THE ROLE OF HEREDITARY PREDISPOSITION (POLYMORPHIC MARKERS OF GLUTATHIONE-S-TRANSFERASE, CATALASE, ENDOTHELIAL NITROGEN OXIDE SYNTHASE GENES) AND SOME ADVERSE ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF BRONCHO-OBSTRUCTIVE PATHOLOGY IN CHILDREN LIVING IN RADIOACTIVELY CONTAMINATED AREAS. / РОЛЬ СПАДКОВОЇ СХИЛЬНОСТІ (ПОЛІМОРФНИХ МАРКЕРІВ ГЕНІВ ГЛУТАТІОН-S-ТРАНСФЕРАЗ, КАТАЛАЗИ, ЕНДОТЕЛІАЛЬНОЇ СИНТАЗИ ОКСИДУ АЗОТУ) ТА ДЕЯКИХ НЕСПРИЯТЛИВИХ ЧИННИКІВ ДОВКІЛЛЯ У ВИНИКНЕННІ БРОНХООБСТРУКТИВНОЇ ПАТОЛОГІЇ У ДІТЕЙ, МЕШКАНЦІВ РАДІОАКТИВНО ЗАБРУДНЕНИХ ТЕРИТОРІЙ.

OBJECTIVE: summarizing the results of many years of research by the authors on the influence of gene polymorphisms encoding xenobiotic biotransformation enzymes (GSTТ1, GSTM1, GSTР1), antioxidant protection (С^262Т of the catalase gene), endothelial nitric oxide synthase (4a/4b VNTR polymorphism of the eNOS gene), and some environmental factors on the occurrence of broncho-obstructive disorders and the development of bronchial asthma in children, residents of radioactively contaminated areas. MATERIALS AND METHODS: The examined school-aged children were residents of radioactively RCA who had no clinical signs of respiratory pathology. Deletion polymorphism of catalase gene (CAT C^262T), polymorphism of glutathione-S-transferase gene (GSTТ1, GSTM1, GSTР1) and the polymorphism in the 4th intron (4a/4b) of the eNOS gene were studied in the molecular genetics laboratory of the State Institution «Reference Center for Molecular Diagnostics of Public Health Ministry of Ukraine¼. Molecular genetic studies were performed by polymerase chain reaction. The study of the ventilation lung capacity was carried out by the method of computer spirometry based on the data of the «flow-volume¼ loop analysis. A pharmacological inhalation test with a bronchodilator drug which affects the ß2-adrenergic receptors of the lungs was used to detect early changes in the ventilatory lung capacity - bronchial hyperreactivity. RESULTS AND CONCLUSIONS: One of the leading mechanisms, due to which the implementation of hereditary predisposition to bronchial asthma in children living in radioactively contaminated areas is the polymorphism of certain genes of glutathione-S-transferase, catalase, endothelial nitric oxide synthase. With such polymorphic variants of the GST genes, isoforms of enzymes with reduced activity are produced, which limits their ability to effectively neutralize free radicals, which are formed in excess when free radical oxidation processes are activated due to the constant intake of radionuclides with a long half-life into the body of children. Unfavorable factors that increase the risk of developing broncho-obstructive disorders and the likelihood of their implementation in the form of bronchial asthma in children, residents of radioactively contaminated areas, have been identified. It has been established that among them the leading role is played by hereditary predisposition to this disease. On the part of the child, such negative factors were unfavorable conditions of intrauterine development, the presence of signs of exudative-catarrhal diathesis, manifestations of allergies and frequent respiratory diseases from the first months of life.

CATALASE CRS-262T GENE POLYMORPHISM AND CHANGES IN VENTILATION LUNG CAPACITY IN CHILDREN-RESIDENTS OF RADIOACTIVELY CONTAMINATED TERRITORIES. / POLIMORFIZM SRS-262T GENA KATALAZY I ZMINY VENTYLIaTsIINOÏ SPROMOZhNOSTI LEGENIV U DITEI - MEShKANTsIV RADIOAKTYVNO ZABRUDNENYKh TERYTORII.

OBJECTIVE: to determine the association of catalase С-262Т gene polymorphism with the presence of bronchial hyper-reactivity in children living in radioactively contaminated territories. MATERIALS AND METHODS: There were examined school-age children-residents of radioactively contaminated territories (RCT), who did not have clinical signs of respiratory pathology. Catalase (CAT) С-262Т gene deletion polymorphism was studied in the molecular genetic laboratory of the State Institution «Reference Center for Molecular Diagnostic of Public Health Ministry of Ukraine¼. Determination of the polymorphic variant by the catalase С-262Т gene was performed by Polymerase Chain Reaction (PCR) using specific oligonucleotide primers, followed by Restriction Fragment Length Polymorphism (RFLP) analysis. The CAT С-262Т gene polymorphism in children living in RCT was compared with that in the reference group of practically healthy individuals. Ventilation lung capacity was performed by computer spirometry according to the analysis of the loop «the flow-volume¼. A pharmacological inhalation test with a bronchodilator that acts on ß2-adrenergic receptors of the lungs was used to detect early changes in the ventilatory capacity of the lungs - bronchial hyperreactivity. RESULTS: Comparative analysis showed that in the presence of bronchial hyperreactivity in children living in RCT, the CT genotype was more common than in children without bronchial hyperreactivity, and the frequency of the CC genotype was correspondingly reduced. There was a trend towards a decrease in the frequency of the TT genotype. An analysis of the frequency distribution of allelic variants of the CAT С-262Т gene polymorphism in children living in the RCT revealed a tendency to increase in the frequency of the T-allele and according to the decrease in the frequency of C-allele in the presence of bronchial hyperreactivity.Сonclusions. Thus, among children living in RCT, CT-homozygotes of CAT С-262Т gene polymorphism had bronchial hyperreactivity probably more often than CC-heterozygotes. In the presence of bronchial hyperreactivity, there was a trend towards an increase in the frequency of the T-allele and, accordingly, a decrease in the frequency of the C-allele.

ROLE OF GENETIC PREDISPOSITION, GENE POLYMORPHISM OF GLUTATHIONE-S-TRANSFERASE (GSTT1, GSTM1, GSTP1) AND SOME ADVERSE FACTORS IN DEVELOPMENT OF BRONCHIAL ASTHMA IN CHILDREN - RESIDENTS OF RADIOACTIVELY CONTAMINATED AREAS. / ROL' SPADKOVOÏ SKhYL'NOSTI, POLIMORFIZMU GENIV GLUTATION/S/TRANSFERAZ (GSTT1, GSTM1, GSTP1) TA DEIaKYKh NESPRYIaTLYVYKh ChYNNYKIV U ROZVYTKU BRONKhIAL'NOÏ ASTMY U DITEI ­ MEShKANTsIV RADIOAKTYVNO ZABRUDNENYKh TERYTORII.

OBJECTIVE: to determine the influence of hereditary predisposition, polymorphism of GSTT1, GSTM1, GSTP1 genes andenvironmental factors on the development of bronchial asthma in children - residents of radioactively contaminat-ed areas. MATERIALS AND METHODS: School-age children-residents of radioactively contaminated areas with bronchial asthma,and those without clinical signs of respiratory pathology were examined. Genetic, medical, biological and social riskfactors were determined based on the study of anamnestic data and medical records. Ventilation lung capacity wasassessed by the method of computer spirometry. Molecular genetic studies were carried out using polymerase chainreaction (PCR) and restriction fragment length polymorphism (RFLP) for further analysis. RESULTS: Molecular genetic studies of the distribution of genotypes and frequencies of polymorphic variants of thegenes GSTT1, GSTM1, GSTP1 were performed in children living under long-term intake of 137Cs by food chains. It wasfound that in children with BA the tendency to frequency of the deletion variant of the GSTT1 and GSTM1 genes incomparison with children without bronchial and pulmonary pathology was increased. The study of distributing theGSTP1 A313G gene polymorphic variants revealed in children with BA a significant increase in the frequency of AG-genotype, compared with the data of reference group. Adverse factors that increase the risk of developing bron-choobstructive disorders and the probability of their implementation in the form of bronchial asthma in children -residents of RCA have been identified. It is established that among them the leading role is played by hereditarypredisposition to this disease. On the part of the child, such negative factors were unfavorable conditions of fetaldevelopment, the presence of signs of exudative-catarrhal diathesis, manifestations of allergies and frequent respi-ratory diseases from the first months of life. It was found that the risk of developing BA was significantly increasedin children with the GSTT1 and GSTM1 gene deletion genotypes; an increased risk of developing BA in children witha combination of the GSTP1 A313G gene polymorphism with deletion polymorphism of the GSTT1 or GSTM1 gene wasdetermined. Сonclusion. Оne of the leading mechanisms, due to which there is a realization of hereditary predisposition tobronchial asthma in children living under constant intake of radionuclides with a long half-life, is the polymorphismof certain glutathione-S-transferase genes, namely, GSTT1, GSTM1 and A313G gene deletion polymorphism and GSTP1gene polymorphism.

FUNCTION OF EXTERNAL RESPIRATION AND MARKERS OF OXIDATIVE STRESS IN CHILDREN-RESIDENTS OF RADIOACTIVELY CONTAMINATED TERRITORIES. / FUNKTsIIa ZOVNIShN'OGO DYKhANNIa I MARKERY OKSYDATYVNOGO STRESU U DITEY̆ ­ MEShKANTsIV RADIOAKTYVNO ZABRUDNENYKh TERYTORIY̆.

OBJECTIVE: to evaluate the influence of processes of lipid peroxidation, and antioxidant protection on the function of external respiration in children-residents of radioactive contaminated territories. MATERIALS AND METHODS: There were examined children of school age, inhabitants of radioactive contaminated ter- ritories (RCT) without respiratory and pulmonary pathology, and patients with bronchial asthma (BA). Examination of the ventilation lung function was performed by the method of pneumotachography according to the analysis of the «flow-volume¼ loop. End products of lipid peroxidation (LPO), reacting with thiobarbituric acid (malondialde- hyde), enzymes-antioxidants - catalase, superoxide dismutase, glutathione peroxidase, glutathione transferase were studied to determine the signs of oxidative stress. RESULTS: Examinations of ventilation lung function in children-residents of RCT without respiratory and pulmonary pathology showed no significant deviations of its parameters beyond the limits of physiological fluctuations; a decrease in bronchial patency at different levels of the bronchial tree was established in children with BA. An increased incidence of bronchial hyperreactivity was noted in both the patients with BA and those who did not have bronchopulmonary pathology. The absence of an increase in the content of LPO products (malondialdehyde) in blood serum of children-residents of RCT with increased activity of catalase and group of glutathione enzymes indi- cates the sufficiency of compensatory possibilities of antioxidant protection. CONCLUSIONS: Studies of correlation between the function of external respiration and markers of oxidative stress determined that the indices of bronchial patency directly correlate with the activity of enzymes-antioxidants of the glutathione group and inversely - with the content of the LPO products in children-residents of RCT. The frequency of bronchospasm inversely correlated with the activity of glutathione group antioxidants. There are inverse correla- tion of 137Cs content in the body with the activity of glutathione transferase and glutathione peroxidase.

Influence of eNOS gene 4a/b VNTR polymorphism on development of endothelial dysfunction and respiratory system disorders in children - residents of radioactively contaminated areas. / VPLYV VNTR (4a/b) POLIMORFIZMU GENA eNOS NA ROZVYTOK ENDOTELIAL'NOI DYSFUNKTsII TA PORUShEN' SYSTEMY DYKhANNIa U DITEY - MEShKANTsIV RADIOAKTYVNO ZABRUDNENYKh TERYTORIY.

UNLABELLED: Objective is to study the role of еNOS gene polymorphism in the development of endothelial dysfunction and func tional disorders of the respiratory system in children - residents of radioactively contaminated areas. MATERIALS AND METHODS: Total of 184 children were examined to determine the possible associative links between еNOS gene intron 4m polymorphism and indices characterizing the functional state of the endothelium and the bronchopulmonary system. Of them the main group of children consisted of 135 children residents of radioactively contaminated areas, the control group - of 49 healthy children who lived in "clean" regions by the radioactive con tamination and were not belonging to victims of the Chernobyl accident contingents. The molecular genetic study determining the еNOS gene intron 4 polymorphism was performed. An examination of lung ventilation capacity was evaluated using the pneumotachography method. The thermographic method was used for registering the endothe lium dependent reaction of the vascular bed to changes in blood supply conditions. The levels of nitrogen com pounds (NO2 and NO3 ) were determined by the standard method using Hriss reagent. The level of body incorporat ed 137Cs was determined using human radiation counter Skrynner 3M (Institute of Human Ecology). RESULTS: Children of the main group did not differ from that of control and literature data by the frequency of geno types 4a/b and еNOS gene allele polymorphism. An increase in the duration of circulation restoration up to the ini tial level after occlusion test was noted in children of the main group with genotype 4a/4b comparing to children with genotype 4b/4b; a decrease in the nitrite content was observed in blood serum. The integral indices of elastic ity and tensility of the lung tissue, respiratory permeability were decreased; the signs of bronchospasm were record ed 1.5 times more often. These adverse effects were associated with the presence of genotype allele 4a, the signs of endothelial dysfunction and the level of the incorporated 137Cs. CONCLUSIONS: More pronounced changes in vascular endothelial reaction to occlusion and the significant decrease of serum nitrite level in allele 4a carriers, especially in children who live in adverse ecological conditions, give the right to include them into the risk group for the development of endothelial dysfunction, and to conside pulmonary dysfunction as one of its manifestations.

Balance of autonomic nervous system in children having signs of endothelial dysfunction, that were born and are domiciled in contaminated territories. / Vegetatyvnyj gomeostaz u ditej z oznakamy endotelial''noi' dysfunkcii', jaki narodylysja ta postijno prozhyvajut'' na radioaktyvno zabrudnenyh terytorijah.

UNLABELLED: Objective. The study examined the features of functional state of the autonomic nervous system in children having endothelial dysfunction and permanently residing in contaminated areas. Materials and methods. Clinical and instrumental examination of 101 children aged 7-18 years that were born and are domiciled in contaminated territories, including 37 persons with signs of endothelial dysfunction (subgroup IA) and 64 ones with no signs of endothelial dysfunction (IB subgroup) was conducted. The control group being comparable to the subgroups IA and IB by age, gender and clinical examination results included 37 children neither been domiciled in contaminated areas nor were belonging to the contingent of Chornobyl accident survivors. There were 20 apparently healthy children also examined. Results. Due to peculiarities of physiological pathways providing adaptive responses the children having signs of endothelial dysfunction are characterized by a more pronounced dysregulation of autonomous nervous system both in a resting state and under a functional load simulation, and also by a high strain of adaptation pathways. The lack of autonomous support of cardiovascular system is caused by inadequate adaptive responses of both central regulatory bodies (hypothalamus, vasomotor center) and peripheral receptors. Mainly the failure of segmental autonomous (parasympathetic) structures was revealed. The mode of their response to stress in this case corresponds to that in healthy individuals but at a lower functional level. There is a reduced aerobic capacity of the organism by the Robinson index, contributing to low adaptive range to non-specific stress in children being domiciled on contaminated territories including children having the endothelial dysfunction. Conclusions. Endothelial dysfunction was associated with more pronounced manifestations of autonomic dysregulation and reduced aerobic capacity of the organism being the risk factors of development of a range of somatic diseases requiring the development of prevention measures in children permanently residing in contaminated areas. KEYWORDS: autonomous nervous system balance, endothelial dysfunction, children, Chornobyl accident.

[Evaluation of immunity parameters and free radical processes in children-residents of radioactive contaminated territories born to parents irradiated in childhood].

The children--residents of contaminated territories, born from mothers irradiated in their childhood had in remote period of the Chernobyl Disaster an increase in the frequency of disorders connected with immune system activation and depressive types, increase in intensity of free radical processes in blood serum and erythrocytes.