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PubMed1995

Tissue-specific rescue suggests that placental adenosine deaminase is important for fetal development in mice.

Adenosine deaminase (ADA, EC 3.5.4.4) is an essential enzyme of purine metabolism that is expressed at very high levels in the murine placenta where it accounts for over 95% of the ADA present at the fetal gestation site. We have recently shown that ADA-deficient fetuses, which also lack ADA in their adjoining placentas, die during late fetal development in association with profound purine metabolic disturbances and hepatocellular impairment. We have now investigated the potential importance of placental ADA by genetically restoring the enzyme to placentas of ADA-deficient fetuses. This genetic engineering strategy corrected most of the purine metabolic disturbances, prevented serious fetal liver damage, and rescued the fetuses from perinatal lethality. Our findings suggest that placental ADA is important for murine fetal development and illustrate a general strategy for the tissue specific correction of phenotypes associated with null mutations in mice.

Adenosine Deaminase↗

PubMed1993

Fetal development of the human orbit.

The development of the orbits in 70 human fetal skulls was investigated by measuring the width and height of the orbital entrance, as well as the volume and depth of the orbital cavity and the interorbital width. For determination of the orbital volume, we used the imprint method; the remaining parameters were estimated. Our measurements showed a linear growth rate for the orbital width, height, and depth. After transformation to the cubic root, the values of the orbital volume also demonstrated a linear increase. The orbital index (height/width x 100) expressed the change in the oval outline of the orbital entrance during fetal development from a flat, wide form to a nearly round form at birth. No statistically significant difference between the right and left orbit was found.

Anthropometry↗

PubMed1988

Developmental aspects of the rat brain insulin receptor: loss of sialic acid and fluctuation in number characterize fetal development.

In this study, I have investigated the structure of the rat brain insulin receptor during fetal development. There is a progressive decrease in the apparent molecular size of the brain alpha-subunit during development: 130K on day 16 of gestation, 126K at birth, and 120K in the adult. Glycosylation was investigated as a possible reason for the observed differences in the alpha-subunit molecular size. The results show that the developmental decrease in the brain alpha-subunit apparent molecular size is due to a parallel decrease in sialic acid content. This was further confirmed by measuring the retention of autophosphorylated insulin receptors on wheat germ agglutinin (WGA)-Sepharose. An inverse correlation between developmental age and retention of 32P-labeled insulin receptors on the lectin column was observed. Insulin binding increases 6-fold between 16 and 20 days of gestation [61 +/- 25 (+/- SE) fmol/mg protein and 364 +/- 42 fmol/mg, respectively]. Thereafter, binding in brain membranes decreases to 150 +/- 20 fmol/mg by 2 days after birth, then reaches the adult level of 63 +/- 15 fmol/mg. In addition, the degree of insulin-stimulated autophosphorylation closely parallels the developmental changes in insulin binding. Between 16 and 20 days of fetal life, insulin-stimulated phosphorylation of the beta-subunit increases 6-fold. Thereafter, the extent of phosphorylation decreases rapidly, reaching adult values identical with those in 16-day-old fetal brain. These results suggest that the embryonic brain possesses competent insulin receptors whose expression changes markedly during fetal development. This information should be important in defining the role of insulin in the developing nervous system.

Animals↗

PubMed1993

Effect of water temperature on exercise-induced maternal hyperthermia on fetal development in rats.

The objective of this study was to determine if water temperature influenced exercise-induced hyperthermia in swim-trained pregnant rats and the resulting fetal development. Pregnant Sprague-Dawley rats with 6 weeks pre-pregnancy training were exercised daily from day 1 to day 18 of gestation in water that was 34.6 +/- 0.4 degrees C (Cool Water Swimmers--CWS) or 37.6 +/- 0.1 degrees C (Warm Water Swimmers--WWS), for one hour/day. During this time period another group of pregnant rats was immersed to the neck in warm water (37.6 +/- 0.2 degrees C) (Warm Water Controls--WWC). On day 19 of gestation all animals were sacrificed and fetal development assessed. Maternal exercise in warm water elevated maternal body core temperature by 2.3 +/- 0.1 degrees C above resting values, with an increase in fetal abnormalities compared to the same exercise intensity in cool water. Fifty-eight percent of the abnormal fetuses and 60% of the resorption sites were found in the WWS group. Of the abnormalities determined, 65% were from the WWS group and 45% of these fetuses showed micrencephaly. Results suggest cool water may regulate maternal body temperature during swimming exercise and that swimming in warm water should be avoided during gestation because of potential teratogenic effects.

Animals↗

PubMed2006

Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction.

The effects on subsequent fetal development of the presence or absence of serum at different times during IVC of ovine zygotes were studied. Zygotes, recovered from superovulated ewes 36h after intrauterine AI using semen from a single sire, were cultured for 5 days in synthetic oviductal fluid (SOF) media supplemented with either BSA and amino acids (SOF-) or with 10% (v/v) steer serum (SOF+). Serum was present or absent during the first two and last 2 days of IVC giving four treatments (SOF-/SOF-; SOF-/SOF+;SOF+/SOF- and SOF+/SOF+). In total, 224 embryos, including 26 in vivo controls, were transferred singly at day 6 post-AI to synchronous recipients and the products of conception recovered at day 125 of gestation. Presence of serum during IVC had a biphasic effect on embryo development. The inclusion of serum during the first 2 days of IVC retarded early embryo development while the inclusion of serum during the last 2 days of IVC produced more blastocysts by day 6. These effects were independent of each other. The presence of serum during the first 2 days of IVC resulted in increased weights of gravid uterus, placenta, fetus, fetal heart and liver. The incidence of fetuses whose total or organ weights were greater than three standard deviations above the corresponding mean weights of control fetuses was also greater when serum was present during the first 2 days of IVC. However, even when serum was absent throughout IVC there was still an infrequent incidence of fetal weights greater than three standard deviations above the mean for control fetuses. These observations provide evidence that it is the early pre-compaction stages of embryo development that are particularly sensitive to perturbations leading to abnormal fetal development.

Animals↗

PubMed1999

11Beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in human fetal development.

11Beta-Hydroxysteroid dehydrogenase type II (11betaHSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive 11-keto metabolites. The biological significance of 11betaHSD2 activity during fetal development is currently being explored, but the temporal and spatial distributions of the enzyme and receptor have not been examined. We therefore examined their distributions during various stages of human fetal development using immunohistochemistry. Both 11betaHSD2 and MR immunoreactivity were detected in the distal convoluted and collecting tubules of the kidney from early in gestation. Fetal skin, intermediate layer of the epidermis, peridermal cells, and hair follicles were positive for both 11betaHSD2 and MR. Weak 11betaHSD2 and MR immunoreactivity was detected in the superficial ciliated epithelium of the esophagus, the deep layer of gastric epithelial cells, and the superficial epithelium of the small intestine. Columnar epithelium in the terminal bronchiolar budding component of fetal lung and tracheal and bronchial ciliated epithelium were also positive for MR and 11betaHSD2 from early gestation. Colonic epithelium and pancreatic exocrine duct cells, which demonstrated marked immunoreactivity of both MR and 11betaHSD2 in the adult, did not express MR and 11betaHSD2 until very late in gestation. These results imply that mineralocorticoid action in the upper fetal gastrointestinal tract, kidney, skin, and lung is facilitated by 11betaHSD2 and is involved in water and electrolyte transport between fetus and amniotic fluid as well as fetal urine production.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2002

Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study.

OBJECTIVES: The National Institute of Child Health and Human Development Fetal Cell Isolation Study (NIFTY) is a prospective, multicenter clinical project to develop non-invasive methods of prenatal diagnosis. The initial objective was to assess the utility of fetal cells in the peripheral blood of pregnant women to diagnose or screen for fetal chromosome abnormalities. METHODS: Results of fluorescence in situ hybridization (FISH) analysis on interphase nuclei of fetal cells recovered from maternal blood were compared to metaphase karyotypes of fetal cells obtained by amniocentesis or chorionic villus sampling (CVS). After the first 5 years of the study we performed a planned analysis of the data. We report here the data from 2744 fully processed pre-procedural blood samples; 1292 samples were from women carrying singleton male fetuses. RESULTS: Target cell recovery and fetal cell detection were better using magnetic-based separation systems (MACS) than with flow-sorting (FACS). Blinded FISH assessment of samples from women carrying singleton male fetuses found at least one cell with an X and Y signal in 41.4% of cases (95% CI: 37.4%, 45.5%). The false-positive rate of gender detection was 11.1% (95% CI: 6.1,16.1%). This was higher than expected due to the use of indirectly labeled FISH probes in one center. The detection rate of finding at least one aneuploid cell in cases of fetal aneuploidy was 74.4% (95% CI: 76.0%, 99.0%), with a false-positive rate estimated to be between 0.6% and 4.1%. CONCLUSIONS: The sensitivity of aneuploidy detection using fetal cell analysis from maternal blood is comparable to single marker prenatal serum screening, but technological advances are needed before fetal cell analysis has clinical application as part of a multiple marker method for non-invasive prenatal screening. The limitations of the present study, i.e. multiple processing protocols, are being addressed in the ongoing study.

Adult↗

PubMed1998

Maternal regulation of fetal development and health in adult life.

Babies who are small or disproportionate at birth, or who have altered placental growth are now known to have increased rates of coronary heart disease, hypertension and non-insulin-dependent diabetes in adult life. These associations are thought to result from fetal 'programming', whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on the body's structure, physiology and metabolism. Small size at birth and disproportion in head size, length and weight appear to be surrogate markers for the actual influences that programme the fetus. These observations have prompted a re-evaluation of the maternal regulation of human fetal development. Recent studies suggest that the fetus may be considerably more sensitive to the materno-placental supply of nutrients than hitherto imagined. Adult cardiovascular disease may be a consequence of fetal adaptations invoked when the materno-placental nutrient supply fails to match the fetal nutrient demand. Understanding the maternal regulation of human fetal development could lead to public health measures that improve the adult health of future generations.

Animals↗

PubMed2004

Maternal nutrition and fetal development.

Nutrition is the major intrauterine environmental factor that alters expression of the fetal genome and may have lifelong consequences. This phenomenon, termed "fetal programming," has led to the recent theory of "fetal origins of adult disease." Namely, alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology, and metabolism of the offspring, thereby predisposing individuals to metabolic, endocrine, and cardiovascular diseases in adult life. Animal studies show that both maternal undernutrition and overnutrition reduce placental-fetal blood flows and stunt fetal growth. Impaired placental syntheses of nitric oxide (a major vasodilator and angiogenesis factor) and polyamines (key regulators of DNA and protein synthesis) may provide a unified explanation for intrauterine growth retardation in response to the 2 extremes of nutritional problems with the same pregnancy outcome. There is growing evidence that maternal nutritional status can alter the epigenetic state (stable alterations of gene expression through DNA methylation and histone modifications) of the fetal genome. This may provide a molecular mechanism for the impact of maternal nutrition on both fetal programming and genomic imprinting. Promoting optimal nutrition will not only ensure optimal fetal development, but will also reduce the risk of chronic diseases in adults.

Amino Acids↗

PubMed2002

Fetal development in the pig in relation to genetic merit for piglet survival.

The objective of this study was to investigate if litters with different genetic merit for piglet survival differ in late fetal development. In total, 507 fetuses from 46 litters were delivered by Caesarean section at, on average, d 111 of gestation. All litters had known estimated breeding values for piglet survival (EBVps). The obtained range of EBVps of the litters was continuous, and the difference between litters with the lowest and highest EBVps was 16.4%. Analysis of relationships between fetal characteristics and EBVps was performed with litter averages, using linear regression analysis with inclusion of EBVps as a covariate. An increase in EBVps of the litter was associated with decreases in average placental weight (P = 0.01) and within-litter variation in placental weight (P = 0.02), and an increase in average placental efficiency (P = 0.08). Average fetal length decreased with increasing EBVps (P = 0.04), but weights of liver (P = 0.02), adrenals (P = 0.0001), and small intestine (P = 0.01) showed relative increases with increasing EBVps. Average serum cortisol concentrations increased with increasing EBVps (P = 0.0001), but the other blood characteristics (hematocrit, glucose, fructose, albumin, estradiol-17beta) were not related to EBVps. Glycogen concentrations in liver (P = 0.07) and longissimus dorsi muscle (P = 0.04) and total liver glycogen content (P = 0.05) increased with increasing EBVps, whereas heart glycogen concentration decreased with increasing EBVps (P = 0.005). The percentage of carcass fat increased with increasing EBVps (P = 0.05). Relationships of relative liver weight, relative small intestinal weight, and liver and muscle glycogen levels with EBVps were absent after adjustment for differences in cortisol levels between litters. The observed differences in fetal development in relation to EBVps suggest a higher degree of physiological maturity in litters with high EBVps. Differences in fetal cortisol most likely accounted for most of these maturational differences. The results imply that selection for improved piglet survival will lead to slightly smaller piglets that nevertheless have an improved ability to cope with hazards during birth or within the first days of life.

Animals↗

PubMed2002

Studies of 50 Hz circularly polarized magnetic fields of up to 350 microT on reproduction and embryo-fetal development in rats: exposure during organogenesis or during preimplantation.

Groups of mated female Sprague-Dawley rats were simultaneously exposed to 0 (sham exposed), 7, 70, or 350 microT (rms) circularly polarized 50 Hz magnetic fields (MF) for 22 h/day on gestational day 8-15, the period of rat fetal organogenesis (organogenesis study) or from day 0 to day 7 of gestation, the rat preimplantation period (preimplantation study). Developmental toxicity was assessed on gestational day 20. Identical experiments were repeated to confirm reproducibility of both studies. In both studies, statistically significant differences between exposed and sham exposed animals were observed in several measured parameters; however, these differences only appeared in one, but not both replicate experiments and generally at only an isolated exposure level. Because these differences were not reproducible and did not show a dose response relationship, they were not considered related to MF exposure. In the organogenesis study, lower kidney weights of dams were seen at 70 and 350 microT in Experiment 1. Lower dam liver weights and lower mean body weights of viable female and male fetuses were seen at 70 microT in Experiment 2. Otherwise, there were no differences in these parameters or in group means for fetal loss after implantation, number of viable fetuses, fetal body weight and sex ratio, incidences of external, visceral, and skeletal abnormalities or variations, or tissue abnormalities after histopathological examination. In the preimplantation study, dam health and indices for reproduction and embryo-fetal development, including pre or postimplantation loss, number and body weight of live fetuses, and sex ratio, external, skeletal abnormalities and variations, and skeletal ossification did not differ. Dam inorganic phosphorous concentration at 350 microT was elevated in one experiment and depressed in another. In one experiment, visceral abnormalities, primarily thymic remnant in neck and accessory liver lobe, were increased in the 7 microT group. Based on these results from two studies, we conclude that circularly polarized 50 Hz MF exposure of up to 350 microT during the fetal organogenesis or during the preimplantation period does not affect reproduction and embryo-fetal development in Sprague-Dawley rats.

Animals↗

PubMed1988

Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.

Whereas the greatest relative increase in body mass occurs during the third trimester of fetal life, the source of the cholesterol that supports this growth is uncertain. These studies used [3H]water and 125I-cellobiose-labeled low density lipoproteins to quantitate absolute rates of cholesterol acquisition in vivo by the fetus of the rat. Preliminary studies demonstrated that [3H]water administered intravenously to the mother rapidly equilibrated with the body pool of water in the fetus and that 22-microgram atoms of H from the water pool were incorporated into each micromole of newly synthesized cholesterol. After administration of [3H]water to pregnant rats, the rates of sterol synthesis per 100 g of whole body weight were severalfold higher in the fetus than in the dams. Individual organs of the dam such as the liver, however, had much higher synthetic rates than those in the fetus. When maternal hepatic cholesterol synthesis was suppressed by cholesterol feeding, newly synthesized cholesterol disappeared from the maternal blood yet there was essentially no change in the rate of appearance of newly synthesized sterol in the fetus, placenta, and fetal membranes. The placenta did take up low density lipoproteins at rates equal to about one-third of that seen in the maternal liver, but none of the apolipoprotein or cholesterol was transferred to the fetus. These studies indicate that the rat fetus receives little or no cholesterol from the mother but, rather, satisfies its need for cholesterol during fetal development through local synthesis. Furthermore, the fetal membranes appear to be an important site for sterol synthesis in the fetal compartment.

Animals↗

PubMed1989

Expression pattern of the FGF-related proto-oncogene int-2 suggests multiple roles in fetal development.

The FGF-related proto-oncogene int-2 is implicated in mouse embryogenesis, since it is expressed in specific tissues during gastrulation and neurulation (Wilkinson et. al. 1988). Here, we describe the expression of this gene during subsequent fetal development, int-2 transcripts are restricted to Purkinje cells in the cerebellum and to regions of the developing retina containing early-stage differentiating cells. This high level expression is not detected in the mature cerebellum or retina. In addition, int-2 RNA is detected in the mesenchyme of the developing teeth and in sensory regions of the inner ear. This complex and dynamic pattern suggests multiple roles of this proto-oncogene during fetal development of the mouse.

Animals↗

PubMed1988

Thymocyte subpopulations during early fetal development in the BALB/c mouse.

Phenotypic analysis of thymocytes during murine fetal development may be of use in determining the pathways of thymocyte differentiation. The expression of the functionally significant molecules Lyt-2 (CD8), L3T4 (CD4), and the TCR has already been described. However, mAb specific for several other murine lymphocyte surface markers are now available and, although these have been used to characterize adult thymocytes, a detailed analysis of fetal thymocytes with these antibodies has not previously been undertaken. In this study, we have used mAb specific for Thy-1, J11d, Pgp-1, and the IL-2R, in addition to those for Lyt-2 and L3T4, to identify subpopulations of early fetal thymocytes. By using two-color flow cytometric analysis of cells obtained from fetal thymuses on sequential days of gestation, we have been able to follow the development of various subpopulations through early fetal ontogeny. Our data indicate that the earlier thymocytes are found in the J11d+/Pgp-1+ subset which is abundant at fetal day 14 but constitute a numerical minority by day 16.

Aging↗

PubMed1985

The effect of acute maternal toxicity on fetal development in the mouse.

The effects of acute alterations in maternal health status upon fetal development were assessed following exposure of pregnant CD-1 mice on day 8 of gestation to one of ten chemicals at doses calculated to exert either a low or a moderate degree of maternal lethality. The dams were killed on day 18 of gestation, and the fetuses were examined by routine teratological techniques. The chemicals were cacodylic acid, caffeine, deltamethrin, dinoseb, ethylene bisisothiocyanate sulfide (EBIS), endrin, guthion, kepone, sodium salicylate, and toxaphene. Three (cacodylic acid, EBIS, and kepone) produced dose-related increases in the incidence of dams with completely resorbed litters. Prenatal mortality in litters that contained live fetuses at term was elevated only for one chemical (cacodylic acid). Fetal weight was reduced in three instances (cacodylic acid, endrin, and guthion), while the incidence of terata was markedly elevated for two (cacodylic acid and kepone). For two other chemicals (endrin and sodium salicylate), a low incidence was found of defects that were similar to defects induced by those chemicals in other species. These effects appear to be chemospecific in nature and not the result of some indirect maternal action. Thus, maternal health status, as measured by the incidence of lethality in the treated groups and by the magnitude of maternal weight gain in surviving females, presents no simple explanation for many manifestations of fetal toxicity. However, for seven chemicals (excluding deltamethrin, EBIS, and kepone) an increased incidence of supernumerary ribs was observed. For three of these seven chemicals (caffeine, dinoseb, and toxaphene), supernumerary ribs was the only observed fetal effect. There was a significant linear inverse relationship between maternal weight gain during gestation and the incidence of extra ribs in the treated groups compared to their respective controls. Under the experimental conditions of this study, it appears that the incidence of supernumerary ribs increased in response to a nonspecific maternal toxicity.

Abnormalities, Drug-Induced↗

PubMed1975

Experimental studies on the effects of aluminum on pregnancy and fetal development.

The effects of aluminum on pregnancy and fetal development were investigated. Aluminum in the form of aluminum chloride was administered intraperitoneally to pregnant rats at different dose-levels and at different stages of gestation. A high incidence of maternal death followed treatment with high dose-levels of the substance. Maternal weight gain during the entire gestational period was less in treated animals, compared to controls. In many cases, maternal liver was severely damaged as a result of the treatment. The offspring of mothers treated with aluminum chloride showed significant growth retardation as well as skeletal defects. In addition the incidence of fetal deaths and resorption was significantly increased.

Abnormalities, Drug-Induced↗

PubMed1992

Expression of CYP2E1 during human fetal development: methylation of the CYP2E1 gene in human fetal and adult liver samples.

The expression and regulation of cytochrome P450IIE1 (CYP2E1) in adult and fetal human liver has been investigated. Three mRNA transcripts of 1.9, 2.7 and 3.8 kb were detected in all adult liver samples after hybridization with a full length cDNA to CYP2E1 whereas no expression was detected in 12 fetal liver samples studied. Similarly, expression of CYP2E1 was not detected in 11 placental samples (10-17 weeks gestational age) or in two full-term placental samples. CYP2E1 expression was not detected in fetal liver, kidney, lung, placenta (18 weeks gestational age) or liver (6 weeks gestational age) obtained at termination of pregnancy where maternal alcohol abuse had been established. Southern blot analysis of the cytosine methylation status of the CYP2E1 gene revealed substantial methylation of the 3' region of the gene in both adult and fetal human liver samples. No differences were observed in the methylation pattern of fetal liver samples between the gestational ages 12 and 17 weeks. Two small DNA fragments detected by the 5' end of the CYP2E1 cDNA were cleaved by the restriction enzyme HpaII in adult liver DNA but not in the fetal liver DNA samples. Methylation of specific 5' residues in the CYP2E1 gene may be responsible for the lack of transcription of the CYP2E1 gene in fetal liver.

Alcoholism↗

PubMed2005

Fetal development of the female external urinary sphincter complex: an anatomical and histological study.

PURPOSE: We investigated the fetal development of the smooth (lissosphincter) and striated (rhabdosphincter) female external urinary sphincter. Growth and organization of the muscle fibers around the urethra and morphological modifications due to the development of the vagina were analyzed in detail. MATERIALS AND METHODS: A total of 28 human female fetal specimens were investigated in an anatomical and histological study. The sections were processed according to plastination technology. This technique allows examination of structures and organs of the small pelvis with minimal artifacts in all 3 planes. RESULTS: At gestational week 9 the primordium of the external urethral sphincter complex was observed extending along the anterior aspect of the urogenital sinus, before the development of the primitive urethra and the vaginal primordium. From 15 weeks of gestation the lissosphincter and rhabdosphincter could be identified and clearly distinguished. After 20 weeks of gestation both elements acquired an omega-shaped configuration with a narrow posterior connective tissue raphe that was constantly present, fixing both components to the ventral vaginal wall. Both muscles were mainly located in the middle third of the urethra. In the proximal third of the urethra growth of the vagina led to disappearance of the striated muscle fibers of the rhabdosphincter, whereas the lissosphincter seemed to intermingle with the internal layer of the detrusor musculature of the bladder. CONCLUSIONS: The important morphological characteristics of the female adult rhabdosphincter and lissosphincter (omega-shaped configuration, presence of a narrow connective tissue raphe posteriorly and maximum thickness in the middle third of the urethra) are already evident early in fetal development and do not evolve during postnatal growth or by the influence of sex hormones.

Female↗