Features of the polymorphism of the VEGFa G634C gene and the expression of the vasculodothelial growth receptor (CD304⁺) as risk factors for angiogenesis disorders in conditions of rare earth elements

Introduction. Preserving and strengthening the health of the working population of Russia is a priority task of occupational health.

The study aims to research the features of polymorphism of the VEGFa G634C gene and expression of the vascular endothelial growth factor receptor (CD304⁺) as risk factors for angiogenesis disorders in workers exposed to rare earth elements.

Materials and methods. The observation group included 46 people — employees of a non-ferrous metallurgy enterprise exposed to harmful chemical production factors — lanthanides (class of working conditions 3.1). The comparison group included 64 people who are not in contact with harmful production factors (administrative workers). The researchers have used immunological methods in the work: allergosorbent test with enzyme label, membrane immunofluorescence on a flow cytometer, IFA. For statistical processing of the study results, the authors have used the following criteria: Student’s t-test, Mann–Whitney U-test, coefficient of determination (R²), relative risk index (RR), odds ratio (OR) and 95% confidence interval (CI). The authors considered the reliability of the differences to be significant at p<0.05

Results. In the observation group, the following were found: overexpression of lanthanide-specific IgG with an increase in the concentration of yttrium and cerium in the blood (R²=0.44 at p<0.05; OR=2.05; 95% CI=1.03–5.05) (RR=1.32; 95% CI=1.17–6.75); an increased expression level in relation to the comparison group of the neuropilin-1 CD304⁺ semaphorin receptor, which is also a receptor for vascular endothelial growth factor (VEGF), associated with an increase in the concentration of neodymium in the blood (R²=0.94 at p≤0.05; OR=1.27; 95% CI=1.06–3.84; RR=1.22; 95% CI=1.09–4.24). According to the results of the evaluation of the frequency of alleles and genotypes of the gene of the vascular endothelial growth factor VEGFa G634C (rs2010963), which controls the effects of the innate immune response (dendritic cells), the expression level of the G allele was significantly increased in relation to administrative workers (by 1.4 times), while the minor CC genotype was completely absent.

Limitations. The limitations of this study were the limited sample size and the number of literary sources on the issue under study.

Conclusion. In people working under the influence of harmful chemical factors — lanthanides (hazard class 3.1), experts have established the features of the expression of the VEGF gene and receptor: overexpression of the CD304⁺ lymphocyte cluster (HR=1.22; 95% CI=1.09–4.24), increased frequency of the G allele of the VEGFa gene (hazard class 3.1). The VEGFa G634C gene (OR=2.87; CI=1.16–7.07; OR=1.64(1.03–2.38); p<0.005), as well as an increase in the concentration of lanthanide-specific IgG (OR=2.05; 95% CI=1.03–5.05), which forms the risk of developing immunoassociated angiogenesis disorders associated with contamination of the biological environment with rare earth elements.

Ethics. The work was carried out in accordance with the principles of the Helsinki Declaration. The protocol and design of the study were approved by the local committee of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, dated 07/13/2023, Protocol No. 14.

Contribution:
Dolgikh O.V. — concept and design of the study, data collection and processing, text writing, editing;
Zaitseva N.V. — concept and design of the study;
Letyushev A.N. — concept and design of the study;
Chelakova Yu.A. — data collection and processing, text writing, editing.

Funding. The study had no funding.

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

Received: 17.06.2024 / Accepted: 11.06.2024 / Published: 20.08.2024

1. Occupational pathology: national guidelines. M: GEOTAR-Media; 2011 (in Russian).

2. Bukhtiyarov I.V., Chebotarev A.G., Courierov N.N., Sokur O.V. Topical issues of improving working conditions and preserving the health of workers of mining enterprises. Med. truda i prom. ekol. 2019; 7: 424–429 (in Russian). https://doi.org/10.31089/1026-9428-2019-59-7-424-429 https://elibrary.ru/ejxzmd

3. Yegorova A.M. Characteristics of working conditions at an ironworks. Gigiena i sanitariya. 2008; 3: 36–38 (in Russian). https://elibrary.ru/jsaogr

4. Roslyi O.F., Likhacheva E.I., Tartakovskaya L.Ya., et al. Priority issues of occupational medicine in the production and processing of non-ferrous metal alloys. Med. truda i prom. ekol. 2004; 9: 23–26. (in Russian). https://elibrary.ru/owbohl

5. Dolgikh O.V., Krivtsov A.V., Bubnova O.A. Immunogenetic parameters in workers under conditions of combined exposure to dust and industrial noise. Rossiyskiy immunologicheskiy zhurnal. 2015; 2(1): 551–553 (in Russian).

6. Dolgikh O.V., Krivtsov A.V., Lykhina T.S., et al. Features of immunogenetic parameters in employees of non-ferrous metallurgy enterprises. Gigiena i sanitariya. 2015; 94(2): 54–57 (in Russian). https://elibrary.ru/tphjnv

7. Lanin D.V., Zaitseva N.V., Dolgikh O.V. Neuroendocrine mechanisms regulating the functions of the immune system. Uspekhi sovremennoy biologii. 2011; 2(131): 122–134 (in Russian).

8. Izmerov N.F., Kuzmina L.P., Kolyaskina M.M., Lazarashvili N.A. Molecular genetic studies in occupational medicine Gigiena i sanitariya. 2011; 5: 10-14 (in Russian). https://elibrary.ru/mweywa

9. Vlasova E.M., Ustinova O.Yu., Vorobyova A.A., Ponomareva T.A. Substantiation of the early diagnostic program of cardiorespiratory disorders in employees of pre-retirement age involving in metallurgical industry. Meditsina truda i ekologiya cheloveka. 2020; 1: 60–70 (in Russian).

10. Vorobyova A.A., Vlasova E.M. Respiratory treatment status for employees of titanium-magnesium production. Meditsina truda i ekologiya cheloveka. 2019; 4: 21–26 (in Russian).

11. Holder N., Klein R. Eph receptors and ephrins: effectors of morphogenesis. Development. 1999; 126(10): 2033–2044.

12. Wilkinson D.G. Eph receptors and ephrins: regulators of guidance and assembly. Int. Rev. Cytol. 2000; 196: 177–244.

13. Takagi S., Tsuji T., Amagai T., et al. Specific cell surface labels in the visual centers of Xenopus laevis tadpole identified using monoclonal antibodies. Dev. Biol. 1987; 122: 90–100.

14. Takagi S., Hirata T., Agata K., et al. The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron. 1991; 7: 295–307.

15. Nosov A.E., Ivanova Yu.A., Vlasova E.M., et al. Risk factors for the development of production-related pathology of the respiratory and circulatory organs in workers of metallurgical production. Analiz riska zdorov’yu — 2021. Materialy XI Vserossiyskoy nauchno-prakticheskoy konferentsii s mezhdunarodnym uchastiem. 2021; 2: 34–40 (in Russian).

16. Shlyapnikov D.M., Vlasova E.M. A risk-oriented program for the prevention of respiratory diseases in titanium-magnesium production workers. Gigiena i sanitariya. 2017; 96(12): 1171–1175 (in Russian). https://doi.org/10.18821/0016-9900-2017-96-12-1171-1175 https://elibrary.ru/yqxmqq

17. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol. 2001; 280: C1358–C1366.

18. Neufeld G., Cohen T., Gengrinovitch S., Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999; 13: 9–22.

19. Kawasaki T., Kitsukawa T., Bekku Y., et al. A requirement for neuropilin-1 in embryonic vessel formation. Development. 1999; 126: 4895–4902.

20. Kitsukawa T., Shimizu M., Sanbo M., et al. Neuropilin–semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron. 1997; 19: 995–1005.

21. Gu Ch., Rodriguez E.R., Reimert D.V., Shu T., et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell. 2003; 5(1): 45–57.

22. Zachary I.C., Frankel P., Evans I.M., Pellet-Many C. The role of neuropilins in cell signalling. Biochem Soc Trans. 2009; 37(6): 1171–8.

23. Santulli G., Morelli M., Gambardella J. Is Endothelial Dysfunction the Concealed Cornerstone of COVID-19? BMJ. 2020; 368: 1091. https://doi.org/10.1136/bmj.m1091

24. Gambardella J., and Santulli G. What is linking COVID-19 and endothelial dysfunction? Updates on nanomedicine and bioengineering from the 2020 AHA Scientific Sessions. Eur. Heart J. Cardiovasc Pharmacother. 2020; 7(3): e2–e3. https://doi.org/10.1093/ehjcvp/pvaa145

25. Evans P.C., Ed Rainger G., Mason J.C., Guzik T.J., et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020; 116(14): 2177–2184. https://doi.org/10.1093/cvr/cvaa230

26. Rim K.T., et al. Effects of rare earth elements on the environment and human health: A literature review. Toxicol. Environ. Health Sci. 2016; 8: 189–200. https://doi.org/10.1007/s13530-016-0276-y

27. Zhu W.F., Xu S.Q., Shao P.P., et al. Bioelectrical activity of the central nervous system among populations in a rare earth element area. Biol. Trace Elem. Res. 1997; 57: 71–77.

28. Xiao H.Q., Zhang Z.Y., Li F.L., et al. Distribution of ytterbium-169 in rat brain after intravenous injection. Toxicol. Lett. 2005; 155: 247–252.

29. Rim K.T., et al. Toxicological Evaluations of Rare Earths and Their Health Impacts to Workers: A Literature Review. Saf Health Work. 2013; 4(1): 12–26. https://doi.org/10.5491/SHAW.2013.4.1.12