Аннотация
Изучали возможную связь между иммунным ответом на ксено- и эндобиотики и полиморфными локусами генов ферментов биотрансформации у женщин с врожденными пороками развития у плода. Обследованы 232 беременные женщины с врожденными пороками развития (ВПР) у плода и 267 женщин с физиологической беременностью (15-30 недель). Курение в семье оценивали как курение одного из супругов или обоих супругов. IgA и IgG антитела (АТ) в сыворотке крови женщин, специфичные к бензо[а]пирену (БП), 17β-эстрадиолу (Е2) и прогестерону (ПГ), определяли с помощью неконкурентного полуколичественного иммуноферментного анализа. Были рассчитаны индивидуальные соотношения уровней АТ класса A и G БП/Е2, БП/ПГ. Типирование полиморфизма в генах CYP1A1 (rs4646903), CYP1A2 (rs762551), CYP1B1 (rs1056836), CYP2D6 (rs35742686, rs3892097), GSTP1 (rs1695) и NAT2 (rs1801280, rs1799930, rs1799931) проводили методом ПЦР в режиме реального времени с использованием TaqMan-зондов, типирование полиморфизма генов GSTM1-0 (del) и GSTT1-0 (del) — мультиплексной ПЦР.
Выявлены прямые значимые корреляционные связи между уровнями IgA и IgG АТ к БП и стероидными гормонами (Е2 и ПГ) и между IgA и IgG АТ к Е2 и ПГ у женщин с ВПР у плода и в контрольной группе. Основными значимыми предикторами, ассоциированными с высоким риском ВПР у плода, были соотношение материнских уровней IgA-БП/IgA-ПГ >1,5УЕ (OR=4,70, 95CI%: 2,67-8,26, p<0,0001) и генотип GSTT1 «0/0» (OR=3,32, 95CI%: 1,79-6,13, p=0,001), причем при курении в семье риск значительно увеличивался. Материнские полиморфные локусы генов CYP1-2, GST(M1,P1) и NAT2 самостоятельно не вносили значимого эффекта в предрасположенность к ВПР у плода.
Наши результаты могут быть полезными для ранней диагностики ВПР у плода в комплексе с известными инструментальными и лабораторными методами.
Annotation
The relationship between the immune response to xeno- and endobiotics and polymorphic loci of biotransformation enzyme genes in women with congenital malformations (CMs) in the fetus were studied. We studied 232 pregnant women with CMs in the fetus and 267 women with physiological pregnancy (15-30 weeks). The family smoking factor was assessed as smoking by one or both partners smoking. IgA and IgG antibodies (AB) specific to benzo[a]pyrene (BP), 17β-estradiol (E2) and progesterone (PG) were determined in the blood serum of women using a non-competitive semi-quantitative enzyme immunoassay. Typing of rs4646903 CYP1A1, rs762551 CYP1A2, rs1056836 CYP1B1, rs35742686, rs3892097 CYP2D6, rs1695 GSTP1, and rs1801280, rs1799930, rs1799931 NAT2 genes polymorphism was determined through TaqMan-real-time PCR and GSTM1-0 (del), GSTT1-0 (del) genes polymorphisms was defined through multiplex real-time PCR.
Direct significant correlations were found between the levels of IgA and IgG AB to BP and steroid hormones (E2 and PG) and between IgA and IgG AB to E2 and PG in women with CMs in the fetus and in the control group. The ratio of maternal levels of IgA-BP/IgA-PG >1.5 (OR=4.70, 95CI%: 2.67-8.26, p <0.0001) and GSTT1 genotype "0/0" (OR=3.32, 95CI%: 1.79-6.13, p =0.001) were main significant predictors associated with a high risk of CMs in the fetus, with smoking in the family significantly increasing the risk. The study showed that maternal polymorphic loci of the CYP1-2, GST (M1, P1) and NAT2 genes alone did not significantly affect the predisposition to CMs in the fetus.
Our results may be useful for early diagnosis of fetal CMs in combination with known instrumental and laboratory methods.
Список литературы
1. Nagorneva S.V., Prokhorova V.S., Shelaeva E.V., Khudovecova A.M. The prevalence of congenital fetal anomalies for thepast 5 years (2013–2017). Zhurnal akusherstva I ginekologii. 2018; 67(3): 44-48. DOI: 10.17816/JOWD67344-48. (in Russian)
2. Artymuk N.V., Chervov V.O., Danilova L.N. Hormon-like xenobiotics and gynecological problem. Literature review. Mat` i ditya v Kuzbasse. 2018; 73(2): 20-6. (in Russian)
3. Pavanello S., Campisi M., Mastrangelo G., Hoxha M., Bollati V. The effects of everyday-life exposure to polycyclic aromatic hydrocarbons on biological age indicators. Environ Health. 2020; 19(1):128. DOI: 10.1186/s12940-020-00669-9.
4. Shirshev S.V. Mechanisms of immunoendocrine control of reproductive processes [Mekhanizmy immunoendokrinnogo kontrolya protsessov reproduktsii. Tom 2]. Ekaterinburg: UrO RAN; 2002. (in Russian)
5. Siemienowicz K.J., Wang Yi., Marečková M., Nio-Kobayashi J., Fowler P.A., Rae M.T., et al. Early pregnancy maternal progesterone administration alters pituitary and testis function and steroid profile in male fetuses. Sci. Rep. 2020; 10(1): 21920. DOI: 10.1038/s41598-020-78976-x.
6. Kutsenko S.A. Fundamentals of toxicology [Osnovy toksikologii]. St. Petersburg: Voenno-meditsinskaya akademiya im. S.M. Kirov; 2002. (in Russian)
7. Tabikhanova L.E., Osipova L.P., Churkina T.V., Voronina E.N., Filipenko M.L. Genetic polymorphism of CYP1A1 and CYP2D6 in populations of Buryats, Teleuts and Russians of Eastern Siberia. Vavilovskiy zhurnal genetiki i selektsii. 2018; 22(2):205-11. DOI: 10.18699/VJ18.348. (in Russian)
8. Menzhinskaya I.V., Vanko L.V. Characteristics of autoantibodies to progesterone in women with early pregnancy loss. Rossiyskiy allergologicheskiy zhurnal. 2017; 14(1S): 90-93. DOI: 10.36691/RJA228. (in Russian)
9. Glushkov A.N., Polenok E.G., Mun S.A., Gordeeva L.A., Kostyanko M.V., Kolpinsky G.I., et al. Antibodies specific to chemical carcinogens and sex steroids as well as serum estradiol and progesterone levels in females with breast cancer and lung cancer males. Rossiyskiy immunologicheskiy zhurnal. 2020; 23(1): 69–78. DOI: 10.15789/1028-7221-008-AST. (in Russian)
10. Glushkov A.N., Polenok E.G., Gordeeva L.A., Mun S.A., Kostyanko M.V., Antonov A.V. et al. Immunological imbalance, gene polymorphism of biotransformation enzymes, and steroid hormone receptors in tumors in breast cancer patients. Meditsinskaya Immunologiya. 2022; 24(4): 765-78. DOI: 10.15789/1563-0625-IIG-2493. (in Russian)
11. Gordeeva L.A., Voronina E.N., Sokolova E.A., Ermolenko N.A., Gareeva Yu.V., Sutulina I.M. et al. Association GSTT1, GSTM1, and GSTP1 (Ile105Val) genetic polymorphisms in mothers with risk of congenital malformations in their children in Western Siberia: a case-control study. Prenatal Diagnosis. 2013; 33(11): 1095-1101. DOI: 10.1002/pd.4204.
12. Lin C.-Ju, Li L.-A. Estrogenicity of Major Organic Chemicals in Cigarette Sidestream Smoke Particulate Matter. Atmosphere. 2023; 14(4): 647. DOI: 10.3390/atmos14040647.
13. Artimuk N.V., Elizarova N.N., Polenok E.G. The role of steroid hormones and chemical carcinogen benzo(a)pyrene in premature rupture of membranes in preterm pregnancy. Ginekologiya. 2017; 19 (2): 55–8. (in Russian)
14. Glushkov A.N. Immune-hormonal imbalance in chemical cancerogenesis. Rossiyskiy Immunologicheskiy Zhurnal. 2022; 25(1): 23-36. DOI: 10.46235/1028-7221-1091-IHI. (in Russian)
15. Lin S., Lin C-Ju, Hsieh D.P. H., Li L.-A. ERα phenotype, estrogen level, and benzo[a]pyrene exposure modulate tumor growth and metabolism of lung adenocarcinoma cells. Lung Cancer. 2012; 75(3): 285-92. DOI: 10.1016/j.lungcan.2011.08.010.
16. Glushkov A.N., Krasilnikova K.S., Polenok E.G., Kostyanko M.V. Influence of antibodies to low-molecular xeno- and endobiotics on estradiol and progesterone maintenance in blood serum of pregnant women. Izvestiya Samarskogo nauchnogo tsentra Rossiyskoy akademii nauk. 2014; 16(2): 682-6. (in Russian)
17. Ensembl [Internet]. EMBL-EBI: European Molecular Biology Laboratory (EU) and The Wellcome Trust Sanger Institute (GB). 2023; Human (GRCh38.p13) [Cited 2023 Jun 6]; Available from: https://www.ensembl.org/Homo_sapiens/Info/Index.
18. Kucher A.N. Gene-environment interactions as the basis of health formation. Ekologicheskaya genetika. 2017; 15(4):19-32. DOI: 10.17816/ecogen15419-32. (in Russian)
19. Kobayashi S., Sata F.,Kishi R. Gene-environment interactions related to maternal exposure to environmental and lifestyle-related chemicals during pregnancy and the resulting adverse fetal growth: a review. Environ. Health Prev. Med. 2022; 27(0): 24. DOI: 10.1265/ehpm.21-00033.
20. Gulyaeva L.F., Vavilin V.А., Lyakhovich V.V. Xenobiotic biotransformation enzymes in chemical cancerogenesis [Fermenty biotransformatsii ksenobiotikov v khimicheskom kantserogeneze]. Series «Ecology». Novosibirsk: GPNTB SO RAN, Institut molekulyarnoy biologii i biofiziki SO RAMN; 2000. (in Russian)
21. Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat. Res. 2000; 463(3): 247-83. DOI: 10.1016/s1383-5742(00)00050-8.
22. Kutlina T.G., Valova Ya.V., Karimov D.O., Mukhammadiyeva G.F., Khusnutdinova N.Yu., Smolyankin D.A. et al. Analysis of expression of GSTT and GSTM genes in toxic hepatitis in experimental conditions. Izvestiya Ufimskogo nauchnogo tsentra RAN. 2018; 4(3): 70–4. DOI: 10.31040/2222-8349-2018-4-3-70-74. (in Russian)
23. Sokova E.A. Particularities of human grud-metabolizing system in fetoplacental complex. Biomeditsina. 2008; (1): 14-25. (in Russian)
24. Nakanishi G., Pita-Oliveira M., Bertagnolli L.S., Torres-Loureiro S., Scudeler M.M., Cirino H.S. Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area. OMICS. 2022; 26(10): 528-541. DOI: 10.1089/omi.2022.0090.
25. Kolesnikova L.I., Grebenkina L.A., Darenskaya M.A., Vlasov B.Ya. Oxidative stress as nonspecific pathogenetic link of reproductive disorders (systematic review). Byulleten’ SO RAMN. 2012; 32(1): 58-66. (in Russia)
26. Alves M.M.C., Almeida M., Oliani António Hélio,Breitenfeld L., Ramalhinho A.C. Women with polycystic ovary syndrome and other causes of infertility have a higher prevalence of GSTT1 deletion. Reprod. Biomed. Online. 2020; 41(5): 892-901. DOI: 10.1016/j.rbmo.2020.06.010.
27. Jauniaux E., Poston L., Burton G.J. Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution. Hum. Reprod. Update. 2006; 12(6): 747–55. DOI:10.1093/humupd/dml016.
28. Zhuk T.V., Yavorskaya S.D., Vostrikov V.V. Obesity, reproduction and oxidative stress (literature review). Ozhirenie i metabolizm. 2017; 14(4):16-22. DOI: 10.14341/OMET2017416-22. (in Russian)
29. Madki P., Tejasvi M.L.A., Paramkusam G., Ruheena K. Evaluation of serum immunoglobulins (IgG, IgA, IgM) and circulating immune complexes in oral precancer and cancer patients. Glob. Med. Genet. 2021; 8(3): 95-9. DOI: 10.1055/s-0041-1725157.
30. Menzhinskaya I.V., Beznoshchenko O.S., Saroyan T.T., Korneyeva I.E., Vanko L.V., Sukhikh G.T. Antibodies to reproductive hormones as a possible risk factor for poor outcome of in vitro fertilization cycles. Akusherstvo i ginekologiya. 2012; (2): 42-5. (in Russian)
31. Zhao L., Chen L., Yang T., Wang L., Wang T., Zhang S., et al. Parental smoking and the risk of congenital heart defects in offspring: An updated meta-analysis of observational studies. Eur. J. Prev Cardiol. 2020; 27(12): 1284-93. DOI: 10.1177/2047487319831367.