Persistent in vivo cytogenetic effects of radioiodine therapy: a 21-year follow-up study using multicolor FISH

Abstract

Our previous studies demonstrated the cytogenetic effects in the peripheral blood lymphocytes of a 34-year-old male patient who received ablative radioactive 131iodine therapy (RIT) on two different occasions in 1992 and 1994. Assessment of RIT-induced chromosomal damage by the cytokinesis-blocked micronucleus assay (CBMN) showed the persistence of elevated micronucleus frequency in this patient for more than two decades since the first RIT. Subsequent cytogenetic analysis performed in 2012 revealed both stable and unstable aberrations, whose frequencies were higher than the baseline reported in the literature. Here, we report the findings of our recent cytogenetic analysis peformed in 2015 on this patient using the multicolor fluorescence in situ hybridization (mFISH) technique. Our results showed that both reciprocal and non-reciprocal translocations persisted at higher frequencies in the patient than those reported in 2012. Persistence of structural aberrations for more than two decades indicate that these aberrations might have originated from long-lived T-lymphocytes or hematopoietic stem cells. Our study suggests that the long-term persistence of chromosome translocations in circulating lymphocytes can be useful for monitoring the extent of RIT-induced chromosomal instability several years after exposure and for estimating the cumulative absorbed dose after multiple RITs for retrospective biodosimetry purposes. This is perhaps the first and longest follow-up study documenting the persistence of cytogenetic damage for 21 years after internal radiation exposure.

Use of human lymphocyte G0 PCCs to detect intra- and inter-chromosomal aberrations for early radiation biodosimetry and retrospective assessment of radiation-induced effects

“…Procedure for the fluorescence in situ hybridization (FISH) technique using peptide nucleic acid (PNA) based human telomeric and centromeric DNA probes was essentially the same as described in our previous studies [39, 40]. A cocktail of probe specific for human chromosomes 1, 2 and 4 was obtained from MetaSystems and the FISH procedure using this probe was performed essentially as described by the manufacturers.…”

“…A cocktail of probe specific for human chromosomes 1, 2 and 4 was obtained from MetaSystems and the FISH procedure using this probe was performed essentially as described by the manufacturers. The mFISH technique was performed essentially as described before [39]. Briefly, slides were treated for 1 min with 0.001% acidic pepsin solution (0.01NHCl) at 37°C for 1–2 min followed by two washes of 5 min each in phosphate-buffered saline.…”

Cytogenetic Studies of Chromosome Abnormalities in Thyroid Cancer Patients Before and After Iodine-131 Treatment

“…The number of micronucleus was 10 times higher 5 years after treatment than the number of micronucleus before treatment (11). In their study published in 2017, they examined the same patient's peripheral blood sample by multicolor fluorescent in situ hybridization and found a higher proportion of reciprocal and non-reciprocal translocations compared with their previous study (33). These findings show the persistent effects of IR.…”

Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants

“…Considering the half-life of 131 I (ranging from 1 to 8 days in thyroidectomized and non-thyroidectomized TC patients, respectively) [ 28 ] and of circulating lymphocytes (about 3 years) [ 28 , 38 ], such repeated demonstration of persistent cytogenetic damage is somehow surprising and challenge the widely held views about the mechanisms of IR-induced DNA damage. Possible explanations for the long-term genomic instability of lymphocytes from 131 I-exposed subjects include the introduction, upon irradiation, of DNA damage and cytogenetic alterations (1) in a subset of long-lived naïve T lymphocytes, quiescent cells that survive for prolonged periods of time in a resting stage, retaining the initially inflicted DNA damage and expressing it as micronuclei when stimulated to proliferate in the CBMN assay [ 38 , 42 , 43 ], (2) in hematopoietic stem and progenitor cells that, through clonal expansion, may give rise to mature T lymphocytes with stable and unstable aberrations, perpetuating genomic instability in time (transgenerational effect) [ 38 , 42 , 43 ], and (3) in non-irradiated lymphocytes (a delayed non-targeted effect), as a result of the long-term production and plasma secretion of soluble clastogenic factors by irradiated cells (oxidative stress by-products such as ROS (reactive oxygen species) and inflammatory cytokines such as TNF-α) that may further extend IR-induced cytogenetic damage in time (“bystander effect”) [ 44 ]. The two latter explanations are generally favored, as a large number of studies exist demonstrating either the high frequency of gene mutations and chromosomal aberrations in the progeny of irradiated cells or the production and plasma release of factors with clastogenic activity by irradiated cells (including one on 131 I-treated patients) [ 37 ].…”