Peculiarities of DNA and Histone H3 Methylation in the Hippocampus and Neocortex of Rats Subjected to Pathological Treatments during the Prenatal Period

Abstract—Stress during pregnancy can cause the structural and functional changes in the fetal brain, which subsequently lead to the formation of various neuropsychiatric diseases, including attention deficit hyperactivity disorder, depression, schizophrenia, autism, and others. Among the stress factors that can lead to disorders of fetal development, prenatal hypoxic stress is especially important. Epigenetic mechanisms may play a key role in the development of brain disorders, which are caused by stressful effects of various nature. The aim of this work was to study the age-related characteristics of DNA methylation (meDNA) and histone H3 at lysines 4 (meН3К4) and 9 (meН3К9) in the cells of the rat hippocampus and neocortex that are the most sensitive brain structures after severe hypobaric hypoxia (180 mmHg, 3 h) or administration of a synthetic glucocorticoid dexamethasone (0.8 mg/kg), which models the stress response of the mother’s body, on the 14–16th day of prenatal ontogeny. Using immunohistochemistry we detected age-related modifications of the intensity of meDNA and meH3K9 (but not meH3K4) in control animals, namely a decrease in the level of meDNA and meH3K9 in 18-month-old rats compared to 3-month-old rats. Severe hypobaric hypoxia or administration of dexamethasone on the 14–16th day of prenatal ontogeny led to a prolonged (up to 18 month) increase in the level of meDNA in all the brain structures studied. We also observed a progressive decrease in the level of meH3K4, an activating modification of chromatin, in the hippocampus and neocortex of rats. However, the level of meH3K9, an inhibitory modification of chromatin, in animals that were subjected to adverse treatments during the prenatal period decreased to a lesser extent with age than in the control rats. These data indirectly reflect a decrease in the transcriptional activity of the genome of prenatally stressed animals, which may underlie long-term changes in their learning abilities.