The effect of the CYP1A1 gene polymorphisms of the first phase of the xenobiotic biotransformation system in combination with a high anthropogenic load on the development of “great obstetrical syndromes” and congenital malformations

Introduction. The perinatal period largely determines the state of human health throughout his subsequent life. Congenital malformations and pathological states combined under the common term “great obstetrical syndromes” (preeclampsia, premature birth, death of the fetal egg or delay in its development) make a significant contribution to infant mortality, affecting the demographic situation. The frequency of these pathologies increases in the regions with high anthropogenic load.

Materials and methods. A survey of one hundred thirty one pregnant woman lived in Novokuznetsk was conducted. Out of 93 examined women with “great obstetrical syndromes” there were 39 women with preeclampsia, 16 ones with intrauterine fetal growth retardation, 38 women who gave birth to premature babies. 11 women who gave birth to babies with congenital malformations and 27 women with a standard pregnancy. Using the polymerase chain reaction method, variants of the CYP1A1*2A gene of the first phase of the xenobiotic biotransformation system were identified in all subjects examined.

Results. The AG genotype of the CYP1A1*2A (rs4646903) gene was shown to be reliably associated with the development of “great obstetrical syndromes”: intrauterine growth retardation (χ² = 10.64; OR = 20.22), prematurity (χ² = 6.68; OR = 10.59), preeclampsia (χ² = 3.04; OR = 5.69) – and congenital malformations of the fetus (χ² = 7.3; OR = 14.86). No connection was found between the AA genotype and these pathologies.

Limitation. The study was of a pilot nature, so it is advisable to increase the sample.

Conclusion. The identified genotypes can be considered as markers of reproductive disorders and used in assessing individual predisposition to the development of “great obstetrical syndromes” and congenital malformations in planning and clinical pregnancy care in women living in ecologically unfavourable regions.

Compliance with ethical standards. The study was approved by the local Ethics Committee of the Federal State Budgetary Scientific Institution “Research Institute for Complex Problems of Hygiene and Occupational Diseases” (Protocol of the Meeting № 3, § 2 dated November 17, 2022) conducted in accordance with the generally accepted scientific principles of the Declaration of Helsinki of the World Medical Association “Ethical Principles for Medical Research Involving Human Subjects” as amended 2013. All participants gave informed voluntary written consent to participate in the study.

Contribution:
Gulyaeva O.N. – concept and design of the study, collection and processing of material, statistical processing, editing;
Ulanova E.V., Zagorodnikova O.A., Zoteeva A.I. – collection and processing of material;
Zhukova A.G. – concept of the study, editing;
Renge L.V. – concept of the study, editing.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgement. The study had no sponsorship.

Received: December 27, 2024 / Revised: February 20, 2025 / Accepted: March 26, 2025 / Published: April 30, 2025

1. Romero R. Prenatal medicine: The child is the father of the man. J. Matern Fetal Neonatal Med. 2009; 22(8): 636–9. https://doi.org/10.1080/14767050902784171

2. Di Renzo G.C. The great obstetrical syndromes. J. Matern Fetal Neonatal Med. 2009; 22(8): 633–5. https://doi.org/10.1080/14767050902866804

3. Zarudii F.S., Gromakova L.S., Rakhmanova R.T., Frolov A.L. Preeclampsia (review). Vestnik Bashkirskogo gosudarstvennogo meditsinskogo universiteta. 2014; (3): 19–35. https://elibrary.ru/sjyupn (in Russian)

4. Dhariwal N.K., Lynde G.C. Update in the management of patients with preeclampsia. Anesthesiol. Clin. 2017; 35(1): 95–106. https://doi.org/10.1016/j.anclin.2016.09.009

5. Sidorova I.S., Milovanov A.P., Nikitina N.A., Bardachova A.V., Rzaeva A.A. Severe preeclampsia and eclampsia: critical conditions for the mother and fetus. Akusherstvo i ginekologiya. 2013; (12): 34–40. https://elibrary.ru/rtecmf (in Russian)

6. Sidorova I.S., Nikitina N.A. Preeclampsia in the focus of a practitioner’s attention. Akusherstvo i ginekologiya. 2014; (6): 4–9. https://elibrary.ru/shjwfd (in Russian)

7. Bikmetova E.S., Trishkin A.G., Artymuk N.V. The friquency and risk factors for intrauterine growth restriction. Mat’ i ditya v Kuzbasse. 2012; (S1): 27–31. https://elibrary.ru/owzhth (in Russian)

8. Degtyareva E.A., Zakharova O.A., Kufa M.A., Kantemirova M.G., Radzinskiy V.E. The efficacy of prognosis and early diagnostics of fetal growth retardation. Rossiiskii vestnik perinatologii i pediatrii. 2018; 63(6): 37–45. https://doi.org/10.21508/1027-4065-2018-63-5-37-45 https://elibrary.ru/yqzjnb (in Russian)

9. Podzolkova N.M., Denisova Yu.V., Skvortsova M.Yu., Denisova T.V., Shovgenova D.S. Fetal growth restriction: unresolved issues of risk stratification, early diagnosis, and obstetric management. Voprosy ginekologii, akusherstva i perinatologii. 2021; 20(5): 76–86. https://doi.org/10.20953/1726-1678-2021-5-76-86 https://elibrary.ru/qsfyia (in Russian)

10. Radzinsky V.E. Big decisions for a small fetus. StatusPraesens. Ginekologiya, akusherstvo, besplodnyi brak. 2021; (3): 7–9. https://elibrary.ru/uggxnw (in Russian)

11. Olina A.A. Missed miscarriage and hyperprolactinemia. Is there a place for plant-derived medicines? RMZh. Mat’ i ditya. 2020; 3(2): 64–9. https://doi.org/10.32364/2618-8430-2020-3-2-64-69 https://elibrary.ru/pnrdrp (in Russian)

12. Olina A.A., Sadykova G.K., Galinova I.V. Structure of reproductive losses. Permskii meditsinskii zhurnal. 2017; 34(6): 59–66. https://doi.org/10.17816/pmj34659-66 https://elibrary.ru/ylauwo (in Russian)

13. Federal State Statistics Service. Russian Statistical Yearbook; 2024. Available at: https://eng.rosstat.gov.ru/Publications/document/74811 (in Russian)

14. Shabalov N.P., Sofronova L.N. Neonatology [Neonatologiya]. Moscow: GEOTAR-Media; 2020. https://doi.org/10.33029/9704-5770-2-NEO-2020-1-720 (in Russian)

15. Antonova V.L., Bogacheva E.V., Kitayeva Yu.Yu. Role of exogenous factorsin malformations formini. Ekologiya cheloveka. 2010; (6): 30–5. https://elibrary.ru/mdxakb (in Russian)

16. Federal State Statistics Service. Health care; 2024. Available at: https://rossta t.gov.ru/folder/13721 (in Russian)

17. Kasimovskaya N.A., Shatova E.A. Congenital cleft lip and palate in children: prevalence in Russia and worldwide, risk factors. Voprosy sovremennoi pediatrii. 2020; 19(2): 142–5. https://doi.org/10.15690/vsp.v19i2.2107 https://elibrary.ru/kljajx (in Russian)

18. Gulyaeva O.N., Zhukova A.G., Kazitskaya A.S., Luzina F.A., Alekseeva M.V., Renge L.V., et al. The degree of anthropogenic load, gene polymorphism of the xenobiotic biotransformation system and congenital malformations as links in the same chain. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2021; 100(7): 658–62. https://doi.org/10.47470/0016-9900-2021-100-7-658-662 https://elibrary.ru/tavxmv (in Russian)

19. Gulyaeva O.N., Kislitsyna V.V., Zhukova A.G., Kazitskaya A.S., Yadykina T.K., Matoshin S.V., et al. Combination of gene forms of phases I and II of the xenobiotic biotransformation system and the risk of pregnancy disorders in women living in a large industrial city. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2024; 103(7): 754–60. https://doi.org/10.47470/0016-9900-2024-103-7-754-760 https://elibrary.ru/cqobho (in Russian)

20. Gulyaeva L.F., Vavilin V.A., Lyakhovich V.V. Xenobiotic Biotransformation Enzymes in Chemical Carcinogenesis: An Analytical Review [Fermenty biotransformatsii ksenobiotikov v khimicheskom kantserogeneze: analiticheskii obzor]. Novosibirsk; 2000. https://elibrary.ru/hkznnl (in Russian)

21. Liakhovich V.V., Vavilin V.A., Zenkov N.K., Menshchikova E.B. Reactive oxygen species during monooxygenase reactions. Byulleten’ Sibirskogo otdeleniya Rossiiskoi akademii meditsinskikh nauk. 2005; 118(4): 7–12. https://elibrary.ru/hrpncf (in Russian)

22. Myllynen P., Pasanen M., Vähäkangas K. The fate and effects of xenobiotics in human placenta. Expert Opin. Drug Metab. Toxicol. 2007; 3(3): 331–46. https://doi.org/10.1517/17425255.3.3.331

23. Avery M.L., Meek C.E., Audus K.L. The presence of inducible cytochrome P450 types 1A1 and 1A2 in the BeWo cell line. Placenta. 2003; 24(1): 45–52. https://doi.org/10.1053/plac.2002.0876

24. Li J., Chen Y., Mo S., Nai D. Potential Positive Association between cytochrome P450 1A1 gene polymorphisms and recurrent pregnancy loss: a meta-analysis. Ann. Hum. Genet. 2017; 81(4): 161–73. https://doi.org/10.1111/ahg.12196

25. Stejskalova L., Pavek P. The function of cytochrome P450 1A1 enzyme (CYP1A1) and aryl hydrocarbon receptor (AhR) in the placenta. Curr. Pharm. Biotechnol. 2011; 12(5): 715–30. https://doi.org/10.2174/138920111795470994

26. Sambrook J., Fritsch E.F., Maniatis T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.

27. Spitsyn V.A. Human Biochemical Polymorphism (Anthropological Aspects) [Biokhimicheskii polimorfizm cheloveka (antropologicheskie aspekty)]. Moscow; 1985. (in Russian)

28. Artamonova V.G. Actual problems of industrial ecology and prevention of occupational diseases. Vestnik Rossiiskoi akademii meditsinskikh nauk. 1998; (1): 38–42. (in Russian)

29. Kislitsyna V.V., Surzhikov D.V., Likontseva Yu.S., Shtaiger V.A. Trend in indices of public health risk caused by air pollution in an industrial center. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2024; 103(4): 358–64. https://doi.org/10.47470/0016-9900-2024-103-4-358-364 https://elibrary.ru/ssaprt (in Russian)

30. Persson I., Johansson I., Ingelman-Sundberg M. In vitro kinetics of two human CYP1A1 variant enzymes suggested to be associated with interindividual differences in cancer susceptibility. Biochem. Biophys. Res. Commun. 1997; 231(1): 227–30. https://doi.org/10.1006/bbrc.1997.6051

31. Tselousova O.S., Kochetova O.V., Akhmadishina L.Z., Koritina G.F., Viktorova T.V. Polymorphic variants of genes of cytochrome P450 (CYP1A1, CYP2E1, CYP2D6) in development of predispositions to professional toxic defeat of the liver. Byulleten’ Vostochno-sibirskogo nauchnogo tsentra Vostochno-sibirskogo nauchnogo tsentra Sibirskogo otdeleniya Rossiiskoi akademii meditsinskikh nauk. 2009; (1): 136–40. https://elibrary.ru/kysidv (in Russian)

32. Thier R., Brüning T., Roos P.H., Rihs H.P., Golka K., Ko Y., et al. Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes. Int. J. Hyg. Environ. Health. 2003; 206(3): 149–71. https://doi.org/10.1078/1438-4639-00209