[EPIGENETIC FACTORS OF NEUROBIOLOGIC CHANGES IN FETUSES OF PREGNANT WOMEN WITH NEUROPSYCHIATRIC DISORDERS].

During prenatal development, the fetus is particularly vulnerable to the environmental harmful effects. It has been proved that the placenta is a significant modulator of the intrauterine environment that links maternal and fetal nervous systems. Emerging evidence indicates that epigenetic modifications prior to the birth may have substantial influence on brain development and may exert various neurobehavioral deficits. This review demonstrates association between maternal prenatal distress and depression and fetal long-term neurobiological and behavioral outcomes. Further investigation of the epigenetic dysregulation of fetal neurodevelopment may suggest new mechanisms in the interplay between genes and environment, and provide novel insights in the pathophysiology and prevention of neuropsychiatric disorders.

[FETAL PROGRAMMING OF METABOLIC DISORDERS].

Our knowledge of fetal programming has developed notably over the years and recent data suggest that an unbalanced diet prior and during pregnancy can have early-onset and long-lasting consequences on the health of the offspring. Specific negative influences of high dietary glucose and lipid consumption, as well as undernutrition, are associated with development of metabolic syndrome, insulin resistance and diabetes in the offspring. The mechanisms underlying the effects of maternal hyperglycemia on the fetus may involve structural, metabolic and epigenetic changes. The aim of this review is to illustrate how adverse intrauterine environment may influence molecular modifications in the fetus and cause epigenetic alterations in particular. It has been demonstrated that prenatal epigenetic modifications may be linked to the pathogenesis and progression of the adult chronic disorders. Studies on epigenetic alterations will contribute to a better understanding of the long-term effects of in utero exposure and may open new perspectives for disease prevention and treatment.

[Gestational and non-gestational factors for perinatal programming of insulin resistance].

Insulin resistance is well known problem in type 2 diabetes mellitus (T2DM). Various factors play roles in the mechanisms of prenatal programming of insulin resistance. Gestational or non-gestational factors are illustrated in the present paper. Adipocytes (fat cells) produce at least 50 proteins (adipokines; peptides, cytokines, etc.), and a large part of them are involved in prenatal development of insulin resistance. The role of pro-inflammatory cytokines as the tumor necrosis factor 1 (TNF alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) is documented. Leptin from adipocytes as well as from the placenta is involved in pathology of metabolism and plays a role as a gestational factor for the prenatal insulin resistance and the risk for T2DM. Epigenetic mechanisms as the methylation of DNA and histones, the acetylation of histones are documented for prenatal development of insulin resistance. Epigenetic modulations may explain the risk of T2DM for generations. New data indicated that the placenta does not produce adiponectin and it is also one of the important factors for the development of gestational diabetes and risk for the fetus. Taken together all factors documented in the present paper may predict the risk for prenatal T2DM.

Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis.

Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells.

Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25-(OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25-(OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25-(OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production.