Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

Rudqvist, Nils; Schüler, Emil; Parris, Toshima Z.; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

doi:10.1016/j.nucmedbio.2014.11.006

Cited by 22 publications

(29 citation statements)

References 30 publications

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“…Few GO terms related to DNA and gene expression integrity were identified in the present study. This is in agreement with previous results on transcriptional changes in thyroid tissue after 131 I and 211 At [ 11 , 13 ]. Monte Carlo simulations have shown that 1.2 Gy after 211 At irradiation corresponds to a mean value of one alpha particle track per thyroid follicular cell [ 32 ].…”

Section: Discussionsupporting

confidence: 94%

“…Few of the 102 previously proposed genes were identified in the present study. This is in agreement with our previous studies on thyroid tissue after 131 I and 211 At administration and in kidneys after 177 Lu-octreotate administration [ 11 , 13 , 16 ]. An explanation may be that most of these biomarkers were defined in in vitro studies and after acute external exposure.…”

Section: Discussionsupporting

confidence: 94%

“…We have previously studied the transcriptional response in thyroid tissue 24 h after 131 I and 211 At administrations [ 11 , 13 ]. These studies showed that the number of regulated transcripts varied with absorbed dose/dose-rate in a similar way with the lowest number of regulated transcripts in the groups that received the highest absorbed dose/dose-rate, but the dose-response relationship was not fully monotonous.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration

et al. 2015

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Background 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation has been the preferential accumulation of released 211At in the thyroid gland, which is a critical organ for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional expression in mouse thyroid gland.MethodsBALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively; mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially expressed transcripts and enriched GO terms were determined with adjusted p-value <0.01 and fold change >1.5, and p-value <0.05, respectively.ResultsIn total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered 1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected in the present study. Regulation of immunological processes were prevalent at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy).

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration

et al. 2015

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“…At high doses (0.5, 4 Gy), the latter activated P53 pathway while the former triggered TGFβ. In accordance to that, TGFβ and SMAD (canonical TGFβ pathway) were also regulated in normal thyroid gland after 131 I administration in mice 23 and the profound diversity of biological responses to radiation doses were also recapitulated in vivo. So far, the main limitations of these models are: 1) the lack of temporal points; 2) most of the approaches have been conducted in immortalized cells; 3) Speciesspecific molecular alterations in response to radiation (i.e, RET/PTC only detected in humans).…”

Section: Acute Effects Of Ionization Radiation On Thyroid Cellssupporting

confidence: 76%

Radiation-induced senescence and thyroid cancer: a barrier or a driving force

Penha

Lima

Pinto

2015

PAJAR, Pan Am. J. Aging Res.

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Aims: The main goal of this review-article was to shed light on the impact of senescence on thyroid carcinogenesis, a promising but still neglected field. Source of data: PubMed database and Google Scholar search was performed for English language articles with terms: ionizing radiation exposure, thyroid cancer, radiation signature, rET/PTC, senescence and radiation-induced senescence. We have no date restrictions. Summary of findings: Ionizing radiation (Ir) is undoubtedly the most well-characterized risk factor for thyroid cancer of the papillary histotype and its pivotal role as senescence inducer has been proposed. a paradoxical role of senescence on carcinogenesis -a barrier to cancer cell proliferation in early steps and a driving force to cancer progression by secreting proinflamatory cytokines and matrix degrading enzymes -is the heart of the matter of age-related cancer and bring to life new insights to thyroid cancer research field. This review-article briefly points out the major findings that link ionizing radiation to thyroid carcinogenesis, highlighting the molecular alterations mediated by acute and chronic radiation exposure in thyroid cells. Conclusions: Evidences provided by our group and other few reports suggest that, like other oncogenic stimuli in different cell types, Ir induces a senescent phenotype in thyroid cells, what could represent an initial barrier to transformation. However, how senescence could contribute to tumor progression still remains elusive. The comprehension of these mechanisms could not only help elucidating thyroid cancer initiation and progression, but could also indicate new therapeutical targets.Keywords: Ionizing radiation; Thyroid cancer; Senescence; DNa damage; rET/PTC. RESUMOObjetivos: O principal objetivo deste artigo de revisão foi lançar luz sobre o impacto da senescência na carcinogênese da tiroide, um campo promissor, mas ainda negligenciado. Fonte dos dados: pesquisa nos bancos de dados PubMed e Google Scholar realizada para artigos em inglês com os termos: exposição à radiação ionizante, câncer de tireoide, radiação assinatura, rET/PTC, senescência e senescência induzida por radiação. Não houve restrições quanto a data. Resumo das constatações: radiação ionizante (Ir) é, sem dúvida, o fator de risco mais bem caracterizado para o câncer de tireoide de histotipo papilar e seu papel central como indutor de senescência tem sido proposto. Um papel paradoxal da senescência na carcinogênese -uma barreira a proliferação celular cancerígena em etapas precoces e uma força motriz para a progressão do câncer através de secreção de citocinas pró-inflamatórias e enzimas matriz degradantes -é o foco principal sobre o câncer relacionado à idade e trazem à vida novos insights para a investigação do câncer de tiroide. Este artigo de revisão mostra brevemente as principais conclusões que apontam a radiação ionizante à carcinogênese de tireoide, destacando as alterações moleculares mediadas pela exposição aguda e crônica à radiação em células da tireoide. Conclusões:...

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“…To the best of our knowledge, this study is the first to carry out RNA sequencing to obtain the gene expression profile of human thyrocytes following 131 I exposure. Thyroid transcriptomic data after 131 I exposure have been obtained by microarray analysis in rat and mouse models and showed a distinct dose-dependent gene response (53,54). Given the limited number of conditions that can be examined in a single primary culture, one limitation of this study is the relatively small number of samples that at our disposal (4 samples for each condition) for RNA sequencing.…”

Section: And γ Radiation Did Not Induce Apoptosis In Human Thyrocytmentioning

confidence: 99%

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

Kyrilli¹,

Gacquer²,

Detours³

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

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Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

Abstract: This work may contribute with new knowledge of potential normal tissue effects or complications that may occur after exposure to ionizing radiation in diagnostic and therapeutic nuclear medicine, and due to radioactive fallout or accident with radionuclide spread.

Cited by 22 publications

References 30 publications

Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration

Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration

Radiation-induced senescence and thyroid cancer: a barrier or a driving force

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

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