V. I. Minina

Assessing the level of chromosome aberrations in peripheral blood lymphocytes in long-term resident children under conditions of high exposure to radon and its decay products.

In this study, the frequency and spectrum of chromosomal aberrations were analysed in samples of peripheral blood from 372 (mean age = 12.24 ± 2.60 years old) long-term resident children in a boarding school (Tashtagol city, Kemerovo Region, Russian Federation) under conditions of high exposure to radon and its decay products. As a control group, we used blood samples from people living in Zarubino village (Kemerovo Region, Russian Federation). We discovered that the average frequencies of single and double fragments, chromosomal exchanges, total number of aberrations, chromatid type, chromosome type and all types of aberrations were significantly increased in the exposed group. This is evidence of considerable genotoxicity to children living under conditions of high exposure to radon compared to children living under ecological conditions without increased radon radiation.

Chromosome aberrations in peripheral blood lymphocytes of lung cancer patients exposed to radon and air pollution.

Lung cancer is one of the most common forms of cancer. The aim of this study was to validate chromosome aberrations in peripheral blood lymphocytes of lung cancer patients living in a region with high air pollution and increased background radon levels as a biomarker of cancer risk. A total of 417 lung cancer patients and 468 control participants were analysed using a chromosome aberration assay in peripheral blood lymphocytes. The results showed that chromatid-type aberrations (2.26±1.58 vs. 1.60±1.58) and chromosome-type aberrations (CSAs) (0.96±1.36 vs. 0.42±0.70) in lung cancer patients were increased significantly in comparison with the controls. The most significant two-fold increase was detected for CSAs (nonsmoking patients: 0.84±1.54 vs. 0.41±0.73%, smoking patients: 0.99±1.31 vs. 0.44±0.67%). The frequency of dicentric and ring chromosomes, double minutes and rogue cells was significantly higher (P=0.002, 0.00002, 0.01, 0.0007) in the lung cancer patients. As both analysed groups lived in the same environment, our results show that increased radon levels were not the only source for the detected genome damage. Using binomial logistic regression, the estimated odds ratios and 95% confidence intervals adjusted for the main confounders (smoking, occupational exposure, age) were 1.31 (1.20–1.40) for chromatid-type aberrations, 1.28 (1.17–1.33), and 1.68 (1.49–1.88) for CSAs. It may be suggested that lung cancer patients show a significant increase in genome damage that may be caused by an interplay between exposure and individual low capacity of DNA repair, leading to genome instability.

Association of DNA Repair Gene Polymorphism with Chromosomal Aberrations Frequency in Human Lymphocytes

Analysis of the association between several DNA repair gene polymorphisms and the level of chromosomal aberrations (CAs) in lymphocytes of two groups of adolescents was carried out: in a group of 256 donors exposed to indoor radon and a control group of 94 donors. In a group of children with living conditions exposing them to high doses of radon (>200 Bq/m3), the level of CAs was significantly higher among carriers of genotypes hOGG1 Cys/Cys, hOGG1 Ser/Cys, ADPRT Ala/Ala, and ADPRT Val/Ala. No significant association between the level of CA and XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, and APE1 Asp148Glu polymorphisms was found.

DNA excision repair and double-strand break repair gene polymorphisms and the level of chromosome aberration in children with long-term exposure to radon

Abstract Purpose: To study polymorphic variants of repair genes in people affected by long-term exposure to radon. The chromosome aberration frequency in peripheral blood lymphocytes was used as the biological marker of genotoxicity. Materials and methods: Genotyping of 12 single nucleotide polymorphisms in DNA repair genes (APE, XRCC1, OGG1, ADPRT, XpC, XpD, XpG, Lig4 and NBS1) was performed in children with long-term resident exposure to radon. Quantification of the aberrations was performed using light microscopy. Results: The total frequency of aberrations was increased in carriers of the G/G genotype for the XpD gene (rs13181) polymorphism in recessive model confirmed by the results of ROC-analysis (‘satisfactory predictor’, AUC = 0.609). Single chromosome fragments frequency was increased in carriers of the G/G genotype in comparison with the T/T genotype. In respect to the total frequency of aberrations, the G/G genotype for the XpG gene (rs17655) polymorphism was also identified as a ‘satisfactory predictor’ (AUC = 0.605). Carriers of the T/C genotype for the ADPRT gene (rs1136410) polymorphism were characterized by an increased level of single fragments relative to the T/T genotype. Conclusion: The relationships with several types of cytogenetic damage suggest these three SNP (rs13181, rs17655 and rs1136410) may be considered radiosensitivity markers.

Role of Gene-Gene Interactions in the Chromosomal Instability in Workers at Coal Thermal Power Plants

The 23 polymorphic variants in genes encoding the enzymes of xenobiotics biotransformation (CYP1A1 (rs4646903), CYP1A2 (rs762551), GSTP1 (rs1138272, rs1695), GSTM1 (del), and GSTT1 (del)), DNA repair (XRCC1 (rs25489, rs25487), APEX1 (rs1130409), hOGG1 (rs1052133), ADPRT (rs1136410), XPD (rs13181), XPG (rs17655), XPC (rs2228001), ATM (rs1801516), NBS (rs1805794), XRCC2 (rs3218536), and XRCC3 (rs861539)), antioxidant system (MnSOD (rs4880) and GPx1 (rs1050450)), cell cycle control and apoptosis (TP53 (rs1042522)), DNA methylation (MTHFR (rs1801133) and MTR (rs1805087)), and chromosomal aberrations in lymphocytes in the workers at thermal power plants were analyzed. We found that allelic variants in the CYP1A1 (rs4646903), hOGG1 (rs1052133), XRCC1 (rs25487), and APEX1 (rs1130409) genes were associated with an increased level of chromosomal aberrations in workers. Informative models of gene-gene interactions including CYP1A1 (rs4646903, T>C), CYP1A2 (rs762551, C>A), GSTT1 (del); XRCC1 (rs25487, G>A), MTHFR (rs1801133, C>T), GSTT1 (del); XRCC1 (rs25487, G>A), APEX1 (rs1130409, T>G), TP53 (rs1042522, G>C) determining the formation of the increased frequency of chromosomal aberrations in the workers at coal thermal power plants were discovered.

Associations of polymorphisms in the cytokine genes IL1β (rs16944), IL6 (rs1800795), IL12b (rs3212227) and growth factor VEGFA (rs2010963) with anthracosilicosis in coal miners in Russia and related genotoxic effects

Anthracosilicosis (AS), a prevalent form of pneumoconiosis among coal miners, results from the accumulation of carbon and silica in the lungs from inhaled coal dust. This study investigated genotoxic effects and certain cytokine genes polymorphic variants in Russian coal miners with АS. Peripheral leukocytes were sampled from 129 patients with AS confirmed by X-ray and tissue biopsy and from 164 asymptomatic coal miners. Four single-nucleotide polymorphisms were genotyped in the extracted DNA samples: IL1β T-511C (rs16944), IL6 C-174G (rs1800795), IL12b A1188C (rs3212227) and VEGFA C634G (rs2010963). Genotoxic effects were assessed by the analysis of chromosome aberrations in cultured peripheral lymphocytes. The mean frequency of chromatid-type aberrations and chromosome-type aberrations, namely, chromatid-type breaks and dicentric chromosomes, was found to be higher in AS patients [3.70 (95% confidence interval {CI}, 3.29-4.10) and 0.28 (95% CI, 0.17-0.38)] compared to the control group [2.41 (95% CI, 2.00-2.82) and 0.09 (95% CI, 0.03-0.15)], respectively. IL1β gene T/T genotype (rs16944) was associated with AS [17.83% in AS patients against 4.35% in healthy donors, odds ratio = 4.77 (1.88-12.15), P < 0.01]. A significant increase in the level of certain chromosome interchanges among AS donors is of interest because such effects are typical for radiation damage and caused by acute oxidative stress. IL1β T allele probably may be considered as an AS susceptibility factor among coal miners.

Polymorphism of genes of the antioxidant system in the development of predispositions to lung cancer

We analyzed the polymorphic loci in the genes of the antioxidant system enzymes, such as GSTP1 (313A>G and 341C>T), MnSOD (47С>Т), GPx1 (599C>T), and CAT (–262C>>T), among 497 residents of Kemerovo oblast (Western Siberia, Russia). The analysis of the single-locus effects demonstrated a significant protective effect of the major C allele in the GPx1 (599C>T) locus. The MDR analysis of the gene-gene interactions showed that the GPx1 and the CAT genes work in close cooperation and mutually reinforce the risk of development of squamous cell lung cancer among the inhabitants of the industrial region.

Dynamics of the level of chromosomal aberrations in residents of industrial cities under the conditions of changing atmospheric pollution

The level and range of chromosomal aberrations in residents of Kemerovo, a large industrial center of Western Siberia, was studied in two periods of time: from 1986 to 2000 and from 2001 to 2012. Cytogenetic studies were performed on 668 persons (333 persons in the first period and 335 persons in the second period). The frequency of aberrations among residents in Kemerovo was lower in 2001–2012 than in 1986–2000, which is consistent with the reduced emission of pollutants into the air in Kemerovo. The new background level of chromosomal aberrations in Kemerovo’s residents, who do not come into contact with industrial genotoxicants, was established at 1.48 ± 0.08% and can be used in further genetic and ecological studies.

Influence of DNA repair genes polymorphism on the karyology of buccal epithelium cells in humans exposed to radon

DNA samples from 318 children and adolescents (174 males, 144 females), exposed to radon at home and 65 children (23 males, 42 females) in the control group have been studied. Using the micronucleus test on buccal epithelial cells we identified a significant increase in the number of cells with cytogenetic and proliferative abnormalities in the exposed group. Associations between NBS1 (rs1805794), ATM (rs1801516), and ADPRT (rs1136410) genes polymorphisms and karyological abnormalities in buccal epithelial cells were investigated. For the exposed group, an association of NBS1 Glu185Gln polymorphism with an increased frequency of “broken egg”-type protrusions and apoptotic bodies was established. The NBS1 185Glu/Gln and the ATM1 1853Asp/Asp genotypes were associated with elevated levels of cytogenetic damage, while the NBS1 185Glu/Glu and ATM 1853Asp/Asn genotypes demonstrated a protective role. No significant associations were found in the control group.

Genotoxic effects of the combined influence of radon and heavy metals depending on polymorphism of genes of monooxygenase system enzymes

The correlation between the level of chromosomal aberrations and CYP1A genotypes in adolescents of the Tashtagol boarding school (Kemerovo region) exposed to a combined effect of high doses of radon and heavy metals has been studied. It was found that the level of chromosomal aberrations shows a statistically significantly increase in carriers of at least one CYP1A1*2A (A2455G) allele. The frequency of ring chromosomes shows a statistically significant increase in carriers of the CYP1A1 *1A*1A (T3801C) genotype. The frequency of multiple chromosomal aberrations was higher in carriers of the CYP1A2*1A*1A genotype. A conclusion on the important role of polymorphic CYP1A loci in genotoxic effects of radon and heavy metals is made.