akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2023.427akusherstvo-1822Research ArticleREVIEW ARTICLESНАУЧНЫЕ ОБЗОРЫEpigenetic mechanisms of intrauterine fetal senescence: little-known effects of hyperhomocysteinemia during pregnancyЭпигенетические механизмы внутриутробного «старения» плода: малоизвестные эффекты гипергомоцистеинемии при беременностиhttps://orcid.org/0000-0002-6542-5953БеспаловаО. Н.BespalovaO. N.

Беспалова Олеся Николаевна – д.м.н., зам. директора по научной работе

199034 Санкт-Петербург, Менделеевская линия, д. 3

Olesya N. Bespalova – MD, Dr Sci Med, Deputy Director for Research

3 Mendeleevskaya Liniya, Saint Petersburg 199034

https://orcid.org/0000-0003-4116-0222ПачулияО. В.PachuliiaO. V.

Пачулия Ольга Владимировна – к.м.н., врач акушер-гинеколог, ученый секретарь

199034 Санкт-Петербург, Менделеевская линия, д. 3

Olga V. Pachuliia – MD, PhD, Obstetrician-Gynecologist, Scientific Secretary

3 Mendeleevskaya Liniya, Saint Petersburg 199034

https://orcid.org/0009-0007-4567-7831СазоноваА. П.SazonovaA. P.

Сазонова Анастасия Павловна – ординатор

199034 Санкт-Петербург, Менделеевская линия, д. 3

Anastasiia P. Sazonova – MD, Intern

3 Mendeleevskaya Liniya, Saint Petersburg 199034

nastenka.sazonova.97@mail.ruhttps://orcid.org/0000-0003-1951-8312МилютинаЮ. П.MilyutinaYu. P.

Милютина Юлия Павловна – к.б.н., старший научный сотрудник группы биохимии

199034 Санкт-Петербург, Менделеевская линия, д. 3

Yuliya P. Milyutina – MD, PhD (Biology), Senior Researcher, Biochemistry Group

3 Mendeleevskaya Liniya, Saint Petersburg 199034

КорнюшинаЕ. А.KornyushinaE. A.

Корнюшина Екатерина Амировна – к.м.н., старший научный сотрудник, врач II акушерского отделения патологии беременности

199034 Санкт-Петербург, Менделеевская линия, д. 3

Ekaterina A. Kornyushina – MD, PhD, Senior Researcher, Physician, II Obstetric Department of Pregnancy Pathology

3 Mendeleevskaya Liniya, Saint Petersburg 199034

https://orcid.org/0000-0002-0365-8532КореневскийА. В.KorenevskiyA. V.

Кореневский Андрей Валентинович – д.б.н., ведущий научный сотрудник группы биохимии

199034 Санкт-Петербург, Менделеевская линия, д. 3

Andrey V. Korenevskiy – MD, Dr Sci Biol, Leading Researcher, Biochemistry Group

3 Mendeleevskaya Liniya, Saint Petersburg 199034

ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта»РоссияResearch Institute of Obstetrics, Gynecology and Reproductology named after D.O. OttRussian Federation202311112023175638653Copyright © Bespalova O.N., Pachuliia O.V., Sazonova A.P., Milyutina Y.P., Kornyushina E.A., Korenevskiy A.V., 20232023Беспалова О.Н., Пачулия О.В., Сазонова А.П., Милютина Ю.П., Корнюшина Е.А., Кореневский А.В.Bespalova O.N., Pachuliia O.V., Sazonova A.P., Milyutina Y.P., Kornyushina E.A., Korenevskiy A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/1822

Today, a whole body of evidence base has been formed showing the negative effect of hyperhomocysteinemia (HHC) during pregnancy on the intrauterine fetal development: risk factors associated with development of congenital neural tube defects, congenital heart defects and non-syndromic oral facial clefts. In addition, numerous studies have shown that HHC is a risk factor for serious pregnancy complications such as repeated pregnancy loss, preterm birth, preeclampsia, placental abruption, intrauterine growth restriction, gestational diabetes mellitus. At the same time, despite multiple clinical and experimental studies, the significance of HHC effects continues to support the interest to this issue. In recent years, new data were revealed about littleknown phenomena pregnancy-associated maternal HHC such as "epigenetic fetal aging" and "fetal atherogenesis". Epigenetic aging is an individual indicator of aging that captures interindividual differences at disease onset throughout life occurring during intrauterine development being reveaked as DNA hypomethylation. Moderate HHC during pregnancy causes fetal DNA hypomethylation, which, according to recent research, may represent the main mechanism underlying health in childhood and adulthood. "Fetal atherogenesis" is another understudied HHC effect emphasizing that the formation of atherosclerotic plaques begins not in adulthood, but in utero. A body of studies has shown that the formation of thickening and fatty streaks in vascular intima involved in the pathogenesis of atherosclerosis begins antenatally. The discovery of new aspects of negative intrauterine HHC impact on fetal development necessitates a detailed study of HHC causes as non-modifiable (genetic defects in enzyme systems), and more importantly, conditionally modifiable causes (lack of cofactors, excessive methionine consumption, medications) for their timely leveling. It is also important to study approaches to HHC correction at the preconception stage of a female reproductive function in order to correctly "program" fetus and newborn development.

На сегодняшний день сформирована внушительная доказательная база негативного влияния гипергомоцистеинемии (ГГЦ) при беременности на внутриутробное развитие плода: увеличение риска врожденных дефектов нервной трубки, врожденных пороков сердца, несиндромных расщелин полости рта. Также многочисленные исследования показали, что ГГЦ является фактором риска реализации таких серьезных акушерских осложнений, как привычное невынашивание беременности, преждевременные роды, преэклампсия, преждевременная отслойка плаценты, задержка развития плода, гестационный сахарный диабет. В тоже время, несмотря на множество клинических и экспериментальных исследований, значимость и многогранность эффектов ГГЦ продолжает поддерживать интерес исследователей к проблематике. В последние годы получены данные о малоизвестных явлениях, ассоциированных с ГГЦ матери при беременности, таких как «эпигенетическое старение плода» и «плодовый атерогенез». Эпигенетическое старение – это индивидуальный показатель старения, который фиксирует межиндивидуальные различия во времени начала какого-либо заболевания на протяжении всей жизни, оно имеет место во внутриутробном развитии и выражается в гипометилировании ДНК. Умеренная ГГЦ при беременности вызывает гипометилирование ДНК у плода, что, согласно результатам последних исследований, может являться основным механизмом, определяющим здоровье в детском и взрослом возрасте. «Плодовый атерогенез» – это еще один малоизученный эффект ГГЦ. Данный термин подчеркивает, что формирование атеросклеротических бляшек начинается не во взрослом возрасте, а внутриутробно. Существует ряд исследований, которые показали, что образование утолщений и жировых прожилок интимы сосудов, участвующих в патогенезе атеросклероза, начинается антенатально. Открытие новых аспектов негативного влияния ГГЦ при беременности на развитие плода обуславливает необходимость подробного изучения причин ГГЦ как немодифицируемых (генетические дефекты ферментных систем), и что еще более важно, условно-модифицируемых причин (недостаток кофакторов, избыточное потребление метионина, прием лекарственных препаратов) для своевременного их нивелирования. Также представляется важным изучение подходов к коррекции ГГЦ на прегравидарном этапе реализации репродуктивной функции женщины для формирования корректной «программы» развития плода и новорожденного.

гипергомоцистеинемияГГЦакушерские осложнения«плодовый атерогенез»«эпигенетическое старение плода»hyperhomocysteinemiaHHCpregnancy complications"fetal atherogenesis""epigenetic fetal aging"Работа подготовлена в рамках выполнения поисковой научной темы – государственного задания Министерства науки и высшего образования Российской Федерации № 1022040700837-4-3.2.2-1-11 «Разработка технологии раннего прогнозирования и профилактики врожденных пороков развития плода и перинатальной патологии на основе оценки нутриентного статуса, биохимических и молекулярно-генетических маркеров на этапе прегравидарной подготовки и при беременности».The study was prepared within the framework of the research topic – state assignment of the Ministry of Science and Higher Education of the Russian Federation No. 1022040700837-4-3.2.2-1-11 "Development of technology for early prediction and prevention of fetal congenital malformations and perinatal pathology based on assessed nutritional status, biochemical and molecular genetic markers at the stage of preconception preparation and pregnancy".ReferencesБицадзе В.О., Самбурова Н.В., Макацария Н.А, Мищенко А.Л. 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The authors declare that there are no conflicts of interest present.