The placenta is the first organ to be created during mammalian development. As the main link between the mother and the fetus it has more diverse functions than any other organ, serving as a digestive, excretory, respiratory, endocrine, and immune system. The outer layer of the placenta, the trophoblast, plays a key role in fetal development by orchestrating all these functions. Recent research has associated perturbations of maternal conditions (such as malnutrition, stress or inflammation) with alterations of the trophoblasts' endocrine, transport and metabolic processes. As reviewed here, adaptations to these conditions enable the fetus to survive, but at the cost of permanently changing its physiology and structure. Moreover, these adaptations trigger fetal programming that increases predisposition to various pathological conditions in adult life, typically metabolic, cardiovascular or CNS diseases.
- Keywords
- Fetal development, Fetal programming, Placenta, Pregnancy, Trophoblast,
- MeSH
- Models, Biological MeSH
- Humans MeSH
- Maternal-Fetal Exchange drug effects physiology MeSH
- Placenta physiology MeSH
- Pregnancy MeSH
- Trophoblasts cytology drug effects physiology MeSH
- Fetal Development drug effects physiology MeSH
- Xenobiotics toxicity MeSH
- Prenatal Exposure Delayed Effects etiology physiopathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Xenobiotics MeSH
Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.
- Keywords
- functional brain imaging, prenatal immune programming, prenatal stress, sex, stress circuitry,
- MeSH
- Cytokines blood MeSH
- Adult MeSH
- Hypothalamus diagnostic imaging MeSH
- Connectome * MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Stress, Psychological diagnostic imaging MeSH
- Sex Factors MeSH
- Pregnancy MeSH
- Prenatal Exposure Delayed Effects diagnostic imaging MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Cytokines MeSH
The origin of immune cells and their products have been studied in the prenatal period in miniature pigs. Macrophages were first detected on day 25, and myelocytes and lymphoid cells by day 28. Membrane antigens SLA-DR and CD45 were found by day 22, membrane molecules MG-7, 8/1, CD1, CD2 and 74-22 by day 28, Gamma/delta T cells were found initially in extrathymic sites (in the liver). The first gamma/delta T cells were detected as early as 40 days of gestation. The expression of fibronectin, Thy-1 and its message, Ig isotypes and the first induction of IFN alpha were described.
Low amounts of immunoglobulins, produced without any known cause of stimulation, can be detected in sera and cells of fetal and colostrum deprived newborn pigs. These immunoglobulins are believed to represent the preimmune antibody repertoire on the basis of their polyspecificity and reactivity against self antigens. In vitro activation of liver and spleen cells with various polyclonal B cell activators (PBA) results in pronounced immunoglobulins synthesis as measured in the culture media by enzyme-linked immunosorbent assay. Intrauterine injection of fetal and germfree pigs with PBA led to increased IgM, IgG and IgA levels in sera. Specific responses during fetal development were studied after intrauterine immunization. Antibodies to the heapten and its carrier flagellin, could be detected 7 days after the immunization of 55-day-old fetuses. Fetal and colostrum germfree pigs may be useful experimental models in which developmental immunity can be studied in the absence of maternal antibodies and environmental antigens.
- MeSH
- Embryonic and Fetal Development immunology MeSH
- Hematopoietic System embryology immunology MeSH
- Immunoglobulins biosynthesis MeSH
- Lymphoid Tissue embryology immunology MeSH
- Animals, Newborn immunology MeSH
- Swine embryology immunology MeSH
- Intestinal Mucosa immunology MeSH
- Antibody Formation immunology MeSH
- Uterus immunology MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Immunoglobulins MeSH
Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system.
- Keywords
- Non-Alcoholic Fatty Liver Disease, developmental programming, intra-abdominal fat, maternal nutrition, obesity,
- MeSH
- Alanine Transaminase blood MeSH
- Aspartate Aminotransferases blood MeSH
- Maternal Nutritional Physiological Phenomena * MeSH
- Liver metabolism MeSH
- Blood Glucose metabolism MeSH
- Disease Models, Animal MeSH
- Mice, Knockout MeSH
- Mice, Obese MeSH
- Mice MeSH
- Obesity genetics MeSH
- Perinatal Care MeSH
- Receptor, Melanocortin, Type 4 deficiency genetics MeSH
- Gene Expression Regulation MeSH
- Pregnancy MeSH
- Triglycerides blood MeSH
- Prenatal Exposure Delayed Effects genetics MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Alanine Transaminase MeSH
- Aspartate Aminotransferases MeSH
- Blood Glucose MeSH
- MC4R protein, mouse MeSH Browser
- Receptor, Melanocortin, Type 4 MeSH
- Triglycerides MeSH
Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.
- MeSH
- Biomarkers MeSH
- Humans MeSH
- Metabolic Networks and Pathways MeSH
- Disease Susceptibility MeSH
- Placenta metabolism MeSH
- Premature Birth diagnosis etiology metabolism MeSH
- Gene Expression Regulation MeSH
- Risk Factors MeSH
- Gene Expression Profiling MeSH
- Pregnancy MeSH
- Transcriptome * MeSH
- Tryptophan metabolism MeSH
- Computational Biology methods MeSH
- Pregnancy Outcome MeSH
- Inflammation complications etiology MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Biomarkers MeSH
- Tryptophan MeSH
BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/-) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/- offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/- offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. CONCLUSIONS: Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease.
- Keywords
- Echocardiography, Fetal programming, Heart remodelling, Hif1a haploinsufficiency, Maternal diabetes,
- MeSH
- Diabetes Mellitus, Experimental complications metabolism pathology MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit genetics metabolism MeSH
- Ventricular Function, Left MeSH
- Diabetes, Gestational * metabolism pathology MeSH
- Haploinsufficiency MeSH
- Gene-Environment Interaction MeSH
- Cardiovascular Diseases genetics metabolism pathology physiopathology MeSH
- Mutation * MeSH
- Myocardium metabolism pathology MeSH
- Mice, Knockout MeSH
- Ventricular Remodeling MeSH
- Risk Factors MeSH
- Pregnancy MeSH
- Gene Expression Regulation, Developmental MeSH
- Prenatal Exposure Delayed Effects * MeSH
- Animals MeSH
- Check Tag
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Hypoxia-Inducible Factor 1, alpha Subunit MeSH
- Hif1a protein, mouse MeSH Browser
BACKGROUND: The purpose of this study was to confirm that women with latent toxoplasmosis have developmentally younger fetuses at estimated pregnancy week 16 and to test four exclusive hypotheses that could explain the observed data. METHODS: In the present retrospective cohort study we analysed by the GLM (general linear model) method data from 730 Toxoplasma-free and 185 Toxoplasma-infected pregnant women. RESULTS: At pregnancy week 16 estimated from the date of the last menstruation, the mothers with latent toxoplasmosis had developmentally younger fetuses based on ultrasound scan (P = 0.014). Pregnancy of Toxoplasma-positive compared to Toxoplasma-negative women was by about 1.3 days longer, as estimated both from the date of the last menstruation (P = 0.015) and by ultrasonography (P = 0.025). CONCLUSION: The most parsimonious explanation for the observed data is retarded fetal growth during the first weeks of pregnancy in Toxoplasma-positive women. The phenomenon was only detectable in multiparous women, suggesting that the immune system may play some role in it.
- MeSH
- Time Factors MeSH
- Adult MeSH
- Cohort Studies MeSH
- Toxoplasmosis, Congenital complications physiopathology MeSH
- Humans MeSH
- Linear Models MeSH
- Pregnancy Complications, Parasitic physiopathology MeSH
- Parity MeSH
- Antibodies, Protozoan analysis MeSH
- Retrospective Studies MeSH
- Fetal Growth Retardation etiology physiopathology MeSH
- Pregnancy MeSH
- Ultrasonography, Prenatal MeSH
- Fetal Development physiology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antibodies, Protozoan MeSH
The presented review lists primary immunodeficiencies which essentially involve a mutation in genes coding for functionally important molecules, membrane antigens (e.g., MHC), chains of lymphokine receptors, protein kinases of the signal cascade, transcription factors, and some important regulators of cellular metabolism. Mutations are expressed as early as during embryogenesis (lymphopoiesis-I) as well as during induction of the immune response by antigen ligand binding to cell receptors, TCR, BCR (immunopoiesis-II). Immunodeficiencies are classified by the stage of development (I) or immune response induction (II) in which they occur most markedly, even in clinical terms. It has been pointed out that the same autoactivation stimuli and mechanisms, allowing differentiation-maturation of cells during embryogenesis (action of stem cell factor (SFC), IL-3, IL-7, and activation cascade), serve even later as a functional prerequisite for an adaptive immune response to antigen. As a result, this attempt to classify primary immunodeficiencies by differentiation periods (when they become evident most markedly in terms of their function) has an inherent logical limitation. Some early mutations turn immediately lethal, some express themselves by blocking embryonic lymphopoiesis while other mutations do not become demonstrable until after cell stimulation by antigens. This explains why the developmental differentiation scheme is bound to turn, in the future, into an immunodeficiency classification by localization of gene mutations and their incidence in time, e.g., increased mutation incidence during proliferation following cell stimulation by antigen stimuli.
- MeSH
- Antigens immunology MeSH
- Embryonic and Fetal Development MeSH
- Humans MeSH
- Ligands MeSH
- Receptors, Antigen immunology MeSH
- Immunologic Deficiency Syndromes genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Antigens MeSH
- Ligands MeSH
- Receptors, Antigen MeSH
Prenatal development of cord blood monocytes and tissue macrophages was studied in pig foetuses by immunophenotyping and functional assays. The function of peripheral blood monocytes was compared in germ-free and conventional piglets. First macrophages were identified by electron microscopy in foetal liver on the 25th day of gestation. Monoclonal antibodies against porcine CD45 and SWC3 antigens were used for flow cytometric identification of myelomonocytic cells in cell suspensions prepared from the yolk sac, foetal liver, spleen and cord blood. Leukocytes expressing the common myelomonocytic antigen SWC3 were found in all organs studied since the earliest stages of development. Opsonized zymosan ingestion assay was used to determine the phagocytic capacity of foetal mononuclear phagocytes isolated from cord blood, liver and spleen. In the foetal liver, avid phagocytosis of apoptic cells had been found to occur before cells were able to ingest zymosan in vitro. The first cells capable of ingesting zymosan particles were found on the 40th day of gestation in umbilical blood and 17 days later in foetal spleen and liver. Their relative proportion increased with age. Cord blood monocytes and peripheral blood monocytes in germ-free piglets had low oxidatory burst activity as shown by iodonitrophenyl tetrazolium reduction assay. A remarkable increase of oxidatory burst activity was observed in conventional piglets, probably due to activation of immune mechanisms by the microflora colonizing gastrointestinal tract.
- MeSH
- Leukocyte Common Antigens analysis MeSH
- Apoptosis MeSH
- Microscopy, Electron MeSH
- Phagocytosis MeSH
- Fetal Blood cytology MeSH
- Gestational Age MeSH
- Immunophenotyping MeSH
- Liver cytology embryology MeSH
- Macrophages immunology physiology MeSH
- Histocompatibility Antigens Class II analysis MeSH
- Monocytes immunology physiology MeSH
- Antibodies, Monoclonal MeSH
- Swine MeSH
- Flow Cytometry MeSH
- Spleen cytology embryology MeSH
- Yolk Sac cytology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Leukocyte Common Antigens MeSH
- Histocompatibility Antigens Class II MeSH
- Antibodies, Monoclonal MeSH
