CC BY
9
UDC 618.19-006.6-053.2/.9-084-02:614.876:621.039.5.004.6(477.41)
https://doi.org/10.32402/ dovkil2021.01.029
ПРОФ1ЛАКТИКА РАКУ МОЛОЧНО1 ЗАЛОЗИ У РАЙОНАХ, ЩО ПОСТРАЖДАЛИ В1Д АВАР11 НА ЧОРНОБИЛЬСЬК1Й АТОМН1Й ЕЛЕКТРОСТАНЦ11, ПОЧИНАЮЧИ В1Д ДИТЯЧОГО В1КУ
Бандажевський Ю.1., Дубова Н.Ф.
BREAST CANCER PREVENTION IN DISTRICTS AFFECTED BY THE CHORNOBYL NUCLEAR POWER PLANT ACCIDENT BEGINNING FROM CHILD AGES
1 BANDAZHEVSKYI Yu.I., 2DUBOVAYA N.F.
1Ecology and Health Coordination and Analytical Centre, Ivankiv, Ukraine 2National PL. Shupyk Medical Academy of Postgraduate Education, Kyiv, Ukraine
blood level of homocysteine - a product of the metabolism of the essential amino acid methionine - exceeds the physiological threshold in more than 75.0% of children aged 12-17 years old in districts located near the Chornobyl nuclear power plant (Ivankivsky and Polessky districts) [1].
This effect associated with the abnormal functioning of the folate cycle (FC) is based on both genetic changes and the environmental impact on a growing organism caused by the accident at the Chornobyl nuclear power plant [2].
The abnormal functioning of the folate cycle in adults is known to be the basis for the development of cancers, in particular, breast cancer [3-5], which incidence in Kyiv region is the highest among all the regions of Ukraine and increas-
es annually (fig. 1) [8-12].
Special attention in the etiology of breast cancer is given to carriers of the T risk allele of the MTHFR:677 genetic polymorphism [13, 14].
Taking this into account, the aim of this study was to make an assessment of the prevalence of this allele in a group of girls from Ivankivsky and Po-lisky districts located near the Chornobyl exclusion zone. In addition, we assessed variants of combined carriership of the T allele with risk alleles of other genetic polymorphisms regulating the FC.
Material and methods. The group under analysis included 251 girls aged 8-17 years old. All the children had blood drawn from the ulnar vein after fasting in the morning in order to carry out genetic analysis. The following
ПРОФ1ЛАКТИКА РАКУ МОЛОЧНО1 ЗАЛОЗИ У РАЙОНАХ, ЩО ПОСТРАЖДАЛИ В1Д АВАРИ НА ЧОРНОБИЛЬСЬКЙ АТОМН1Й ЕЛЕКТРОСТАНЦИ, ПОЧИНАЮЧИ В1Д ДИТЯЧОГО В1КУ 1 Бандажевський Ю.1., 2Дубова Н.Ф. 1Координащйний аналтичний центр «Екологя iздоров'я», смт. 1ванюв, Укра1на 2Нащональна медична академ1я пiслядипломноï освти iM. П.Л. Шупика, м. Ки)'в
Метою роботи була о^нка поширеност алел'1 ризику Т генетичного полiморфiзму MTHFR:677 у груп двчаток i31ванювського i Полського районiв, розташованих поблизу Чорнобильсько'/' зони в'щчуження, i варiантiв поеднаного но^йства алел '1 Т з алелями ризику iнших генетичних полiморфiзмiв, що конт-ролюють фолатний цикл. Методи. lмунохiмiчний, статистичний. Результати. Генетичну схильнiсть до ризику виникнення раку молочноï залози проаналiзо-вано у груп'1, що складалася з 251 двчаток-ni^rniB. Виявлено носйство алел '1 Т полiмор-
ф'зму МТ^Я:С677Т у 142 дтей (56,6%). Гомозиготний варiант Т/Тзустр'чався у 25 дв-чаток ( 10,0%). у 60 з них (23,9%) рееструвала-ся компаунд-гетерозиготнсть за алелями 677СТ/1298АС гена MTHFR. Висновки. Виявленi генетичнi змiни фолатно-го циклу призводять до значного зниження активност мет'лентетрапдрофолатредуктази i, в'щпов'щно, збльшення вмсту гомоцисте)'ну у кровi, створюючи умови для розвитку онко-лопчних захворювань молочноï залози. Зважаючи на високий рiвень генетичноï схильносл, з урахуванням послйного впливу на органiзм радоактивних елементiв i продук-тв 1'хнього розпаду, виникнення через це серйозних порушень обмiну речовин, необх'щ-но видляти групу ризику дтей щодо ймовiр-ност виникнення онколопчних захворювань молочно}' залози.
Ключовi слова: фолатний цикл, алелi ризику, рак молочноï залози, дiвчатка-пiдлiтки, радоактивно забруднен територн.
© Бандажевський Ю.1., Дубова Н. Ф. СТАТТЯ, 2021.
29 Environment & Health № 1 2021
BREAST CANCER PREVENTION IN DISTRICTS AFFECTED BY THE CHORNOBYL NUCLEAR POWER PLANT ACCIDENT BEGINNING FROM CHILD AGES 1Bandazhevskyi Yu.l., 2Dubovaya N.F. 1 Ecology and Health Coordination and Analytical Centre, Ivankiv, Ukraine 2National P.L. Shupyk Medical Academy of Postgraduate Education, Kyiv, Ukraine
The aim of this paper was to assess the prevalence of the T risk allele of the MTHFR:677 genetic polymorphism in a group of girls from Ivankivsky and Polisky districts located near the Chornobyl exclusion zone. In addition, we assessed variants of combined carriership of the T allele with risk alleles of other genetic polymorphisms regulating the folate cycle.
Research methods. Immunochemical, statistical. Results. Genetic predisposition to breast cancer risk was analyzed in a group of 251 adolescent girls. Carriership of the T allele of the MTHFR:C677T polymorphism was found in
142 children (56.6%), while the homozygous T/T variant was found in 25 girls, or in 10.0% of cases. Compound heterozygosity for the 677CT/1298AC alleles of the MTHFR gene was recorded in 60 individuals, or in 23.9% of cases.
Conclusions. The revealed genetic changes in the folate cycle lead to a significant decrease in the activity of methylenetetrahy-drofolate reductase, and, accordingly, to an increase in the level of homocysteine in the blood, creating conditions for the occurrence of breast cancer.
Given the high level of genetic predisposition, taking into account the constant impact on the body of radioactive elements and their decay products, the occurrence, as a consequence, of serious metabolic disorders, it is necessary to identify the breast cancer risk group of children.
Keywords: folate cycle, risk alleles, breast cancer, adolescent girls, radiation contaminated areas.
allelic variants were identified at a laboratory certified under quality standards with the consent of parents: C677T and
A1298C of the MTHFR gene (methylenetetrahydrofolate reductase), A2756G of the MTR gene (Bi2-dependent
Figure 1
Dynamics of standardized (per 100 000 of population; Ukrainian standard) breast cancer incidence ratio for women in Ukraine and Kyiv region
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Table 1
Prevalence of genetic polymorphism risk alleles in the examined
Subgroup №, number of polymorphisms Girls group of girls from Ivankivsky and Polisky districts
Abs. number Percentage, %
№ 1 - «0» 6 2.39
№ 2 - «1» 37 14.74
№ 3 - «2» 112 44.62
№ 4 - «3» 75 29.88
№ 5 - «4» 21 8.37
Total 251 100.0
methionine synthase) and A66G of the MTRR gene (methionine synthase reductase). For this purpose, a realtime PCR method was used. Analyser and test kit: DT-96 detecting thermocycler, DNA-Technology (Russia).
Results and discussion. The absence of risk alleles of all polymorphisms under study was found in 2.39% of cases. The largest number of cases fell within carriers of risk alleles of two polymorphic alleles (table 1).
The largest number of cases of the carriership of neutral allele homozygotes in the group of children under study was accounted for by the MTR:A2756G polymorphism that affects the synthesis of Bi2-dependent methionine synthase, the smallest number of cases fell within the MTRR:A66G polymorphism that has an impact on the synthesis of methionine synthase reductase, an enzyme that restores the activity of B12-dependent methionine syn-thase.
The largest percentage among the risk allele homozy-gous carriership figures is associated with the MTRR: A66G polymorphism.
The carriership of the MTHFR:C677T polymorphism T allele was observed in 142 girls (56.6%), while the T/T homozygous variant was found in 25 girls or in 10.0% of cases (table 2). This genotype variant leads to a significant decrease in the activity of methylenetetrahy-drofolate reductase and, accordingly, an increase in blood homocysteine levels [15].
It is placed on the same level as the TT genotype of the same polymorphism in terms of the degree of inhibition of the methylenetetrahydrofolate re-ductase enzyme activity, and accordingly, the degree of increase in the blood level of homocysteine [17].
In the group of girls under study, compound heterozygos-ity for the MTHFR gene 677CT/1298AC alleles was found in 60 girls or in 23.9% of cases, while the carriership of the 677 MTHFR polymorphism TT homozygous variant was observed in 25 girls, or in 10.0% of cases. Thus, there is genetically determined predisposition to the abnormal functioning of the FC and the increase in the blood homocysteine level in 85 girls or in 33.9% of cases in the studied population of children (table 3).
Heterozygous associations of the MTHFR:C677T and MTRR: A66G, as well as MTR:A2756G and MTRR:A66G polymorphisms were noticed to be an internal factor contributing to the occurrence of severe diseases, including congenital defects [17, 18].
In the group of girls under study, the compound heterozy-gosity of the MTHFR:677CT/
MTRR:66AG polymorphisms was observed in 61 girls, or in 24.3% of cases, the compound heterozygosity of the MTR: 2756AG/MTRR:66AG polymorphisms was found in 37 girls, or in 14.7% of cases (table 3). Attention should be given to the compound heterozygosity of the MTR: 2756AG/MTHFR:677CT polymorphisms in 35 girls, or in 13.9 of cases, because there occurs a combined disruption of the functioning of the main enzyme systems of the FC. In this case, the environmental effect in the form of radiation will be a provoking factor. The combinations of a homozygous variant of one polymorphism and a heterozygous variant of another one were observed less frequently, while the combinations of homozygous variants of risk alleles of these polymorphisms were not found at all (table 3).
Thus, we should acknowledge that the girls of the examined group from the districts bordering the Chornobyl exclusion zone have a high level of genetic predisposition to cancer, including breast cancer.
Hyperhomocysteinemia, a condition when the level of homocysteine in the blood exceeds the physiological
nPOB^EMM HOPHOBM^fl =
threshold is a manifestation of dysfunction of the genetic system that controls the folate cycle. This condition in children of Ivankovsky and Polessky districts was especially evident after forest fires in the Chornobyl exclusion zone [19].
In particular, the blood concentration of homocysteine above 10 [jmol/L was reported in 89 out of 137 examined girls from these districts (65.0%) after the 2015 forest fires [20].
At the same time, hyperho-mocysteinemia was not associated with the number of the folate cycle genetic polymorphisms under study, despite the carriership of several variants of the latter by the majority of girls in the group under analysis. In addition, there was a clear direct association between the blood homocys-teine level and the severity of the genetic risk associated with a genetic polymorphism responsible for the synthesis of methylenetetrahydrofolate reductase - the main enzyme of the FC (table 4) [20].
In order to carry out correlation studies that determine an association between blood Hcy levels and genetic abnormalities in the FC, in a number of
Table 2
Frequency of polymorphic alleles of folate cycle genes in examined girls from Ivankivsky
and Polisky districts
Gene, polymorphism Genotype variants
«Neutral» allele Homozygous variant «Risk» allele Heterozygous variant «Risk» allele Homozygous variant
Abs. number % Abs. number % Abs. number %
MTR:A2756G 157 62.5 80 31.9 14 5.6
MTHFR:A1298C 122 48.6 110 43.8 19 7.6
MTHFR:C677T 109 43.4 117 46.6 25 10.0
MTRR:A66G 45 17.9 120 47.8 86 34.3
cases under consideration, the MTHFR C677T genotypes under analysis were assessed using a point system (0-2) depending on how they affect Hcy formation - R genetic risk scores: «0» - 677CC genotype - no risk; «1» - 677CT genotype - low risk; «2» - 677TT genotype - high risk [15].
The strongest association was reported ith the homozygous variant of the MTHFR: 677 T/T risk allele [15]. At the same time, the external environmental factor in the form of radionuclides and wood combustion products contributed to a decrease in the activity of this enzyme by
Table 3
Prevalence of combinations of folate cycle genetic polymorphisms in the group of girls (n = 251)
MTHFR:C677T and MTHFR:A1298C polymorphism genotypes
CT677 - AC1298 CT677 - CC1298 TT677 - AC1298 TT677 - CC1298
n % n % n % n %
60 23.9 0 0 0 0 0 0
MTHFR:C677T and MTRR:A66G polymorphism genotypes
CT677 - AG66 CT677 - GG66 TT677 - AG66 TT677 - GG66
n % n % n % n %
61 24.3 41 16.3 11 4.4 8 3.2
MTR:A2756G and MTHFR:C677T polymorphism genotypes
AG2756 - CT677 AG2756 - TT677 GG2756 - CT677 GG2756 -TT677
n % n % n % n %
35 13.9 6 2.4 9 3.6 0 0
MTR:A2756G and MTRR:A66G polymorphism genotypes
AG2756 - AG66 AG2756 - GG66 GG2756 - AG66 GG2756 - GG66
n % n % n % n %
37 14.7 29 11.6 8 3.2 1 0.4
Table 4
Results of correlation analysis between homocysteine, vitamins B9 and B12 levels, number of polymorphisms and genetic risk scores in the group of girls [15]
Parameter Correlation coefficient, significance p Parameter
Hcy B12 B9 Npol Risk
Hcy Spearman's 1.000 - 0.213* - 0.378** - 0.028 0.303**
Sig. (2-tailed) 0.013 0.0001 0.747 0.0001
N 137 137 137 137 137
B12 Spearman's - 0.213* 1.000 0.208* - 0.082 - 0.011
Sig. (2-tailed) 0.013 0.015 0.343 0.897
N 137 137 137 137 137
Bg Spearman's - 0.378** 0.208* 1.000 0.047 - 0.193*
Sig. (2-tailed) 0.0001 0.015 0.582 0.024
N 137 137 137 137 137
Npol Spearman's - 0.028 - 0.082 0.047 1.000 0.285**
Sig. (2-tailed) 0.747 0.343 0.582 0.001
N 137 137 137 137 137
Risk Spearman's 0.303** - 0.011 - 0.193* 0.285** 1.000
Sig. (2-tailed) 0.0001 0.897 0.024 0.001
N 137 137 137 137 137
Note: Hcy - homocysteine, N - number of observations, Npol - number of polymorphisms. * - correlation is significant at the 0.05 level (2-tailed), ** - correlation is significant at the 0.01 level (2-tailed).
blocking energy processes in the cell [19]. ~
Conclusions
1. In the population of girls living in districts bordering the Chornobyl exclusion zone, a predisposition to abnormal functioning of the folate cycle and an increase in the blood level of homocysteine associated with the MTHFR:677 genetic polymorphism T allele was identified in 56.6% of cases. A homozygous variant of the T allele carriership was reported in 10.0% of cases, the compound heterozygosity for the 677CT/1298AC alleles of the MTHFR gene was observed in 23.9% of cases.
2. The compound heterozy-gosity of the MTHFR:677CT/ MTRR:66AG, MTR:2756AG/ MTRR:66AG and MTR:2756AG /MTHFR:677CT polymorphisms observed in 24.3%, 14.7% and 13.9% of cases respectively also contributes to the abnormal homocysteine metabolism.
3. The genetic changes in the folate cycle that were found provide conditions for the occurrence of cancers, including breast cancer.
4. Taking into account the high level of a genetic predisposition and constant effect of radioactive elements and their decay products on the organism, and as a result, the occurrence of serious metabolic disorders, it is necessary to identify a children's breast cancer risk group.
.niTEPATyPA
1. Bandazheuskyi Yu., Dubovaya N. The Role of the Folate Cycle Genome in Establishing Links between Homocysteine, Hormones of the Pituitary-Thyroid Axis and Vitamins of the «B» Group in Children from the Districts, Bordering the Chornobyl Exclusion Zone. Innovative Scientific Researches: European Development Trends and Regional Aspect: Monograph. 4-th ed. Riga, Latvia : Baltija Publishing, 2020. P. 42-62.
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ПРОФИЛАКТИКА РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ В РАЙОНАХ, ПОСТРА ДАВШИХ ОТ АВАРИИ НА ЧЕРНОБЫЛЬСКОЙ АТОМНОЙ ЭЛЕКТРОСТАНЦИИ, НАЧИНАЯ С ДЕТСКОГО ВОЗРАСТА 1Бандажевский Ю.И., 2Дубовая Н.Ф. 1 Координационный аналитический центр «Экология и здоровье», пгт. Иванков, Украина Национальная медицинская академия последипломного образования им. П.Л. Шупика, г. Киев
Целью работы была оценка встречаемости аллели риска Т генетического полиморфизма MTHFR:677 в группе девочек из Иванковского и Полесского районов, расположенных вблизи Чернобыльской зоны отчуждения, и вариантов сочетанного носи-тельства аллели Т с аллелями риска других генетических полиморфизмов, контролирующих фолатный цикл. Методы исследования. Иммунохимический, статистический. Результаты. Генетическая предрасположенность к риску возникновения рака молочной железы проанализирована в группе, состоящей из 251 девочек-подростков. Выявлено носительство аллели Т поли-
морфизма MTHFR:С677Т у 142 детей (56,6%), при этом гомозиготный вариант Т/Т встречался у 25 девочек, или в 10,0% случаев. У 60 лиц, или в 23,9% случаев, регистрировалась компаунд-гетерозигот-ность по аллелям 677СТ/1298АС гена MTHFR.
Выводы. Выявленные генетические изменения фолатного цикла приводят к значительному снижению активности метилен-тетрагидрофолатредуктазы и, соответственно, увеличению содержания гомоци-стеина в крови, создавая условия для возникновения онкологических заболеваний молочной железы.
Учитывая высокий уровень генетической предрасположенности, а также постоянное воздействие на организм радиоактивных элементов и продуктов их распада, возникновение, как следствие этого, серьезных нарушений обмена веществ, необходимо выделять группу риска детей в отношении возникновения онкологических заболеваний молочной железы.
Ключевые слова: фолатный цикл, аллели риска, рак молочной железы, девочки-подростки, радиоактивно загрязненные территории.
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Надйшло до редакцИ 14.11.2020
УДК 612.354:616.36-055: 616-001.28
https://doi.org/10.32402/ dovkil2021.01.035
ЗАКОНОМ1РНОСТ1 ФОРМУВАННЯ ЗАХВОРЮВАНЬ ПЕЧ1НКИ У ПОСТРАЖДАЛИХ ВНАСЛ1ДОК АВАР11 НА ЧОРНОБИЛЬСЬК1Й АЕС
Чумак А.А., Сарюсова Е.О., Альохша С.М., Медведовська Н.В., Овсяншкова Л.М., Малишевська 6.М.
PATTERNS OF LIVER DISEASE FORMATION IN VICTIMS OF THE CHORNOBYL NUCLEAR POWER PLANT ACCIDENT
1CHUMAK A.A., 1SARKISOVA E.O., 1ALEKHINA S.M., 2MEDVEDOVSKA N.V., 12OVSIANNIKOVA L.M., 12MALYSHEVSKA Y.M 1State Institution «National Research Center for Radiation Medicine of the NAMS of Ukraine» 2Scientific Coordination Department of the National Academy of Medical Sciences , of Ukraine
Non-alcoholic fatty liver disease (NAFLD) is a problem not only of modern hepatology, but also has a global importance for the state of human health, which is both due to the broad reach and the consequences of the progression of this pathology - the development of the liver cirrhosis, hepato-cellular carcinoma, liver-cell deficiency [1].
ЗАКОНОМ1РНОСТ1 ФОРМУВАННЯ ЗАХВОРЮВАНЬ ПЕЧ1НКИ У ПОСТРАЖДАЛИХ ВНАСЛ1ДОК АВАР11 НА ЧОРНОБИЛЬСЬКЙ АЕС 1 Чумак А.А., 1 Сарюсова Е.О., 1Альохна С.М., 2Медведовська Н.В., 1,2Овсяннкова Л.М., 12Малишевська €.М.
1ДУ «Нацональний науковий центр ращашйно! медицини НАМН Укра/ни», м. Ки/в
2Науково-координашйне управлння НАМН Укра/ни, м. Кш'в
Метою дослдження стало визначення механ'зм'в форму-вання та прогре^ентност хро^чних дифузних захворювань печiнки у постраждалих внаслдок аварп на ЧАЕС з розробкою д1агностичних критерпв фiброзних змн з цею патолопею. Матер'алами дослдження були результати обстеження та лiкування в умовах клiнiки ДУ «ННЦРМ НАМН Укра/ни» постраждалих внасл'щок Чорнобильськоi катастрофи, 57 з яких, за критерiями включення та виключення, було вдне-сено до основноi групи.
Методи дослдження: загальноклМчне обстеження, iнструментальнi дослдження (ультразвукова дiагностика органв черевноi порожнини), бiохiмiчнi, медико-статистич-нi, iнформацiйно-аналiтичнi.
Результати до^дження. Доведено, що у постраждалих внаслдок Чорнобильськоi катастрофи основною патолопею печiнки е неалкогольна жирова хвороба печiнки (НАЖХП), на тл'1 якоi розвиваеться виражене порушення жирового обм '1ну, достов'рне зниження холестерину, бета-лпопротеi-дiв, що можна вважати маркером розвитку цирозу в УЛНА, хворих на НАЖХП; наведено чинники прогресування цирозу з манiфестацiею захворювання на стади декомпенсацИ. Ключовi слова: постраждал'1 внаслдок Чорнобильськоi катастрофи, хронiчнi дифузш захворювання печнки, НАЖХП, НАСГ.
© ЧумакА.А., Сарюсова Е.О., Альохна С.М., Медведовська Н.В., Овсяннкова Л. М., Малишевська е. М. СТАТТЯ, 2021.
