Influence of Polymorphisms of DNA Repair and GST Genes on Genotoxic Damage and Mutagen Sensitivity in Workers Occupationally Exposed to Very Low Doses of Ionizing Radiation

Stufano Stufano,De Benedictis De Benedictis,Lovreglio Lovreglio,Drago Drago,Ledda Ledda,Chiarappa Chiarappa,Soleo Soleo,Resta Resta,Vimercati Vimercati,Bagnulo Bagnulo,Rapisarda Rapisarda

doi:10.3390/app9235175

Abstract

The study investigated the influence of genetic polymorphisms of the enzymes for DNA repair and detoxification of reactive intermediates on spontaneous and bleomycin-induced (BLM) genotoxic damage in 43 workers exposed to very low doses of ionizing radiation (IR) (mean cumulative dose 5.31 mSv) and 43 subjects with no occupational exposure to IR (controls). In all the subjects examined, the frequency of chromosome aberrations (CAs) and micronuclei (MN), both spontaneous and BLM-induced, the Comet assay parameters (tail intensity), the genotypic variants of the DNA repair enzymes XRCC1 (Arg194Trp, Arg280His, Arg399Gln), XRCC3 (Thr241Met), XPD (Lys751Gln), and of the detoxification enzymes GSTM1 and GSTT1 (null genotype) and BLMH (A1450G) were determined. Among the biomarkers considered, only the frequency of total CAs (p < 0.05), and in particular of chromosome breaks (p < 0.01), was found to be significantly higher in the exposed workers than the controls. The frequency of spontaneous MN was higher in subjects with at least one allelic variant in XRCC1 than in carriers of the wild-type, but again only in exposed workers (p = 0.046). Linear regression analysis showed a positive dependency of the frequency of spontaneous chromosome breaks on occupational exposure, and a dependency of the frequency of BLM-induced MN negative on occupational exposure and positive on alcohol consumption and the null GSTM1 genotype. In conclusion, the frequency of chromosome breaks seems to be a useful cytogenetic biomarker for exposure to very low doses of IR, while only the combined effect of different gene variants or genetic, occupational, and lifestyle habits factors seems to be able to modulate the genotoxic effect of very low doses of IR.

Highlights

Prolonged occupational exposure to high doses of ionizing radiation (IR) can cause DNA alterations, such as single-strand breaks (SSBs), double-strand breaks (DSBs), damage to purine and pyrimidine bases, and DNA-protein crosslinking, that can result in cell death or neoplastic transformation [1].Appl
The aim of this study was, to verify whether the genotoxic effects and mutagen sensitivity in workers with occupational exposure to very low doses of IR can be modulated by genetic polymorphisms of the enzymes involved in DNA repair and detoxification of reactive intermediates induced by IR
No relation was found between occupational exposure, sex, and cigarette smoking and spontaneous and BLM-induced DNA damage biomarkers, except for spontaneous chromosomal breaks, that appeared to be associated with occupational exposure (p < 0.05), and for TI and TI Endo III, that showed significantly higher values in females (p < 0.01 for both comparisons; Table 6)

Summary

Introduction

Prolonged occupational exposure to high doses of ionizing radiation (IR) can cause DNA alterations, such as single-strand breaks (SSBs), double-strand breaks (DSBs), damage to purine and pyrimidine bases, and DNA-protein crosslinking, that can result in cell death or neoplastic transformation [1].Appl. Increased genotoxic damage has been observed in workers with occupational exposure to IR at lower doses than the authorized dose limits, consisting of an increased frequency of chromosome aberrations (CAs) and micronuclei (MN), as compared to control groups with no occupational exposure [3,4,5]. These genotoxic effects were not shown to be correlated to the cumulative dose of IR exposure [6]. The Comet assay yielded discordant results in regards to increased

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