing radiation-induced changes in kallikrein gene expression and identified canonical pathways should be further assessed.
Highlights
131I and 211At are used in nuclear medicine and accumulate in the thyroid gland and may impact normal thyroid function
Hierarchical clustering subdivided the exposure groups into two larger clusters: one smaller branch containing groups with higher absorbed dose levels (1.4–32 Gy from 211At and 8.5 Gy from 131I at 24 h) and a larger branch with the remaining groups (Fig. 1). At both 1 h and 6 h after 211At administration, a higher absorbed dose/dose rate resulted in a higher number of regulated genes (Table 1)
Regulated genes were associated with biological functions using previously published literature reports and various databases, in addition to upstream and downstream regulation analysis and canonical pathway analysis generated by Ingenuity Pathway Analysis (IPA) software
Summary
131I and 211At are used in nuclear medicine and accumulate in the thyroid gland and may impact normal thyroid function. The aim of this study was to determine transcriptional profile variations, assess the impact on cellular activity, and identify genes with biomarker properties in thyroid tissue after 131I and 211At administration in mice. Methods: To further investigate thyroid tissue transcriptional responses to 131I and 211At administration, we generated a new transcriptional dataset that includes re-evaluated raw intensity values from our previous 131I and 211At studies. The result is a transcriptional profile, i.e. a snapshot of the radiation-induced cellular activity at the mRNA level. This can be used to determine the impact of radiation on biological functions and canonical pathways, to predict upstream regulation of target molecules, and for biomarker discovery without the risk of bias in focusing on a specific set of signalling pathways only
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