Do neurotrophins regulate the feto-placental development?

Numerous data highlight the importance of a fine regulation of the fetal growth for the individual's subsequent susceptibility to diseases. Recent evidence suggests that neurotrophins may have important functions during pregnancy and that they could modulate fetal growth. We hypothesize that neurotrophins may participate in fetal growth by different pathways: (1) these molecules may participate in the development and the maturation of both central and peripheral fetal organs, including the placenta; (2) neurotrophins may constitute a link between the maternal nutrition and the fetal nutrients demand and thus could act as a nutrient sensor for the development and efficiency of the placenta; (3) maternal and placental neurotrophins may control the fetal development directly but also by activating the production and release of others growth factors. In conclusion, neurotrophins may participate to a new pathway controlling fetal growth and may be implicated, at least in part, under physiopathological conditions in disturbances of the fetal growth trajectory.     

Maternal microchimerism—Allogenic target of autoimmune disease or Normal Biology?

Chimerism is the state of cells from two distinct individuals living within one body. Fetal cells pass into a mother during pregnancy, where they may persist at low levels for years, creating a state of fetal microchimerism. At the same time, maternal cells pass into the fetus, leading to maternal microchimerism that can persist into adulthood. Hematopoietic stem cell transplantation also creates a state of chimerism, and can lead to a complication of chronic multi-organ inflammation called graft-versus-host disease, (GVHD). The similarities between GVHD and some autoimmune diseases like scleroderma, lupus and myositis suggest that chimerism may be involved in the pathogenesis of both. Maternal and fetal microchimerism in the blood and in tissues have been associated with autoimmune diseases. However, many healthy individuals harbor maternal and fetal cells. Human and animal studies have begun to elucidate the mechanisms for normal tolerance to maternal and fetal microchimeric cells, and how this tolerance may be broken in states of chronic inflammatory disease.     

An immunologic hypotheses concerning some congenital diseases and malformations

Congenital diseases such as hyaline membrane disease perhaps may come about by transplacental passage of high titred IgG anti HLA antibodies to a fetal pulmonary tissue. Conceivably transplacental passage of high titred anti HLA antibodies (or as yet unidentified antibodies) may interfere with development of tissues at any stage of embryonic and fetal development where the HLA antigen (or other antigen) are present.     

氧化应激状态的评价

机体代谢过程中活性氧不断地通过非酶促反应和酶促反应产生,每日约有1％-3％的摄入氧转变为超氧阴离子(superoxideanion,O2-)及其活性衍生物,但在抗氧化酶以及外源性和内源性抗氧化剂的协同作用下被不断清除,在生理情况下,ROS的生成     

Maternal obesity, metabolic disease, and allostatic load

Maternal obesity is a risk factor for many metabolic diseases for the mother, both during gestation and post partum, and for the child in later life. Obesity and pregnancy both result in altered physiological states, significantly different from the state of the non-obese, non-reproductive adult female. The concept of allostasis may be more appropriate for understanding the physiology of both pregnancy and obesity. In pregnancy these altered physiological states are adaptive, in both the evolutionary and physiological senses of the word. Obesity, however, represents a state outside of the adaptive evolutionary experience of our species. In both cases the altered physiological state derives at least in part from signals from an active endocrine organ. In obesity this is adipose tissue, and in pregnancy it is the placenta. The signaling molecules from adipose tissue and placenta all have multiple functions and can affect multiple organ systems. Placenta acts as a central regulator of metabolism for both the maternal and fetal compartments, in essence acting as a "third brain" during pregnancy. Both adipose tissue and placenta express many proinflammatory cytokines; obesity and pregnancy are states of low-grade inflammation. Both obesity and pregnancy are also states of insulin resistance, and maternal obesity is associated with fetal insulin resistance. We argue that obesity during pregnancy leads to sustained and inappropriate activation of normally adaptive regulatory circuits due in part to competing and conflicting signaling from adipose tissue and placenta. This results in allostatic load, leading to the eventual break down of regulatory mechanisms. The result is impaired metabolic function of the mother, and altered development of metabolic systems and potentially altered neural appetite circuits for the offspring.     

Embryonic and fetal cells which are not diseased or defective; possible sources of genes for disease prevention or treatment

Cancer and other diseases may be a natural biological event, the activities of which may be dependent on the constitution of the individual. Where fetal and embryonic cells are not diseased or faulty or defective, they may be useful as therapies against cancer and other diseases.     

Diet induced epigenetic changes and their implications for health

Dietary exposures can have consequences for health years or decades later and this raises questions about the mechanisms through which such exposures are 'remembered' and how they result in altered disease risk. There is growing evidence that epigenetic mechanisms may mediate the effects of nutrition and may be causal for the development of common complex (or chronic) diseases. Epigenetics encompasses changes to marks on the genome (and associated cellular machinery) that are copied from one cell generation to the next, which may alter gene expression, but which do not involve changes in the primary DNA sequence. These include three distinct, but closely inter-acting, mechanisms including DNA methylation, histone modifications and non-coding microRNAs (miRNA) which, together, are responsible for regulating gene expression not only during cellular differentiation in embryonic and foetal development but also throughout the life-course. This review summarizes the growing evidence that numerous dietary factors, including micronutrients and non-nutrient dietary components such as genistein and polyphenols, can modify epigenetic marks. In some cases, for example, effects of altered dietary supply of methyl donors on DNA methylation, there are plausible explanations for the observed epigenetic changes, but to a large extent, the mechanisms responsible for diet-epigenome-health relationships remain to be discovered. In addition, relatively little is known about which epigenomic marks are most labile in response to dietary exposures. Given the plasticity of epigenetic marks and their responsiveness to dietary factors, there is potential for the development of epigenetic marks as biomarkers of health for use in intervention studies.     

Feto-maternal cell trafficking

The embryonic and fetal development in the maternal uterine environment implies that different population of fetal progenitors must be in close contact to the maternal tissues. Accordingly, fetal mesenchymal and hematopoietic stem and progenitor cells have been described in the placenta and the fetal blood. Seeding in the materinal circulation, fetal progenitor cells can be detected in the circulation of pregnant women during most pregnancies. Decades after delivery, fetal CD34⁺ or mesenchymal stem cells are still detectable in maternal circulation or bone marrow. Recent studies point to the possibility for fetal progenitor cells persisting after pregnancy to home to maternal injured tissue and to adopt various phenotypes. Fetal cells in various maternal tissues can express epithelial, hepatocytic, hematopoietic, renal, cardiomyocytic, glial, or neuronal markers in human as well as mouse models. This apparent multipotency has been attributed to a fetal population of stem/progenitor cells acquired by the mother during pregnancy, named the pregnancy-associated progenitor cells. We will discuss the possible origins of this cell population and review the most recent data suggesting that these fetal microchimeric cells may participate in maternal tissue regeneration processes. An erratum to this article is available at .     

Recent advances in the genetics of preterm birth

Preterm birth is associated with short- and long-term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene–environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing.     

Redox regulation of the coagulation cascade

Enhanced coagulation and thrombosis are linked to a variety of cardiovascular and metabolic diseases, as well as to cancer. Many of these diseases are also associated with enhanced levels of reactive oxygen species (ROS). Indeed, ROS have been made responsible for promoting many of these diseases. They have been shown not only to be cytotoxic, but also to serve as signaling molecules in a variety of cells. Recently, evidence accumulated that ROS and the redox state are also important in the control of blood coagulation and thrombosis.     

Induced tolerance and chimaerism in human fetuses using coelocentesis: a medical opportunity to avert genetic disease?

Coelocentesis offers a new opportunity for gaining access tothe coelomic cavity of human embryos from 28 days post-fertilization(42 days menstrual age). With this technique, cells can be extractedfrom the cavity for the genetic typing of embryos in early pregnancy.Coelocentesis may also offer a unique opportunity of inducingtolerance to foreign grafts and chimaerism in these human embryosby replacing donor cells into the coelomic cavity. This cavityappears to be closely associated with the fetal haemopoieticsystem. The optimal age to inject stem cells designed to producechimaerism may be at 5-6 weeks embryonic age, and these graftedcells may induce tolerance later in gestation. Two successivecoelocenteses would be needed, the first to extract fetal cellsto type the fetus, and a second within a few days to injectthe donor cells into the coelomic cavity. Alternatively, non-invasivemethods of diagnosis such as lower uterine pole extramembra-noussampling of fetal trophoblast, or the extraction of fetal cellsfrom maternal blood, could be combined with coelocentesis. Iftolerance and chimaerism can be established, repeated tissuegrafts could be carried out during fetal life and after birth,so that disorders caused by single or multiple gene defectsin the haemopoietic system and other organs may be corrected.     

Characterization of prenatal growth and development in the crab-eating macaque (Macaca fascicularis) by ultrasound

Diagnostic ultrasound is a valuable tool for the examination of various anatomical structures in vivo. Improvements in technology have increased its effectiveness and provided a noninvasive method for the in utero observation of a variety of structural and functional events. Ultrasound is utilized in our laboratory to monitor a variety of studies during embryonic and fetal development. Basic to these evaluations is the ability to assess normal growth and development. The cynomolgus, or crab-eating macaque (Macaca fascicularis), has been observed in utero by ultrasound from early gestation to term. The earliest detection of implantation is by the identification of a developing gestational sac (GS), which may be visualized on gestational day (GD) 14-15. Positive identification of the GS on GD 16-18 and appearance of the embryo, yolk sac, and cardiac motion on GD 21-25 confirms pregnancy. Once the embryo is evident, measurements of the greatest length (GL) may be used to assess normal growth or to aid in the prediction of gestational age. During the fetal period, a variety of growth parameters aid in fetal evaluation. The gender of the fetus can be accurately identified as early as GD 70-75. An assessment of viability and condition can be determined by the observation of embryonic and fetal heart rates and gross body movement.     

The epigenetics of the hypothalamic‐pituitary‐adrenal axis in fetal development

The hypothalamic‐pituitary‐adrenal (HPA) axis is an important hormonal mechanism of the human body and is extremely programmable during embryonic and fetal development. Analyzing its development in this period is the key to understanding in fact how vulnerabilities of congenital diseases occur and any other changes in the phenotypic and histophysiological aspects of the fetus. The environment in which the mother is exposed during the gestational period can influence this axis. Knowing this, our objective was to analyze in recent research the possible impact of epigenetic programming on the HPA axis and its consequences for fetal development. This review brought together articles from two databases: ScienceDirect and PUBMED researched based on key words such as “epigenetics, HPA axis, cardiovascular disease, and circulatory problems” where it demonstrated full relevance in experimental and scientific settings. A total of 101 articles were selected following the criteria established by the researchers. Thus, it was possible to verify that the development of the HPA axis is directly related to changes that occur in the cardiovascular system, to the cerebral growth and other systems depending on the influence that it receives in the period of fetal formation.     

The role of cilia for hydrocephalus formation

Hydrocephalus is a common finding in newborns. In most cases, it is caused by intraventricular hemorrhage associated with prematurity, whereas in some patients the cause of hydrocephalus can be traced back to genetic changes, associated with disease syndromes such as RASopathies, lysosomal storage diseases, dystroglycanopathies, craniosynostosis but also ciliopathies. Ciliopathies are a group of diseases that can affect multiple organ systems due to dysfunction or the absence of cilia. Cilia are small organelles, extending from the cell surface. Nonmotile monocilia are ubiquitously present during cell development fulfilling chemosensory functions, whereas specialized epithelia such as the ependyma, lining the inner surface of the brain ventricles, exhibit multiciliated cells propelling fluids along the cell surface. This review highlights ciliopathies and their pathophysiology in congenital hydrocephalus. While nonmotile ciliopathies are often associated with severe prenatal hydrocephalus combined with other severe congenital brain malformations, motile ciliopathies, especially those associated with defects in multiciliogenesis can cause hydrocephalus and chronic lung disease.     

Scientific and practical aspects of prenatal diagnosis

Prenatal diagnostics (PD) is a relatively new branch of medical genetics enjoining presently a rapid practical and scientific progress. The key practical issues related with detecting the pregnant women at high risk of fetal congenital and inherited pathologies have already been solved, and a variety of fetal examinations by non-invasive (ultrasound) and invasive (cytogenetics, biochemistry and molecular tests) methods have been elaborated. Their practical application are totally dependant on the managerial and financial input in the discussed field of medicine. Further advancement in PD are tensely associated with early pregnancy stages (trimester 1), with the molecular diagnostic tools in the diagnosis of chromosomal diseases and with a comprehensive use of Pregnancy Genetic Form worked out and used already at our institute. DP opens up the promising opportunities for analyzing the human genome activity at the initial development stages, which comprises the revision of previously-obtained data on the cytogenetics of human embryo evolution, human chromosomes' functioning and of temporary embryonic organs as observed during the mentioned stages; it also comprises an analysis and application of umbilical and embryonic cells (embryonic cell therapy) and elaboration of scientific fundamentals for embryonic gene therapy. PD should not be referred to only as a set of diagnostic methods for it is also a good starting-ground for research of human embryo-genesis.     

Role of redox reactions in the vascular phenotype of hyperhomocysteinemic animals

Hyperhomocysteinemia is a risk factor for cardiovascular disease, stroke, and thrombosis. Several animal models of hyperhomocysteinemia have been developed by using both dietary and genetic approaches. These animal models have provided considerable insight into the mechanisms underlying the adverse vascular effects of hyperhomocysteinemia. Accumulating evidence suggests a significant role of altered cellular redox reactions in the vascular phenotype of hyperhomocysteinemia. Redox effects of hyperhomocysteinemia are particularly important in mediating the adverse effects of hyperhomocysteinemia on the endothelium, leading to loss of endothelium-derived nitric oxide and vasomotor dysfunction. Redox reactions also may be key factors in the development of vascular hypertrophy, thrombosis, and atherosclerosis in hyperhomocysteinemic animals. In this review, we summarize the metabolic relations between homocysteine and the cellular redox state, the vascular phenotypes that have been observed in hyperhomocysteinemic animals, the evidence for altered redox reactions in vascular tissue, and the specific redox reactions that may mediate the vascular effects of hyperhomocysteinemia.     

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins. I. Alpha-fetoprotein induction by ethionine

The neoplastic cellular phenotype expresses many embryonic features. These features are believed to occur by derepression of embryonic genes during the carcinogenic process. A specific case is the ability of ethionine, a hepatocarcinogen, to induce an embryonic protein known as alpha-fetoprotein. A mechanism is proposed for this derepression process along with supporting evidence. It is hypothesized that the repressor protein for the alpha-fetoprotein gene must be modified (methylated) before it is functional and if for any reason this does not occur, alpha-fetoprotein will be produced. This simple theory can explain a variety of states of the liver cell in which alpha-fetoprotein is expressed namely i) fetal, ii) ethionine-treated, iii) neoplastic, and iv) tyrosinemic liver cells.