medlitГигиена и санитарияHygiene and Sanitation0016-99002412-0650Federal Scientific Center of Hygiene named after F.F. Erisman10.47470/0016-9900-2024-103-11-1417-1422omdcezmedlit-4471Research ArticleПРОФИЛАКТИЧЕСКАЯ ТОКСИКОЛОГИЯ И ГИГИЕНИЧЕСКОЕ НОРМИРОВАНИЕPREVENTIVE TOXICOLOGY AND HYGIENIC STANDARTIZATIONПолиморфизм кандидатных генов MTNR1B C/G (rs10830963) и TCF7L2 C/T (rs7903146) у детей как фактор риска формирования патологии гепатобилиарной системы в условиях контаминации биосред тяжёлыми металлами (на примере свинца)Polymorphism of candidate genes MTNR1B C/G (rs10830963) and TCF7L2 C/T (rs7903146) in children as a risk factor for the development of hepatobiliary system pathology in conditions of contamination of biological media with heavy metals (using lead as an example)https://orcid.org/0000-0003-4860-3145ДолгихОлег ВладимировичDolgikhOleg V.

Доктор мед. наук, зав. отд. иммунобиологических методов диагностики ФБУН «ФНЦ МПТ УРЗН», 614045, Пермь, Россия

DSc (Medicine), Head of the Department of Immunobiological Diagnostic Methods of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, Perm, 614045, Russian Federation

https://orcid.org/0000-0002-0114-3930КазаковаОльга АлексеевнаKazakovaOlga A.

Канд. биол. наук, ст. науч. сотр. – зав. лаб. иммуногенетики ФБУН «ФНЦ МПТ УРЗН», 614045, Пермь, Россия

PhD (Medicine), senior researcher of the Immunogenetics laboratory of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, Perm, 614045, Russian Federation

https://orcid.org/0009-0001-8957-9164ЛучниковаВиктория АлександровнаLuchnikovaViktoria A.

Мл. науч. сотр. лаб. иммунологии и аллергологии ФБУН «ФНЦ МПТ УРЗН», 614045, Пермь, Россия

e-mail: bezdenezhka@yandex.ru

Junior researcher at the Laboratory of Immunology and allergology of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, Perm, 614045, Russian Federation

e-mail: bezdenezhka@yandex.ru

bezdenezhka@yandex.ruФБУН «Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения» Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человекаРоссияFederal Scientific Center for Medical and Preventive Health Risk Management TechnologiesRussian Federation2024171220241031114171422Copyright © Долгих О.В., Казакова О.А., Лучникова В.А., 20242024Долгих О.В., Казакова О.А., Лучникова В.А.Dolgikh O.V., Kazakova O.A., Luchnikova V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rjhas.ru/jour/article/view/4471Введение

Введение. Влияние свинца на здоровье с учётом вероятного механизма его молекулярных взаимодействий в организме изучено недостаточно.

Цель исследования – оценка полиморфизма генов MTNR1B C/G (rs10830963) и TCF7L2 C/T (rs7903146) у детей как фактора риска формирования патологии гепатобилиарной системы в условиях контаминации биосред тяжёлыми металлами (на примере свинца).

Материалы и методы

Материалы и методы. Выполнено обследование 93 детей 3–6 лет (39 детей с патологией гепатобилиарной системы и 54 условно здоровых ребёнка), подверженных низкоуровневой аэрогенной экспозиции свинцом (0,1ПДКс.с.) при среднесуточной дозе 0,4 · 10–3 мкг/кг · день. Выполнена оценка частотности аллелей и генотипов кандидатных генов MTNR1B C/G (rs10830963) и TCF7L2-1 C/T (rs7903146), ассоциированных с уровнями контаминации биосред свинцом и патологией гепатобилиарной системы.

Результаты

Результаты. Установлено, что у детей группы наблюдения показана достоверно высокая частота встречаемости G-вариантного аллеля (OR = 1,92; CI: 1,04–3,54) и GG-генотипа (OR = 7,80; CI: 1,58–38,51; p < 0,05) гена MTNR1B, а также C дикого аллеля (OR = 2,07; CI: 1,02–4,20; p < 0,05) и CC-генотипа (OR = 2,42; CI: 1,02–5,70; p < 0,05) гена TCF7L2-1, которые выступают в качестве факторов риска (RR = 1,20–1,43) формирования патологии гепатобилиарной системы, отягощённой контаминацией крови свинцом.

Ограничения исследования

Ограничения исследования. Ограниченность выборки, необходимость верификации результатов в дальнейших наблюдениях.

Заключение

Заключение. Установлено, что дети с патологией гепатобилиарной системы, проживающие на территории, характеризующейся хронической низкоуровневой аэрогенной экспозицией свинцом 0,4 · 10–3 мг/кг · день (0,1 ПДКс.с.), отличались избыточным уровнем содержания свинца в крови, а также нарушениями биоритмов гладкой мускулатуры желчевыводящих путей, сопряжённых с риском (RR = 1,20–1,43) развития патологии гепатобилиарной системы в условиях G-вариантного аллеля (OR = 1,92; CI: 1,04–3,54; p < 0,05) гена MTNR1B, а также C дикого аллеля (OR = 2,07; CI: 1,02–4,20; p < 0,05) гена TCF7L2-1.

Соблюдение этических стандартов. Исследование проведено с соблюдением основ Хельсинкской декларации ВМА и одобрено ЛЭК ФБУН «ФНЦ медико-профилактических технологий управления рисками здоровью населения» (протокол заседания № 4 от 17.01.2022 г.). Все участники дали информированное добровольное письменное согласие на участие в исследовании.

Участие авторов

Участие авторов: Долгих О.В. – концепция и дизайн исследования, редактирование; Казакова О.А. – дизайн исследования, обработка данных, написание текста; Лучникова В.А. – сбор материала и обработка данных. Все соавторы – утверждение окончательного варианта статьи, ответственность за целостность всех частей статьи.

Конфликт интересов

Конфликт интересов. Авторы заявляют об отсутствии явных и потенциальных конфликтов интересов в связи с публикацией данной статьи.

Финансирование

Финансирование. Исследование не имело финансовой поддержки.

Поступила

Поступила: 23.09.2024 / Принята к печати: 19.11.2024 / Опубликована: 17.12.2024

Introduction

Introduction. Lead impact on health considering likely pathways of its molecular interactions in the body have not been given sufficient attention by researchers.

The aim of this study was to assess polymorphism of the MTNR1B C/G (rs10830963) and TCF7L2 C/T (rs7903146) genes in children as a risk factor of hepatobiliary pathology in case of heavy metal contamination in biological media (exemplified by lead).

Materials and methods

Materials and methods. We examined ninety three 3–6 years children (39 children had hepatobiliary pathology and 54 children were considered healthy) who were exposed to low-dose airborne lead (0.1MPLa.d.), the average daily dose being 0.4 · 10–3 µg/kg · day. We estimated frequency of alleles and genotypes of the candidate genes MTNR1B C/G (rs10830963) and TCF7L2-1 C/T (rs7903146) associated with levels of lead contamination in biological media and hepatobiliary pathology.

Results

Results. The children from the observation group were established to have authentically high frequency of the G allele (OR=1.92, CI: 1.04–3.54) and GG genotype (OR=7.80, CI: 1.58–38.51; p<0.05) of the MTNR1B gene, as well as C wild type allele (OR=2.07, CI: 1.02–4.20; p<0.05) and CC genotype (OR=2.42, CI: 1.02–5.70; p<0.05) of the TCF7L2-1 gene, which were risk factors (RR=1.20–1.43) of developing hepatobiliary pathology aggravated by lead contamination in blood.

Limitations

Limitations. Limited sampling, the need to verify the results in further observations.

Conclusion

Conclusion. The study established children with hepatobiliary pathology who lived under long-term low-dose exposure to airborne lead at the dose of 0.4 · 10–3 µg/kg · day (0.1MPLa.d.) to have elevated lead levels in blood and impaired biorhythms of smooth muscles in the bile duct combined with the risk (RR=1.20–1.43) of developing hepatobiliary pathology in carriers of G allele (OR=1.92, CI: 1.04–3.54; p<0.05) of the MTNR1B gene as well as C wild type allele (OR=2.07, CI: 1.02–4.20; p<0.05) of the TCF7L2-1 gene.

Compliance with ethical standards. The study was conducted in compliance with the principles of the Helsinki Declaration of the BMA and approved by the LEK of the Federal State Budgetary Institution “FNC of Medical and Preventive Technologies for Public Health Risk Management” (Minutes of meeting No. 4 dated 01/17/2022). All participants gave informed voluntary written consent to participate in the study.

Contribution

Contribution: Dolgikh O.V. – concept and design of the study, editing the text; Kazakova O.A. – research design, data processing, text writing; Luchnikova V.A. – material collection and data processing. All authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Conflict of interest

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

Acknowledgement

Acknowledgement. The study had no sponsorship.

Received

Received: September 23, 2024 / Accepted: November 19, 2024 / Published: December 17, 2024

свинецотносительный рискген мелатонинового рецептора MTNR1Bген транскрипционного фактора 7 типа 2 переносчика глюкозы TCF7L2патология гепатобилиарной системыдетиleadrelative riskmelatonin receptor MTNR1B genetranscription factor 7-like 2 glucose transporter gene TCF7L2hepatobiliary pathologychildrenReferencesKern M., Audesirk T., Audesirk G. Effects of inorganic lead on the differentiation and growth of cortical neurons in culture. Neurotoxicology. 1993; 14(2–3): 319–27.Kern M., Audesirk T., Audesirk G. Effects of inorganic lead on the differentiation and growth of cortical neurons in culture. Neurotoxicology. 1993; 14(2–3): 319–27.Sánchez-Martín F.J., Fan Y., Lindquist D.M., Xia Y., Puga A. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells. PLoS One. 2013; 8(11): e80558. https://doi.org/10.1371/journal.pone.0080558Sánchez-Martín F.J., Fan Y., Lindquist D.M., Xia Y., Puga A. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells. PLoS One. 2013; 8(11): e80558. https://doi.org/10.1371/journal.pone.0080558Hernández-Plata E., Quiroz-Compeán F., Ramírez-Garcia G., Barrientos E.Y., Rodríguez-Morales N.M., Flores A., et al. Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment. Toxicol. Lett. 2015; 233(2): 78–83. https://doi.org/10.1016/j.toxlet.2015.01.009Hernández-Plata E., Quiroz-Compeán F., Ramírez-Garcia G., Barrientos E.Y., Rodríguez-Morales N.M., Flores A., et al. Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment. Toxicol. Lett. 2015; 233(2): 78–83. https://doi.org/10.1016/j.toxlet.2015.01.009Арушанян Э.Б., Щетинин Е.В. Значение мелатонина для деятельности печени. Медицина. 2018; (2): 35–50. https://doi.org/10.29234/2308-9113-2018-6-2-35-50 https://elibrary.ru/uuxhouArushanyan E.B., Shchetinin E.V. Significance of melatonin for the liver activity. Meditsina. 2018; (2): 35–50. https://doi.org/10.29234/2308-9113-2018-6-2-35-50 https://elibrary.ru/uuxhou (in Russian)Ceci L., Chen L., Baiocchi L., Wu N., Kennedy L., Carpino G., et al. Prolonged administration of melatonin ameliorates liver phenotypes in cholestatic murine model. Cell. Mol. Gastroenterol. Hepatol. 2022; 14(4): 877–904. https://doi.org/10.1016/j.jcmgh.2022.07.007Ceci L., Chen L., Baiocchi L., Wu N., Kennedy L., Carpino G., et al. Prolonged administration of melatonin ameliorates liver phenotypes in cholestatic murine model. Cell. Mol. Gastroenterol. Hepatol. 2022; 14(4): 877–904. https://doi.org/10.1016/j.jcmgh.2022.07.007Meng Z., Guo S., Dong X., Wang Q., Hu D., Liu X., et al. Astrocyte-ablation of Mtnr1b increases anxiety-like behavior in adult male mice. J. Integr. Neurosci. 2023; 22(6): 154. https://doi.org/10.31083/j.jin2206154Meng Z., Guo S., Dong X., Wang Q., Hu D., Liu X., et al. Astrocyte-ablation of Mtnr1b increases anxiety-like behavior in adult male mice. J. Integr. Neurosci. 2023; 22(6): 154. https://doi.org/10.31083/j.jin2206154da Silveira Cruz-Machado S., Pinato L., Tamura E.K., Carvalho-Sousa C.E., Markus R.P. Glia-pinealocyte network: the paracrine modulation of melatonin synthesis by tumor necrosis factor (TNF). PLoS One. 2012; 7(7): e40142. https://doi.org/10.1371/journal.pone.0040142da Silveira Cruz-Machado S., Pinato L., Tamura E.K., Carvalho-Sousa C.E., Markus R.P. Glia-pinealocyte network: the paracrine modulation of melatonin synthesis by tumor necrosis factor (TNF). PLoS One. 2012; 7(7): e40142. https://doi.org/10.1371/journal.pone.0040142Sompub K., Krityakiarana W., Jongkamonwiwat N., Mukda S., Phansuwan-Pujito P., Govitrapong P. Effects of melatonin on myelin-associated inhibitors after severe crush spinal cord injury in a mouse model. Front. Cell. Neurosci. 2016; 10. https://doi.org/10.3389/conf.fncel.2016.36.00156Sompub K., Krityakiarana W., Jongkamonwiwat N., Mukda S., Phansuwan-Pujito P., Govitrapong P. Effects of melatonin on myelin-associated inhibitors after severe crush spinal cord injury in a mouse model. Front. Cell. Neurosci. 2016; 10. https://doi.org/10.3389/conf.fncel.2016.36.00156Villapol S., Fau S., Renolleau S., Biran V., Charriaut-Marlangue C., Baud O. Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke. Pediatr. Res. 2011; 69(1): 51–5. https://doi.org/10.1203/pdr.0b013e3181fcb40bVillapol S., Fau S., Renolleau S., Biran V., Charriaut-Marlangue C., Baud O. Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke. Pediatr. Res. 2011; 69(1): 51–5. https://doi.org/10.1203/pdr.0b013e3181fcb40bVogan K. TCF7L2 and liver function. Nat. Genet. 2013; 45(2): 123. https://doi.org/10.1038/ng.2548Vogan K. TCF7L2 and liver function. Nat. Genet. 2013; 45(2): 123. https://doi.org/10.1038/ng.2548Madhu S.V., Aslam M., Mishra B.K., Mehndiratta M. Rotational night shift work adversely affects expression of TCF7L2 and PPAR-γ genes among healthcare workers with normal glucose tolerance. Int. J. Diabetes Dev. Ctries. 2023; 43(5): 816–20. https://doi.org/10.1007/s13410-022-01159-zMadhu S.V., Aslam M., Mishra B.K., Mehndiratta M. Rotational night shift work adversely affects expression of TCF7L2 and PPAR-γ genes among healthcare workers with normal glucose tolerance. Int. J. Diabetes Dev. Ctries. 2023; 43(5): 816–20. https://doi.org/10.1007/s13410-022-01159-zNorton L., Chen X., Fourcaudot M., Acharya N.K., DeFronzo R.A., Heikkinen S. The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells. Nucleic Acids Res. 2014; 42(22): 13646–61. https://doi.org/10.1093/nar/gku1225Norton L., Chen X., Fourcaudot M., Acharya N.K., DeFronzo R.A., Heikkinen S. The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells. Nucleic Acids Res. 2014; 42(22): 13646–61. https://doi.org/10.1093/nar/gku1225Lipiec M.A., Bem J., Koziński K., Chakraborty C., Urban-Ciećko J., Zajkowski T., et al. TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus. Development. 2020; 147(16): dev190181. https://doi.org/10.1242/dev.190181Lipiec M.A., Bem J., Koziński K., Chakraborty C., Urban-Ciećko J., Zajkowski T., et al. TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus. Development. 2020; 147(16): dev190181. https://doi.org/10.1242/dev.190181Polcyn R., Capone M., Hossain A., Matzelle D., Banik N.L., Haque A. Neuron specific enolase is a potential target for regulating neuronal cell survival and death: implications in neurodegeneration and regeneration. Neuroimmunol. Neuroinflamm. 2017; 4: 254–7. https://doi.org/10.20517/2347-8659.2017.59Polcyn R., Capone M., Hossain A., Matzelle D., Banik N.L., Haque A. Neuron specific enolase is a potential target for regulating neuronal cell survival and death: implications in neurodegeneration and regeneration. Neuroimmunol. Neuroinflamm. 2017; 4: 254–7. https://doi.org/10.20517/2347-8659.2017.59Жукова И.А., Алифирова В.М., Жукова Н.Г. Нейронспецифическая енолаза как неспецифический маркер нейродегенеративного процесса. Бюллетень сибирской медицины. 2011; 10(2): 15–21. https://elibrary.ru/nulijnZhukova I.A., Alifirova V.M., Zhukova N.G. Neurospecific enolase as a nonspecific neurodegenerative process marker. Byulleten’ sibirskoi meditsiny. 2011; 10(2): 15–21. https://elibrary.ru/nulijn (in Russian)Yan Z., Shi X., Wang H., Si C., Liu Q., Du Y. Neurotrophin-3 promotes the neuronal differentiation of BMSCs and improves cognitive function in a rat model of Alzheimer’s disease. Front. Cell. Neurosci. 2021; 15: 629356. https://doi.org/10.3389/fncel.2021.629356Yan Z., Shi X., Wang H., Si C., Liu Q., Du Y. Neurotrophin-3 promotes the neuronal differentiation of BMSCs and improves cognitive function in a rat model of Alzheimer’s disease. Front. Cell. Neurosci. 2021; 15: 629356. https://doi.org/10.3389/fncel.2021.629356Chalazonitis A. Neurotrophin-3 as an essential signal for the developing nervous system. Mol. Neurobiol. 1996; 12(1): 39–53. https://doi.org/10.1007/BF02740746Chalazonitis A. Neurotrophin-3 as an essential signal for the developing nervous system. Mol. Neurobiol. 1996; 12(1): 39–53. https://doi.org/10.1007/BF02740746Pae C.U., Marks D.M., Han C., Patkar A.A., Steffens D. Does neurotropin-3 have a therapeutic implication in major depression? Int. J. Neurosci. 2008; 118(11): 1515–22. https://doi.org/10.1080/00207450802174589Pae C.U., Marks D.M., Han C., Patkar A.A., Steffens D. Does neurotropin-3 have a therapeutic implication in major depression? Int. J. Neurosci. 2008; 118(11): 1515–22. https://doi.org/10.1080/00207450802174589Hayes G., Pinto J., Sparks S.N., Wang C., Suri S., Bulte D.P. Vascular smooth muscle cell dysfunction in neurodegeneration. Front. Neurosci. 2022; 16: 1010164. https://doi.org/10.3389/fnins.2022.1010164Hayes G., Pinto J., Sparks S.N., Wang C., Suri S., Bulte D.P. Vascular smooth muscle cell dysfunction in neurodegeneration. Front. Neurosci. 2022; 16: 1010164. https://doi.org/10.3389/fnins.2022.1010164Kıray H., Lindsay S.L., Hosseinzadeh S., Barnett S.C. The multifaceted role of astrocytes in regulating myelination. Exp. Neurol. 2016; 283(Pt. B): 541–9. https://doi.org/10.1016/j.expneurol.2016.03.009Kıray H., Lindsay S.L., Hosseinzadeh S., Barnett S.C. The multifaceted role of astrocytes in regulating myelination. Exp. Neurol. 2016; 283(Pt. B): 541–9. https://doi.org/10.1016/j.expneurol.2016.03.009Коломейчук С.Н., Корнева В.А., Кузнецова Т.Ю., Коростовцева Л.С., Бочкарев М.В., Свиряев Ю.В. и др. Роль полиморфных вариантов генов рецептора мелатонина MTNR1A и MTNR1B в регуляции эластичности сосудистой стенки у лиц без артериальной гипертензии. Российский кардиологический журнал. 2023; 28(S6): 51–2. https://elibrary.ru/miocdwKolomeichuk S.N., Korneva V.A., Kuznetsova T.Yu., Korostovtseva L.S., Bochkarev M.V., Sviryaev Yu.V., et al. The role of polymorphic variants of the MTNR1A and MTNR1B melatonin receptor genes in the regulation of vascular wall elasticity in people without hypertension. Rossiiskii kardiologicheskii zhurnal. 2023; 28(S6): 51–2. https://elibrary.ru/miocdw (in Russian)Soto-Arredondo K.J., Robles J., Díaz-Cervantes E., Ruiz-Ramírez C., García-Revilla M.A., Wrobel K., et al. Effects of lead and lead-melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats. Biometals. 2018; 31(5): 859–71. https://doi.org/10.1007/s10534-018-0127-1Soto-Arredondo K.J., Robles J., Díaz-Cervantes E., Ruiz-Ramírez C., García-Revilla M.A., Wrobel K., et al. Effects of lead and lead-melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats. Biometals. 2018; 31(5): 859–71. https://doi.org/10.1007/s10534-018-0127-1Omeiza N.A., Abdulrahim H.A., Alagbonsi A.I., Ezurike P.U., Soluoku T.K., Isiabor H., et al. Melatonin salvages lead-induced neuro-cognitive shutdown, anxiety, and depressive-like symptoms via oxido-inflammatory and cholinergic mechanisms. Brain Behav. 2021; 11(8): e2227. https://doi.org/10.1002/brb3.2227Omeiza N.A., Abdulrahim H.A., Alagbonsi A.I., Ezurike P.U., Soluoku T.K., Isiabor H., et al. Melatonin salvages lead-induced neuro-cognitive shutdown, anxiety, and depressive-like symptoms via oxido-inflammatory and cholinergic mechanisms. Brain Behav. 2021; 11(8): e2227. https://doi.org/10.1002/brb3.2227

The authors declare that there are no conflicts of interest present.