| 86301. |
- Langen, Britta, et al.
(författare)
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Radiobiological effects of I-131 exposure in rodents
- 2018
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Ingår i: Meeting with the Japan Society for the Promotion of Science (JSPS) on Environmental Radioactivity: Experience from Japan and Sweden, Gothenburg, Sweden, Nov 15-16, 2018..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 86302. |
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| 86303. |
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| 86304. |
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| 86305. |
- Langen, Britta
(författare)
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Systemic effects after ionizing radiation exposure: Genome-wide transcriptional analysis of mouse normal tissues exposed to (211)At, (131)I, or 4 MV photon beam
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The radionuclides 131I and 211At are used or proposed for a variety of cancer treatments. Both radiohalogens exhibit considerable uptake in the thyroid gland and–to a lower degree–in various other tissues if they are unbound or released from a cancer-targeting agent. The resulting differential exposure throughout the body introduces two paradigms when studying effects in non-thyroid tissues in vivo: 1) low-dose effects of the organ, and 2) systemic effects due to a dominantly exposed regulatory organ. Normal tissue response is an important parameter in risk assessment in order to give the highest possible absorbed dose to malignant tumors while minimizing detrimental side effects in healthy tissue. The aim of this work was to increase fundamental knowledge of normal tissue responses to differential ionizing radiation exposure in vivo and to evaluate key findings regarding circadian rhythm and data convolution. Female BALB/c nude mice were used as a model system and the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid were studied using RNA microarray technology. Genome-wide transcriptional regulation and basically all analytical endpoints studied were tissue-specific. In various tissues, the Angptl4, Per1 and Per2, and Tsc22d3 genes may be potential biomarkers for 211At exposure (Papers I, II). In the thyroid, the Klk1 gene-family may serve as biomarker candidates for 131I exposure (Paper V). Similarity in the extent of regulation irrespective of absorbed dose level generated a hypothesis on thyroid-dependent systemic effects in non-thyroid tissues, which was supported by gene signature and pathway analysis (Papers I, III). Results from partial body irradiation with 4 MV photon beams confirmed the hypothesis (Paper IV). Circadian rhythm affected the extent and quality of regulation in a tissue-specific manner, but key findings showed certain robustness to diurnal variation (Paper V). Deconvolution of microarray data increased detection rate of significantly differentially expressed transcripts in thyroid data, but also confirmed key results derived from convoluted data (Paper VI). In conclusion, low-dose exposure, systemic effects, and circadian rhythm have a pronounced impact on normal tissue response in vivo and should be considered for more accurate risk assessment in radionuclide therapy.
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| 86306. |
- Langen, Britta, et al.
(författare)
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The IRI-DICE hypothesis: ionizing radiation-induced DSBs may have a functional role for non-deterministic responses at low doses
- 2020
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Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 59, s. 349-355
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Tidskriftsartikel (refereegranskat)abstract
- Low-dose ionizing radiation (IR) responses remain an unresolved issue in radiation biology and risk assessment. Accurate knowledge of low-dose responses is important for estimation of normal tissue risk in cancer radiotherapy or health risks from occupational or hazard exposure. Cellular responses to low-dose IR appear diverse and stochastic in nature and to date no model has been proposed to explain the underlying mechanisms. Here, we propose a hypothesis on IR-induced double-strand break (DSB)-induced cis effects (IRI-DICE) and introduce DNA sequence functionality as a submicron-scale target site with functional outcome on gene expression: DSB induction in a certain genetic target site such as promotor, regulatory element, or gene core would lead to changes in transcript expression, which may range from suppression to overexpression depending on which functional element was damaged. The DNA damage recognition and repair machinery depicts threshold behavior requiring a certain number of DSBs for induction. Stochastically distributed persistent disruption of gene expression may explain-in part-the diverse nature of low-dose responses until the repair machinery is initiated at increased absorbed dose. Radiation quality and complexity of DSB lesions are also discussed. Currently, there are no technologies available to irradiate specific genetic sites to test the IRI-DICE hypothesis directly. However, supportive evidence may be achieved by developing a computational model that combines radiation transport codes with a genomic DNA model that includes sequence functionality and transcription to simulate expression changes in an irradiated cell population. To the best of our knowledge, IRI-DICE is the first hypothesis that includes sequence functionality of different genetic elements in the radiation response and provides a model for the diversity of radiation responses in the (very) low dose regimen.
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| 86307. |
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| 86308. |
- Langen, Britta, et al.
(författare)
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Thyroid irradiation and non-targeted effects: in-field and out-of-field responses on the transcriptomic level show tissue-specific similarity
- 2016
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Ingår i: SweRays Workshop, Stockholm, Sweden, Aug 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radiation exposure can result in non-targeted effects that strongly influence cellular responses in non-irradiated tissues. However, radiotherapy planning does not consider out-of-field effects in current risk assessment, because knowledge of these effects is still scarce. Non-targeted effects from the thyroid are of particular concern, since it is a major regulatory gland and often subject to exposure during irradiation of e.g. head and neck, lung and breast tumors. The aim of this study was to characterize in-field and out-of-field responses on the transcriptomic level in vivo after thyroid irradiation. Methods: Anaesthetized female BALB/c nude mice were irradiated with 2 Gy from 4 MV photon beams in a partial body irradiation setup: the thyroid region, the thorax and abdomen, or all three regions combined (n=3/group). Control mice (n=5) were anaesthetized but not irradiated. Mice were killed after 24h and the kidneys, liver, lungs, spleen, and thyroid were sampled. Expression microarray analysis was performed on total RNA extracted from tissue samples. Results: Thyroid irradiation induced complex gene regulation responses in kidney medulla and liver that were highly similar to direct exposure of these tissues. In contrast, kidney cortex showed a lesser degree of similarity between setups, while lungs and spleen exhibited only marginal out-of-field responses. Interestingly, non-targeted effects and in-field responses did not appear to show simple additive behavior. Conclusions: Thyroid exposure can induce significant responses in other tissues similar to direct irradiation, but these non-targeted effects show tissue-specificity. The underlying mechanisms may yield molecular targets for minimizing systemic side-effects in radiotherapy.
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| 86309. |
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| 86310. |
- Langen, Britta, et al.
(författare)
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Transcriptional gene regulation in abdominal organs and the lung after i.v. injection of 211At in mouse
- 2012
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Ingår i: Radiation research society. San Juan, Puerto Rico. 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Astatine-211 (211At) is a promising radionuclide for radiation therapy with a nearly optimal biological effectiveness of emitted α-particles. Despite its potential, few studies have analysed 211At-induced normal tissue responses in vivo. In order to determine the quality and extent of 211At-induced cellular responses in vivo, the transcriptional gene regulation was analysed in the kidney cortex and medulla, liver, lung, and spleen. Female BALB/c nude mice were i.v. injected with 0.064, 0.64, 1.8, 14, and 42 kBq 211At and killed after 24h. Respective organs were excised and stored at -80°C until further analysis. Extracted total RNA was analysed with the Illumina MouseRef-8 Whole Genome Beadchip platform and data processing was performed with Nexus Expression 2.0. A common strong decrease in the total number of regulated transcripts was seen between 0.64 and 1.8 kBq 211At corresponding to absorbed doses between 2 and 50 mGy for all investigated tissues. Only minor responses in previously identified radiation-associated transcripts could be observed at any exposure. Among tissues at similar absorbed dose levels, the similarity in transcript up- and down-regulation decreased with increased absorbed dose. This phenomenon was more pronounced when the increase in absorbed dose corresponded also to an increase between 0.64 and 1.8 kBq 211At. Biological processes associated with regulated transcripts were categorised to assess the regulatory profiles in each tissue at a given exposure. These profiles showed distinct patterns which mirrored the threshold behaviour on the categorical and sub-categorical level of biological processes. The strong regulatory change demonstrated at the low absorbed doses in the tissues studied might be due to both radiation-induced effects of each tissue and physiological response from radiation-induced effects on the 211At-accumulating thyroid gland. These findings demonstrate the complexity of responses in vivo and highlight the need for a better understanding of the physiology when studying effects of ionizing radiation exposure.
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