Embryos can be exposed to environmental factors that induce hypoxia. Currently, our understanding of the effects of hypoxia on early mammalian development is modest. Potential mediators of hypoxia action include the nucleoside adenosine, which acts through A 1 adenosine receptors (A1ARs) and mediates adverse effects of hypoxia on the neonatal brain. We hypothesized that A 1ARs may also play a role in mediating effects of hypoxia on the embryo. When pregnant dams were exposed to hypoxia (10% O2) beginning at embryonic day (E) 7.5 or 8.5 and continued for 24 -96 h, A 1AR؉/؉ embryos manifested growth inhibition and a disproportionate reduction in heart size, including thinner ventricular walls. Yet, when dams were exposed to hypoxia, embryos lacking A 1ARs (A1AR؊/؊) had much more severe growth retardation than A 1AR؉/؉ or ؉/؊ embryos. When levels of hypoxia-inducible factor 1␣ (HIF1␣) were examined, A1AR؊/؊ embryos had less stabilized HIF1␣ protein than A1AR؉/؊ littermates. Normal patterns of cardiac gene expression were also disturbed in A1AR؊/؊ embryos exposed to hypoxia. These results show that short periods of hypoxia during early embryogenesis can result in intrauterine growth retardation. We identify adenosine and A1ARs as playing an essential role in protecting the embryo from hypoxia.cardiac ͉ heart development ͉ hypoxia-inducible factor ͉ intrauterine growth retardation
The purpose of this study was to determine both the short-term effects on cardiac development and embryo growth and the long-term effects on cardiac function and body composition of in utero caffeine exposure. Pregnant mice (C57BL/6) were exposed to hypoxia (10% O(2)) or room air from embryonic days (E) 8.5-10.5, and treated with caffeine (20 mg/kg, i.p.) or vehicle (normal saline, 0.9% NaCl). This caffeine dose results in a circulating level that is equivalent to 2 cups of coffee in humans. Hypoxic exposure acutely reduced embryonic growth by 30%. Exposure to a single dose of caffeine inhibited cardiac ventricular development by 53% in hypoxia and 37% in room air. Caffeine exposure resulted in inhibition of hypoxia-induced HIF1alpha protein expression in embryos by 40%. When offspring from dams treated with a single dose of caffeine were studied in adulthood, we observed that caffeine treatment alone resulted in a decrease in cardiac function of 38%, as assessed by echocardiography. We also observed a 20% increase in body fat with male mice exposed to caffeine. Caffeine was dissolved in normal saline, so it was used as a control. Room air controls were used to compare to the hypoxic mice. Exposure to a single dose of caffeine during embryogenesis results in both short-term effects on cardiac development and long-term effects on cardiac function.
It is known from nutritional studies that vitamin A is an important factor for normal hematopoiesis, though it has been difficult to define its precise role. The vitamin A-deficient (VAD) quail embryo provides an effective ligand "knockout" model for investigating the function of retinoids during development. The VAD embryo develops with a significant reduction in erythroid cells, which has not been noted previously. Activation of the primitive erythroid program and early expression of the erythroid marker GATA-1 occurs, though GATA-1 levels eventually decline, consistent with the erythropoietic and hemoglobin deficits. However, from its early stages, the GATA-2 gene fails to be expressed normally in VAD embryos. The bone morphogenetic protein (BMP)-signaling pathway regulates GATA-2, and BMP4 expression becomes reduced in the caudal embryonic region of VAD embryos. Adding BMP4 to cultured VAD-derived explants rescues the production of erythroid cells, whereas normal embryos cultured in the presence of the BMP antagonist noggin are defective in primitive hematopoiesis. We find that cell clusters of primitive blood islands undergo an inappropriate program of apoptosis in the VAD embryo, which can explain the deficit in differentiated primitive blood cells. We propose that vitamin A-derived retinoids are required for normal yolk sac hematopoiesis and that an embryonic retinoid-BMP-GATA-2 signaling pathway controls progenitor cell survival relevant to primitive hematopoiesis. ( IntroductionThe first hematopoietic cells develop on the extra-embryonic yolk sac in close association with the initial endothelial cells. Mesoderm-derived cell clusters or "blood islands" contain the embryonic or "primitive" erythrocytes and the surrounding endothelial structures that form the extra-embryonic vascular plexus. The association of embryonic blood and endothelial cells led to a hypothesis that both derive from a common progenitor, the hemangioblast. 1 This concept has been supported recently by overlapping gene expression programs and by in vitro lineage analysis using embryonic stem cells. 2 The developmental origin and the relationship between the hemangioblast, the hematopoietic progenitors, and the hematopoietic stem cells that ultimately seed the bone marrow for adult or "definitive" hematopoiesis are not completely defined. Meanwhile, the signaling molecules that control blood island development and primitive hematopoiesis are unknown and may be distinct from definitive hematopoietic cytokines. Primitive erythrocytes are a transient population of relatively large, hyperchromatic cells expressing embryonic globins and are not dependent on the same set of regulatory genes that are required for definitive hematopoiesis. For example, definitive but not primitive erythropoiesis is critically dependent on erythropoietin. 3 Vitamin A-derived retinoids, including retinoic acid (RA), are required for normal embryogenesis and tissue maintenance. 4 Retinoids function as signaling ligands through the activation of RAR and RXR nuclea...
In the present study, we have used single chicken blastoderms of defined early developmental stages, beginning with the prestreak stage, stage 1 (V. Hamburger and H. L. Hamilton, J. Morphol. 88:49-92, 1951), to analyze the onset of cardiac myogenesis by monitoring the appearance of selected cardiac muscle tissue-specific gene transcripts and the functional expression of the myocyte enhancer factor 2 (MEF-2) proteins. Using gene-specific oligonucleotide primers in reverse transcriptase PCR assay, we have demonstrated that the cardiac myosin light-chain 2 (MLC2) and alpha-actin gene transcripts appear as early as stage 5, i.e., immediately after the cardiogenic fate assignment at stage 4. Consistent with this observation is the developmental expression pattern of DNA-binding activity of BBF-1, a cardiac muscle-specific member of the MEF-2 protein family, which also begins at stage 5 prior to MEF-2. Differential expression of DNA-binding complexes is also observed with another AT-rich DNA sequence (CArG box) as probe, but the binding pattern with the ubiquitous TATA-binding proteins remains unchanged during the same developmental period. Thus, the cardiogenic commitment and differentiation of the precardiac mesoderm, as exemplified by the appearance of cardiac MEF-2, MLC2, and alpha-actin gene products, occur earlier than previously thought and appear to be closely linked. The onset of skeletal myogenic program follows that of the cardiogenic program with the appearance of skeletal MLC2 at stage 8. We also observed that mRNA for the MEF-2 family of proteins appears as early as stage 2 and that for CMD-1, the chicken counterpart of MyoD, appears at stage 5. The temporal separation of activation of cardiac and skeletal MLC2 genes, which appears immediately after the respective fate assignments, and those of cardiac MEF-2 and CMD-1, which occur before, are consistent with the established appearance of the myogenic programs and with the acquisition pattern of the two tissue-specific morphological characteristics in the early embryo. The preferential appearance of BBF-1 activity in precardiac moesderm, relative to that of MEF-2, indicates that these two protein factors are distinct members of the MEF-2 family and provides a compelling argument in support of the potential role of BBF-1 as a regulator of the cardiogenic cell lineage determination, while cardiac MEF-2 might be involved in maintenance of the cardiac differentiative state.
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