REVIEW: Epigenetic Mechanisms Involved in the Effects of Maternal Hyperhomocysteinemia on the Functional State of Placenta and Nervous System Plasticity in the Offspring

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Alexander V. Arutjunyan^1,2,a*, Yulia P. Milyutina^1,3, Anastasia D. Shcherbitskaia^1,4, Gleb O. Kerkeshko^1,2, and Irina V. Zalozniaia¹

¹Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, 199034 St. Petersburg, Russia

²St. Petersburg Institute of Bioregulation and Gerontology, 197110 St. Petersburg, Russia

³St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia

⁴Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia

^* To whom correspondence should be addressed.

Received November 23, 2022; Revised February 2, 2023; Accepted February 2, 2023

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According to modern view, susceptibility to diseases, specifically to cognitive and neuropsychiatric disorders, can form during embryonic development. Adverse factors affecting mother during the pregnancy increase the risk of developing pathologies. Despite the association between elevated maternal blood homocysteine (Hcy) and fetal brain impairments, as well as cognitive deficits in the offspring, the role of brain plasticity in the development of these pathologies remains poorly studied. Here, we review the data on the negative impact of hyperhomocysteinemia (HHcy) on the neural plasticity, in particular, its possible influence on the offspring brain plasticity through epigenetic mechanisms, such as changes in intracellular methylation potential, activity of DNA methyltransferases, DNA methylation, histone modifications, and microRNA expression in brain cells. Since placenta plays a key role in the transport of nutrients and transmission of signals from mother to fetus, its dysfunction due to aberrant epigenetic regulation can affect the development of fetal CNS. The review also presents the data on the impact of maternal HHcy on the epigenetic regulation in the placenta. The data presented in the review are not only interesting from purely scientific point of view, but can help in understanding the role of HHcy and epigenetic mechanisms in the pathogenesis of diseases, such as pregnancy pathologies resulting in the delayed development of fetal brain, cognitive impairments in the offspring during childhood, and neuropsychiatric and neurodegenerative disorders later in life, as well as in the search for approaches for their prevention using neuroprotectors.

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KEY WORDS: maternal (prenatal) hyperhomocysteinemia, epigenetic regulation, fetus, newborn, brain, placenta, neuronal plasticity

DOI: 10.1134/S0006297923040016

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