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Human maternal uniparental disomy for chromosome 16 and fetal development.

Two severely growth-retarded fetuses found to have maternal uniparental disomy (UPD) for chromosome 16 and trisomy 16 placental mosaicism both had an unfavourable outcome. Antenatally, the first case was complicated by an unexplained raised maternal serum alpha-fetoprotein concentration, preterm premature rupture of the membranes, and growth retardation detectable at 21 weeks' gestation, whilst the other had an unexplained raised maternal serum human chorionic gonadotrophin level, a two-vessel cord on ultrasound, and cessation of growth at 25 weeks. At post-mortem, both babies had an imperforate anus. Fetal maternal UPD may explain the poor outcome that occurs in some cases of confined placental mosaicism for chromosome 16 and is also associated with specific fetal abnormalities.

Adult↗

Maternal toxicity, embryolethality and abnormal fetal development in CD-1 mice following one oral dose of T-2 toxin.

An experiment was undertaken to determine the teratogenic effect of oral administration of T-2 toxin, a trichothecene mycotoxin. Firstly, a dose response study using 0, 0.5, 1.0, 2.0, 3.0, 3.5 and 4.0 mg/kg T-2 toxin in propylene glycol, on day 9 of pregnancy, was undertaken. Maternal deaths and toxicity was noted in the 4.0 and 3.5 mg/kg groups post-toxin administration. These groups gained less weight throughout gestation than the rest of the groups, because no fetuses were found in the 4.0 mg/kg group and the 3.5 mg/kg group had significantly fewer fetuses than the remaining groups. The total fetal weight was similar among all groups with fetuses, and normal sex ratio of offspring was seen. More major and minor defects were seen in the 3.0 mg/kg T-2 toxin treated group than any other group. Secondly, a day response trial using a single dose of 3.0 mg/kg T-2 toxin given on either days 6, 7, 8, 10, 11 or 12 of gestation was undertaken. Maternal mortality, with placental hemorrhage, was observed. Fetal loss was greater in the T-2 toxin treated groups than in the starved controls. The greatest number of dead term fetuses was seen in mice treated on day 9 of gestation. Normal sex ratios were present in the offspring. Major skeletal defects were more numerous in mice treated on day 7 of gestation, whereas minor defects, retardations and variants were more common in mice treated on day 8. It was concluded that a single oral dose of T-2 toxin in propylene glycol is primarily maternotoxic and embryolethal, and that defective development was possibly secondary to maternal toxicity.

Animals↗

Effects of concurrent exposure to 3-methylcholanthrene and vitamin A on fetal development in rats.

To investigate the effect of the environmental pollutants, polycyclic aromatic hydrocarbons (PAHs), on retinoic acid-induced teratogenesis, all-trans-retinoic acid (RA) dissolved in corn oil (120 mg/kg) was administered orally to pregnant rats at the 11th day of gestation with and without the prior intraperitoneal treatment with 10 mg/kg 3-methylcholanthrene (3-MC) for 3 days. Dams were killed on the 20th day of pregnancy. The examinations of fetuses revealed that 3-MC barely enough to cause induction of P-450 in pregnant dams had profound embryo-toxic effects: the fetal resorption amounted to approximately 60% of total number of implantations. The fetuses survived weighed less than the control fetuses. All of RA-treated mothers had fetuses with abnormalities, and the main malformations were absence of tail (100%), caudal and sacral malformations (100%), and cleft palate (42%). Pregnant dams received both 3-MC and RA had a reduced severity of tail anomaly (33%), while the rest, 67%, had short vestigial tail. Caudal and sacral malformations were detected but at a milder degree. We did not observe cleft palate in this group. The concurrent treatment of dams with 3-MC and RA led to an increased inducibility of cytochrome P-450 and subsequently, CYP1A1 dependent enzyme activity higher than those observed after the injection of 3-MC alone. UDP-glucuronyl-transferase activity was also markedly induced in concurrent 3-MC and RA group higher than that in 3-MC alone. We suggest that the induction of P-450 and alteration of metabolic enzyme activities may play an important role in reducing the teratogenic potency of RA. However, RA-treatment did not retard the embryo-toxic effect of 3-MC but rather potentiated.

Abnormalities, Drug-Induced↗

Histological study of the fetal development of the human acetabulum and labrum: significance in congenital hip disease.

Seventy-four acetabula from a total of 140 normal human fetuses, obtained from abortions and deaths in the prenatal period, were used. The fetuses ranged from 9.1 to 40 cm in crown-rump length and are believed to be between 12 weeks and term. Acetabula were decalcified embedded in paraffin or celloidin, sectioned, and stained using conventional histologic techniques. Sections from the superior one-quarter of the acetabulum were examined for the initial appearance and later spread of osseous tissue. Throughout the fetal period bone was present only in the floor of the acetabulum and did not extend into the socket walls. Ossification was detected initially more posteriorly in the socket floor, and at all ages, ossification was more prominent on the ischial side of the socket. Despite the lack of osseous tissue a well-formed hyaline cartilage socket was present. The fetal labrum was composed of fibrous tissue with the density of fibers increasing with age. Typical-appearing chondrocytes were detected at only the inner articular margin of the labrum. Contributing from one-fifth to one-half of the socket depth, the labrum may play a greater role in containing the femoral head at birth than it does in the mature joint. In seven acetabula, from joints that were neither subluxated nor dislocated, an area of areolar tissue with capillaries was detected at the hyaline cartilage-labrum junction. Such defects may weaken the labrum and contribute to neonatal hip instability.

Acetabulum↗

Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure.

BACKGROUND: A review of the scientific literature suggested the occurrence of low-level incidences of ventricular septal defect (VSD) and midline defect (MD) in rat fetuses and diaphragmatic hernia (DH), VSD, and MD in rabbit fetuses after maternal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin, an NSAID that irreversibly inhibits cyclooxygenase 1 (COX-1) and COX-2, induces DH, VSD, and MD when administered as one dose during the sensitive periods of development in rats. Unlike aspirin, other NSAIDs, including selective COX-2 inhibitors, reversibly inhibit COX activity. To evaluate whether the dysmorphogenesis observed after maternal NSAID exposure correlates with COX-1 or COX-2 inhibition, a series of compounds with different capacities to inhibit COX-1 and COX-2 were administered to pregnant rats and rabbits during the sensitive period for heart development and midline closure. METHODS: The compounds selected, ranked from the most COX-2 selective to the most COX-1 selective based onCOX inhibition in a human whole blood assay, were CJ-19,209, meloxicam, diclofenac, diflunisal, ibuprofen, and ketorolac. Rat dams were treated on gestation days (GDs) 9 and 10, and rabbit does were treated on GDs 9, 10, and 11. The doses selected for evaluation represented the maximum tolerable dose for the compound, with the exception of CJ-19,209, which was dosed at 1000 mg/kg. Fetuses were collected by cesarean section on GDs 21 and 29 for rats and rabbits, respectively, and all fetuses were examined for external and visceral developmental anomalies. RESULTS: In rabbits, diflunisal induced DH, VSD, and MD (omphalocele) and single incidences of VSD and MD (gastroschisis) were noted in the ibuprofen group; no other developmental findings were associated with treatment. In rats, ibuprofen, diflunisal, and ketorolac induced increases in the incidence of VSD. In general the induction of developmental defects was associated with compounds that selectively inhibit COX-1 or have a high ratio of COX-1 to COX-2 inhibition. CONCLUSIONS: Inhibition of COX-1 may be involved in the disruption of heart development, whereas the selective inhibition of COX-2 (as assessed with CJ-19,209) appears to have no effect on heart development and midline closure in rats and rabbits.

Abdominal Wall↗

Influence of n-hexane on embryo and fetal development in mice.

Pregnant outbred albino mice (CD-1) received n-hexane once daily be gavage at doses up to 2.20 g/kg/day on days 6-15 of gestation. Other pregnant mice received higher hexane doses (up to 9.90 g/kg/day), employing a three times a day injection schedule. At the lower, once-daily doses only one dam died and no teratogenic effects occurred. Higher hexane doses (t.i.d.) were toxic: 2 of 25 dams treated with 2.83 g/kg/day, 3 of 34 treated with 7.92 g/kg/day and 5 of 33 treated with 9.90 g/kg/day died. At the 7.92 and 9.90 g/kg/day doses, the average fetal weight was significantly (p less than 0.05) reduced, but the incidence of malformations in treated and vehicle (cotton-seed oil) control groups did not differ significantly. Thus, n-hexane was not teratogenic even at doses toxic to the dam.

Animals↗

Cryptic T cell epitopes in polymorphic immunoglobulin regions: evidence for positive repertoire selection during fetal development.

The adult T cell repertoire is the result of positive and negative intrathymic selective processes. Since non-self antigens are not present in the thymus, self peptides are believed to play a role in the thymic T cell selection. T cell lines raised against a peptide from the second complementarity-determining region (CDR2) of the S107 germ-line immunoglobulin (Ig) do not respond to the intact Ig, indicating that in adult animals this CDR2 epitope is cryptic in the context of intact S107 Ig. To show that the response to self Ig peptide is the result of positive selection, the fetal expression of the S107 germ-line Ig was suppressed by maternal anti-idiotype (Id) injection. Id S107-suppressed mice responded poorly to the CDR2 peptide, indicating that S107 Ig selects positively T cells responding to a polymorphic self epitope. Cross-reactivity of cryptic self Ig with non-self epitopes could be a mechanism to increase the T cell repertoire for foreign antigens.

Amino Acid Sequence↗

Blood-cerebrospinal fluid transfer of plasma proteins during fetal development in the sheep.

1. The penetration of human and sheep plasma proteins from blood into c.s.f. of sheep fetuses (57-86 days gestation) has been studied. The proteins were injected intravenously via cotyledonary vessels. After different time periods the c.s.f. concentrations of marker proteins were estimated by radioactive counting of iodinated human or sheep proteins or by immunoassay of human proteins.2. Several proteins of similar molecular size penetrated into c.s.f. to a different extent in 60 day fetuses. The steady-state c.s.f.: plasma ratios were about 15% for human AFP, 10% for human transferrin and sheep albumin, 7% for human alpha(1)-antitrypsin, and 5% for human albumin. In older fetuses the penetration of protein from blood into c.s.f. was much reduced and no evidence for differential penetration of different proteins was found.3. The penetration of human AFP, transferrin and sheep albumin from blood into c.s.f. was greater than can be accounted for by passive diffusion.4. The results of this paper are discussed in relation to those of the preceding paper on the identification and quantification of proteins in fetal c.s.f. and plasma. The hypothesis is put forward that the choroid plexus of the immature (60 days and less) sheep fetus contains a mechanism for the transcellular transfer of plasma proteins which may be selective in nature and of importance for some aspects of brain development.

Albumins↗

Effects of cyclosporin A on fetal development in the rat.

The fetotoxicity of cyclosporin A (CsA) was examined in multiparous Sprague-Dawley rats given the drug (25 mg/kg/day) during different phases of gestation, the effects on the outcome of pregnancy being ascertained on day 19. CsA given from days 1 to 7 caused a small but significant reduction in litter size, with no significant increase in the number of resorptions. When the drug was administered from day 8 to 14 there was no significant change in litter size, but a very striking increase in the incidence of resorptions. This fetotoxic effect was also evident but less marked when the drug was withheld until day 15. Reduction in fetal weight was only present in the group given CsA from days 8 to 14. In surviving fetuses the presence of focal decidual necrosis was more frequent in mothers receiving CsA, suggesting a possible mechanism whereby CsA may mediate its fetotoxic effects.

Animals↗

Neurohistochemical evaluation of adrenergic innervation in fetal development of the white rat.

Physiological development of adrenergic innervation, an important component of trophic and homeostatic regulation in the mammals was estimated. Our research is directed to evaluate both exo- and endogenous factors contributing to its impairment. The present investigation was carried out on 32 rat fetuses from three various 7-day periods of gestation. Histochemical studies included reactions to catecholamines according to Falck and Owman, and silver staining with AgNO3 according to the Bielschowsky-Gros method. Adrenergic innervation was examined in all fetal body regions, with a special reference to the pelvis. Catecholamines distribution and accumulation in plexuses, ganglia, neurons and chromatophilic cells, as well as serotonine content in mast cells were analyzed. It was found that in the initial period of gestation noradrenaline is absent. In the third week of gestation, the neurotransmitter's accumulation takes place to subsequently decrease gradually until the end of gestation. From this stage synaptic connections of adrenergic innervation with chromatophilic and mast cells could be detected.

Adrenergic Fibers↗

[A study on the constitutional change of taurine and other free amino acids during the fetal development (author's transl)].

In human pregnancy, maternal and umbilical blood of the 22nd week of pregnancy and of the parturition were submitted to the analysis of total free amino acids (FAA) by amino acids analyzer. In addition, the neonatal blood was also submitted until 9 days after birth. The content of FAA in umbilical vein was higher than that of the maternal blood and it decreased at the parturition. However, the content of taurine (T) kept extremely higher level than other amino acids until term and it decreased to the normal level at 9 days after birth. In pregnant rats on day 17, 18 and 19 of gestation, the content of FAA in umbilical vein and fetal artery were 5800-7000 micrograms/dl and 5700-6250 micrograms/dl, respectively. They were two fold higher than that of maternal value. In amniotic fluid, FAA was 4100 micrograms/dl on day 18 and 8850 micrograms/dl on day 20. On the contrary, the content of T in maternal blood on day 18 was the highest value (360 micrograms /dl), and decreased to the half of the value on day 20. T in carotid artery on the same day was 1150 micrograms/dl, but it decreased to 280 micrograms/dl on day 20. In amniotic fluid, it was almost constant in the range of 380-400 micrograms/dl. When the pregnant rat was stressed by starvation, FAA was increased in both umbilical and fetal blood but it was almost constant in amniotic fluid. T was increased both in maternal and fetal blood. When the degree of starvation, T value also increased in fetal blood. From these data, we discussed on the possible mechanism of the production of T during pregnancy and after birth.

Amino Acids↗

Prenatal selection and fetal development disturbances occurring in carriers of G6PD deficiency.

The incidence of spontaneous abortions in women with glucose-6-phosphate dehydrogenase (G6PD) deficiency was studied. In 78 families where the wife was a heterozygous carrier of G6PD deficiency the percentage of unsuccessful pregnancies with spontaneous abortions occurring in the first trimester was higher (21.7%, calculated from 258 pregnancies) than in the control group (9.3%, calculated from 678 pregnancies.

Abortion, Spontaneous↗

Insulin receptors in the developing fetal lung.

Fetal lung insulin receptor numbers and affinities were studied in rat pregnancies from 15 to 22 days gestation. Insulin receptor binding capacities were found to increase six-fold from approximately 100 fmoles insulin bound/mg lung DNA at 15 days gestation to approximately 600 fmoles bound/mg DNA at 22 days gestation. However, the affinity constants of the receptors were unchanged during this same period (high affinity, 1.9 +/- 0.4 S.E. and low affinity, 0.03 +/- 0.01 S.E.). The results suggest that the lung may become increasingly more sensitive to insulin as development progresses.

Animals↗

Chemical changes in human skeletal muscle during fetal development.

Skeletal muscle samples obtained from 6 nonmacerated stillborn fetuses and 18 liveborn neonates who died within 24 h of birth were analyzed. Gestational age ranged from 19 to 44 weeks. 17 neonates were normally grown (NG) and 7 were intrauterine growth retarded (IGR). Chemical components were expressed in milliliters or grams per 100 g of tissue. As gestation progressed, total water (TW) and extracellular water (ECW) contents decreased, intracellular water (ICW) content and nitrogen content remained stable, and intracellular/total water ratio (ICW/TW) increased. Fat content was negligible throughout gestation. Compared to their NG peers, IGR neonates had muscle with decreased ECW and increased ICW/TX, whereas TW, ICW and nitrogen contents were similar. These preliminary data provide a basis for further studies of muscle composition and for discussion of existing hypotheses on the effect of fetal growth retardation upon body composition.

Body Composition↗

Mechanisms of action of drugs of abuse on the developing fetal brain.

The consequences of public health of the acquisition and use of drugs of abuse have been well demonstrated. Despite intense effort, however, progress has been slow in recent years in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. The use of animal models allows the investigator to determine the specific biological contributions of prenatal exposure to drugs of abuse on neurodevelopmental outcome while controlling for covariates that have confounded clinical studies, such as altered nutrition in pregnancy, suboptimal rearing environment of the young, and availability of drug and nondrug stimulation to the offspring. This article selectively reviews the preclinical literature on the gestational effects of drugs of abuse with particular emphasis on cocaine, ethanol, and the opiate narcotics. Mechanisms of drug action on the mature and developing brain are summarized. A model of developmental impact on the brain regions underlying drug-induced reward and reinforcement and its potential postnatal importance is presented.

Alcoholism↗

Antisense transcription of a murine FGFR-3 psuedogene during fetal developement.

In a search for new protein tyrosine kinases (PTKs) in early hemopoietic cells, we have identified a sequence closely related to the Fibroblast Growth Factor Receptor (FGFR) family. A cDNA isolated from a mouse embryo library was 89% identical to FGFR-3 in both its coding and 3' untranslated regions. However, the region homologous to exons 5 to 9 of FGFR-3 was missing. In addition, the ORF was interrupted by several stop codons and frame shifts, indicating that this sequence is not functional. These transcripts were therefore copied from a novel FGFR-3 pseudogene, that we called psiFGFR-3. Partial analysis of this gene showed the absence of introns, which is a characteristic feature of a processed pseudogene. psiFGFR-3 gene was localized on Chromosome 1H4-6. Its transcription was shown to be antisense and its expression was restricted to fetal tissues. These results indicate that psiFGFR-3 has been inserted in Chromosome 1 in antisense orientation close to a heterologous promoter.

Alternative Splicing↗

The fetal development of the human uterine cervix from the 12th to the 31st postmenstrual week as revealed by scanning electron microscopy. Anatomical and clinical correlations.

To clarify the differentiation of the human uterine cervix, fetuses of the 12th, 15th, 18th, 20th, 21st, 22nd, and 31st postmenstrual week were studied by Scanning Electron Microscopy. At the 12th week the endocervical epithelium consisted of microvillous cells, often showing single cilia and anlages of tubular glands. At the 15th week the cervical canal was entirely formed and its surface cells appeared columnar. At the 18th week these cells were replaced by flat or slightly raised cells, provided with thin microplicae. At the 20th week the endocervical epithelium appeared pseudostratified with higher, apically-convex and shorter basal cells; glands developed in form of tubular invaginations of the luminal epithelium. At the 21st week in the lower part of the endocervix polymorphic, globose cells with short and stubby microvilli and others elongated, having short microplicae, were observed. These latter likely corresponded to the so-called columnar cells undergoing squamous metaplasia. Among microvillous and/or metaplastic cells, a number of apoptotic cells, as globose elements with a ruffled and invaginated surface, were also noted. At the 22nd week evident plicae palmatae were found, covered by microvillous secreting cells. These showed smooth bulged apices releasing droplets by a "micro-apocrine" mechanism. These features increased at the 31st week, when many droplets were noted also around the mouth of the cervical glands. Only at this phase of development fully ciliated cells were found often contacting secretory material. Mature squamous exfoliating cells with complex microplicae covered an hypertrophied portio vaginalis. The squamous cells extended toward a squamo-columnar junction in form of flat, tongue-like projections. Their tips consisted of immature squamous metaplastic cells, which were endocervical columnar progressively becoming elongated elements, exhibiting short microvilli. The above features are rather similar to those occurring during the adult reproductive age. Therefore, it might be hypothesized that, during pregnancy, a common gestational hormonal background may induce somewhat similar morpho-dynamic processes in the cells and tissues of the fetal reproductive tract mimicking what occurs in the adult female.

Cervix Uteri↗