Retrospective Evaluation of Cytogenetic Effects Induced by Internal Radioiodine Exposure: A 27-Year Follow-Up Study.

Radioiodine (131I) is widely used in the treatment of hyperthyroidism and as an effective ablative therapy for differentiated thyroid cancer. Radioiodine (131I) constitutes 90% of the currently used therapies in the field of nuclear medicine. Here, we report the cytogenetic findings of a long-term follow-up study of 27 years on a male patient who received two rounds of radioiodine treatment within a span of 26 months between 1992 and 1994 for his papillary thyroid cancer. A comprehensive cytogenetic follow-up study utilizing cytokinesis blocked micronucleus assay, dicentric chromosome assay, genome wide translocations and inversions was initiated on this patient since the first administration of radioiodine in 1992. Frequencies of micronuclei (0.006/cell) and dicentric chromosomes (0.008/cell) detected in the current study were grossly similar to that reported earlier in 2019. The mFISH analysis detected chromosome aberrations in 8.6% of the cells in the form of both unbalanced and balanced translocations. Additionally, a clonal translocation involving chromosomes 14p; 15q was observed in 2 of the 500 cells analyzed. Out of the 500 cells examined, one cell showed a complex translocation (involving chromosomes 9, 10, and 16) besides 5 other chromosome rearrangements. Collectively, our study indicates that the past radioiodine exposure results in long-lasting chromosome damage and that the persistence of translocations can be useful for both retrospective biodosimetry and for monitoring chromosome instability in the lymphocytes of radioiodine exposed individuals.

Evaluation of Low-dose Radiation-induced DNA Damage and Repair in 3D Printed Human Cellular Constructs.

ABSTRACT: DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) are considered to be the most critical lesion that when unrepaired or misrepaired leads to genomic instability or cell death depending on the radiation exposure dose. The potential health risks associated with exposures of low-dose radiation are of concern since they are being increasingly used in diverse medical and non-medical applications. Here, we have used a novel human tissue-like 3-dimensional bioprint to evaluate low-dose radiation-induced DNA damage response. For the generation of 3-dimensional tissue-like constructs, human hTERT immortalized foreskin fibroblast BJ1 cells were extrusion printed and further enzymatically gelled in a gellan microgel-based support bath. Low-dose radiation-induced DSBs and repair were analyzed in the tissue-like bioprints by indirect immunofluorescence using a well-known DSB surrogate marker, 53BP1, at different post-irradiation times (0.5 h, 6 h, and 24 h) after treatment with various doses of γ rays (50 mGy, 100 mGy, and 200 mGy). The 53BP1 foci showed a dose dependent induction in the tissue bioprints after 30 min of radiation exposure and subsequently declined at 6 h and 24 h in a dose-dependent manner. The residual 53BP1 foci number observed at 24 h post-irradiation time for the γ-ray doses of 50 mGy, 100 mGy, and 200 mGy was not statistically different from mock treated bioprints illustrative of an efficient DNA repair response at these low-dose exposures. Similar results were obtained for yet another DSB surrogate marker, γ-H2AX (phosphorylated form of histone H2A variant) in the human tissue-like constructs. Although we have primarily used foreskin fibroblasts, our bioprinting approach-mimicking a human tissue-like microenvironment-can be extended to different organ-specific cell types for evaluating the radio-response at low-dose and dose-rates of IR.

A comparative validation of biodosimetry and physical dosimetry techniques for possible triage applications in emergency dosimetry.

Large-scale radiological accidents or nuclear terrorist incidents involving radiological or nuclear materials can potentially expose thousands, or hundreds of thousands, of people to unknown radiation doses, requiring prompt dose reconstruction for appropriate triage. Two types of dosimetry methods namely, biodosimetry and physical dosimetry are currently utilized for estimating absorbed radiation dose in humans. Both methods have been tested separately in several inter-laboratory comparison exercises, but a direct comparison of physical dosimetry with biological dosimetry has not been performed to evaluate their dose prediction accuracies. The current work describes the results of the direct comparison of absorbed doses estimated by physical (smartphone components) and biodosimetry (dicentric chromosome assay (DCA) performed in human peripheral blood lymphocytes) methods. For comparison, human peripheral blood samples (biodosimetry) and different components of smartphones, namely surface mount resistors (SMRs), inductors and protective glasses (physical dosimetry) were exposed to different doses of photons (0-4.4 Gy; values refer to dose to blood after correction) and the absorbed radiation doses were reconstructed by biodosimetry (DCA) and physical dosimetry (optically stimulated luminescence (OSL)) methods. Additionally, LiF:Mg,Ti (TLD-100) chips and Al2O3:C (Luxel) films were used as reference TL and OSL dosimeters, respectively. The best coincidence between biodosimetry and physical dosimetry was observed for samples of blood and SMRs exposed toγ-rays. Significant differences were observed in the reconstructed doses by the two dosimetry methods for samples exposed to x-ray photons with energy below 100 keV. The discrepancy is probably due to the energy dependence of mass energy-absorption coefficients of the samples extracted from the phones. Our results of comparative validation of the radiation doses reconstructed by luminescence dosimetry from smartphone components with biodosimetry using DCA from human blood suggest the potential use of smartphone components as an effective emergency triage tool for high photon energies.

Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation.

Cells exposed to ionizing radiation have a wide spectrum of DNA lesions that include DNA single-strand breaks, DNA double-strand breaks (DSBs), oxidative base damage and DNA-protein crosslinks. Among them, DSB is the most critical lesion, which when mis-repaired leads to unstable and stable chromosome aberrations. Currently, chromosome aberration analysis is the preferred method for biological monitoring of radiation-exposed humans. Stable chromosome aberrations, such as inversions and balanced translocations, persist in the peripheral blood lymphocytes of radiation-exposed humans for several years and, therefore, are potentially useful tools to prognosticate the health risks of radiation exposure, particularly in the hematopoietic system. In this review, we summarize the cytogenetic follow-up studies performed by REAC/TS (Radiation Emergency Assistance Center/Training site, Oak Ridge, USA) on humans exposed to internal and external radiation. In the light of our observations as well as the data existing in the literature, this review attempts to highlight the importance of follow-up studies for predicting the extent of genomic instability and its impact on delayed health risks in radiation-exposed victims.

Detection of Simple, Complex, and Clonal Chromosome Translocations Induced by Internal Radioiodine Exposure: A Cytogenetic Follow-Up Case Study after 25 Years.

Here, we report the findings of a 25-year cytogenetic follow-up study on a male patient who received 2 rounds of radioiodine treatment within a span of 26 months (1.78 GBq in 1992 and 14.5 GBq in 1994). The patient was 34 years old with a body mass index of 25 at the time of the first radioiodine treatment. Multicolor FISH and multicolor banding (mBAND) techniques performed on the patient detected inter- and intrachromosomal exchanges. Although the frequency of chromosome translocations remained essentially the same as reported in our earlier study (0.09/cell), the percentage of reciprocal (balanced) translocations increased from 54.38 to 80.30% in the current study. In addition to simple chromosome translocations, complex exchanges (0.29%) involving more than 2 chromosomes were detected for the first time in this patient. Strikingly, a clonal translocation involving chromosomes 14 and 15, t(14p;15q), was found in 7 of the 677 cells examined (1.03%). The presence of complex and clonal translocations indicates the onset of chromosomal instability induced by internal radioiodine exposure. mBAND analysis using probes specific for chromosomes 1, 2, 4, 5, and 10 revealed 5 inversions in a total of 717 cells (0.69%), and this inversion frequency is several-fold higher than the baseline frequency reported in healthy individuals using the classical G-banding technique. Collectively, our study suggests that stable chromosome aberrations such as translocations and inversions can be useful not only for retrospective biodosimetry but also for long-term monitoring of chromosomal instability caused by past radioiodine exposure.

Optimization and validation of automated dicentric chromosome analysis for radiological/nuclear triage applications.

Dicentric Chromosome Assay (DCA) is the most preferred cytogenetic technique for absorbed radiation dose assessment in exposed humans. However, DCA is somewhat impractical for triage application owing to its labor intensive and time consuming nature. Although lymphocyte culture for 48 h in vitro is inevitable for DCA, manual scoring of dicentric chromosomes (DCs) requires an additional time of 24-48 h, making the overall turnaround time of 72-96 h for dose estimation. To accelerate the speed of DC analysis for dose estimation, an automated tool was optimized and validated for triage mode of scoring. Several image training files were created to improve the specificity of automated DC analysis algorithm. Accuracy and efficiency of the automated (unsupervised) DC scoring was compared with the semi-automated scoring that involved human verification and correction of DCs (elimination of false positives and inclusion of true positives). DC scoring was performed by both automated and semi-automated modes for different doses of X-rays and γ-rays (0 Gy-5 Gy). Biodoses estimated from the frequencies of DCs detected by both automated (unsupervised) and semi-automated (supervised) scoring modes were grossly similar to the actual delivered doses in the range of 0.5 to 3 Gy of low LET radiation. We suggest that the automated DC tool can be effectively used for large scale radiological/nuclear incidents where a rapid segregation is essential for prioritizing moderately or severely exposed humans to receive appropriate medical countermeasures.