Adaptive-filtering of trisomy 21: risk of Down syndrome depends on family size and age of previous child

The neonatal incidence rate of Down syndrome (DS) is well-known to accelerate strongly with maternal age. This non-linearity renders mere accumulation of defects at recombination during prolonged first meiotic prophase implausible as an explanation for DS rate increase with maternal age, but might be anticipated from chromosomal drive (CD) for trisomy 21. Alternatively, as there is selection against genetically disadvantaged embryos, the screening system that eliminates embryos with trisomy 21 might decay with maternal age. In this paper, we provide the first evidence for relaxed filtering stringency (RFS) to represent an adaptive maternal response that could explain accelerating DS rates with maternal age. Using historical data, we show that the proportion of aberrant live births decrease with increased family size in older mothers, that inter-birth intervals are longer before affected neonates than before normal ones, and that primiparae exhibit elevated levels of DS incidence at higher age. These findings are predicted by adaptive RFS but cannot be explained by the currently available alternative non-adaptive hypotheses, including CD. The identification of the relaxation control mechanism and therapeutic restoration of a stringent screen may have considerable medical implications.     

Zur Ätiologie des Mongolismus

Beside the rare cares of translocation mongolism, Down syndrome is caused by meiotic malsegregation of chromosomes, No. 21. The meiotic error can take place in both sexes and was found twice as frequently in the female as in the male. The same 2:1 ratio was found concerning nondisjunction in the first and in the second meiotic division. The rate of meiotic errors, which occur at random, is largely dependent on age; this tendency is more pronounced in oogenesis than in spermatogenesis. The results of prenatal chromosomal diagnosis indicate that the recurrence risk of trisomy 21 is not above the age-dependent average.     

Toxic metals in amniotic fluid and altered gene expression in cell-free fetal RNA

Both exposures to toxic metals, as well as deficiencies in essential metals, during pregnancy has been linked to a variety of negative reproductive outcomes. The exact etiologies of such outcomes and the effects of fetal exposure to these metals are largely unknown. Therefore, the ability to assess levels of these elements is critical to determining the underlying causes of such conditions and the effects that both essential and nonessential metals have on fetal development. Thus, using cell-free fetal RNA from amniotic fluid, we set out to measure the association between amniotic fluid levels of toxic and essential metals and fetal gene expression. We find that arsenic was associated with increased expression of 3 genes known to play roles in both birth-related and reproductive effects. The results highlight the potential for detrimental health effects of prenatal metals exposure and the potential to identify biomarkers of environmental exposure during this critical developmental period.     

Genome-wide abnormalities in embryos: Origins and clinical consequences

Ploidy or genome-wide chromosomal anomalies such as triploidy, diploid/triploid mixoploidy, chimerism, and genome-wide uniparental disomy are the cause of molar pregnancies, embryonic lethality, and developmental disorders. While triploidy and genome-wide uniparental disomy can be ascribed to fertilization or meiotic errors, the mechanisms causing mixoploidy and chimerism remain shrouded in mystery. Different models have been proposed, but all remain hypothetical and controversial, are deduced from the developmental persistent genomic constitutions present in the sample studied and lack direct evidence. New single-cell genomic methodologies, such as single-cell genome-wide haplotyping, provide an extended view of the constitution of normal and abnormal embryos and have further pinpointed the existence of mixoploidy in cleavage-stage embryos. Based on those recent findings, we suggest that genome-wide anomalies, which persist in fetuses and patients, can for a large majority be explained by a noncanonical first zygotic cleavage event, during which maternal and paternal genomes in a single zygote, segregate to different blastomeres. This process, termed heterogoneic division, provides an overarching theoretical basis for the different presentations of mixoploidy and chimerism.     

Fetal akinesia/hypokinesia sequence: Prenatal diagnosis and intra-familial variability

Intrauterine fetal movement plays a key role in normal embryonic and fetal development (Moessinger, 1983). When movement is absent or decreased, abnormal development takes place which can be appreciated in newborns and/or fetuses with the fetal akinesia/ hypokinesia sequence. This sequence is caused by a number of heterogeneous entities which result in decreased fetal movements by the action of intrinsic or extrinsic factors. Prenatal diagnosis of the akinesia/hypokinesia sequence may be possible during the second trimester through the use of real-time ultrasonographic evaluation of fetal movement. We report a family with three consecutive affected pregnancies in which the prenatal presentation of this sequence varied. Based on the phenotypic findings of the three affected fetuses, we believe that although they superficially resemble those features found in the New–Laxova syndrome, they are probably affected with a distinctly different lethal form of akinesia/ hypokinesia transmitted in an autosomal recessive fashion.     

Embryonic and fetal globins are expressed in adult erythroid progenitor cells and in erythroid cell cultures

The understanding of human hemoglobin ontogeny during development is of biological and clinical importance. Molecular and immunocytological techniques were used to study the expression of embryonic zeta (ζ), epsilon (ε), and fetal gamma (γ) globin genes in newborn cord blood, peripheral blood from men, pregnant and non-pregnant women, and in vitro mononuclear cell cultures. We have shown that embryonic and fetal globin mRNA and peptides are expressed in cultured erythroid cells and in circulating blood cells from newborns, adult non-pregnant women and from men. The findings suggest that during erythroid cell differentiation in newborns and adults, there is a transient recapitulation of sequential globin chain expression as found during embryonic and fetal development. Furthermore, these findings underscore the need for caution in using embryonic and fetal globin chains as markers to identify erythroid cells of fetal origin in maternal circulation for prenatal diagnosis. Copyright © 2001 John Wiley & Sons, Ltd.     

Fetal behaviour in growth retardation: Its relationship to fetal blood flow

The fetal behaviour of asymmetrical growth retarded fetuses was compared with that of a control group of healthy fetuses. Fetuses underwent simultaneous cardiotocographic and echographic examinations for two consecutive hours at 36–38 weeks of gestation. The distribution of gross fetal body movements, fetal breathing movements and fetal eye movements was analysed during the different fetal heart rate patterns. Furthermore, the incidence and organization of fetal behavioural states was investigated. The degree of vascular peripheral resistance was also evaluated by means of pulsed doppler ultrasonic equipmznt. Growth retarded fetuses were divided into two groups on the basis of the presence or absence of end diastolic flow in the fetal thoracic descending aorta. Growth retarded fetuses showed a delay in the integration of behavioural patterns and a lower coincidence of behavioural states. These findings are particularly evident in the fetuses with a severe increase of peripheral vascular resistance (absence of end diastolic flow in descending aorta). Thus, we suggest that a delay in central nervous system development is present in asymmetrical growth retarded fetuses and that there is a possible relationship of this delay to the degree of peripheral vascular resistance.     

Evidence of a second gamete fusion after the first cleavage of the zygote in a 47,XX, + 18/70,XXX, + 18 mosaic. A remarkable diploid-triploid discrepancy after CVS

A 70,XXX, +18 karyotype was found by chorionic villus sampling, while the fetal fibroblast culture of the affected fetus revealed a 47,XX,+ 18 karyotype. From several possible mechanisms, we assume that a second gamete fusion occurred after the first cell division of the zygote. According to this interpretation, the mosaicism arose in very early pregnancy (at the two-cell stage). This discrepancy can therefore be explained by selection pressure, due to the differentiation processes in the embryonic tissues.     

Fetal and maternal progenitor cells in co-culture respond equally to erythropoietin

To explore potentially selective growth conditions for fetal cells in cultures from the blood of pregnant women, we investigated if fetal and adult erythroid progenitors with different hemoglobin expression programs are differentially responsive to erythropoietin (EPO). Co-cultures of clonogenic cells from 12-week fetal and adult peripheral blood were established, and the development of erythropoietic cells was monitored using flow cytometric profiles of correlated cellular contents of fetal and adult hemoglobin (HbF and HbA, respectively). Adult nucleated red cells were classified as F+A−, F+A+ or F−A+. All fetal cells were F+A−. The population of F+A− cells was flow-sorted and fetal cells were identified by fluorescence in situ hybridization (FISH) using chromosome-specific probes. Delayed EPO addition revealed that all types of erythroid cells entered the EPO-dependent phase with similar kinetics, beginning at about Day 4. The data suggest that fetal and adult erythroid stem/progenitor cells have the same initial maturation kinetics in culture independent of their hemoglobin chain expression program. Fetal and adult cells with different hemoglobin profiles also showed similar EPO dose–response curves, determined for different intervals during the first 2 weeks of culture. Thus, the kinetics of entry into the phase of EPO dependence, as well as the sensitivity to EPO at various stages of development, are essentially the same for erythropoietic progenitor cells derived from adult and early fetal blood, which rules out the possibility of using the timing or concentration of EPO for the selective growth of fetal cells from the blood of pregnant women. Copyright © 2001 John Wiley & Sons, Ltd.     

Noninvasive prenatal testing creates an opportunity for antenatal treatment of Down syndrome

Trisomy 21 (T21) is the most common autosomal aneuploidy that is associated with intellectual disability. It is the focus of many prenatal screening programs across the globe. Pregnant women who receive a prenatal diagnosis of T21 in their fetus currently have the option of continuing or terminating their pregnancy, but no fetal treatment is available. In this paper, we review compelling morphogenetic, cellular, and molecular studies that, taken together, suggest that there is an important window of opportunity during fetal life to positively impact brain development to improve postnatal neurocognition and behavior. Although substantial progress has been made in understanding the basic neurobiology of Down syndrome (DS), the majority of pre-clinical trials is currently focused on adults. There are a number of challenges in the identification and development of novel antenatal therapies for DS, including the lack of toxicity and teratogenicity for the pregnant woman and the fetus, evidence that the compounds can cross the placenta and achieve therapeutic levels, and the demonstration of clinical improvement. Preliminary experiments in mouse models suggest that prenatal treatment of DS is an achievable goal. © 2013 John Wiley & Sons, Ltd.     

Significance of septations in isolated fetal cystic hygroma detected in the first trimester

Recent reports have indicated an increased risk for fetal chromosome abnormalities, especially autosomal trisomy, in fetuses with isolated cystic hygroma, or prominent nuchal membranes, detected by ultrasonography during the first trimester. However, these reports present contradictory information regarding the prognostic significance of septations within the cystic hygroma. We evaluated, in blind fashion, 55 consecutive cases of isolatd fetal cystic hygroma detected at or before 13·9 weeks' gestation to determine the association between septations and fetal chromosome complement. Septations were associated (P<0·05) with an increased risk for fetal chromosome abnormalities. However, the incidence of chromosome abnormalities was also increased (12·5 per cent) among cases not characterized by septations. Thus, we believe it prudent to offer invasive prenatal testing to all women found to be carrying fetuses with cystic hygroma, irrespective of the presence or absence of septations.     

Alpha-fetoprotein in fetal serum,amniotic fluid,and maternal serum

In order to gain more insight into the association between alpha-fetoprotein (AFP) and fetal chromosomal disorders, especially Down's syndrome, we measured AFP in fetal serum, amniotic fluid, and maternal serum at cordocentesis. We compared the concentration and gradient of AFP in these three compartments. Our data confirm earlier findings on second-trimester fetal serum AFP concentration. The results indicate that low maternal serum AFP in pregnancies with fetal chromosomal disorders could result from an impaired fetal kidney function as well as from impaired membrane or placental passage of AFP, rather than from reduced fetal AFP production.     

Fetal brain and placental programming in maternal obesity: A review of human and animal model studies

Both human epidemiologic and animal model studies demonstrate that prenatal and lactational exposure to maternal obesity and high-fat diet are associated with adverse neurodevelopmental outcomes in offspring. Neurodevelopmental outcomes described in offspring of obese women include cognitive impairment, autism spectrum disorder (ASD), attention deficit hyperactivity disorder, anxiety and depression, disordered eating, and propensity for reward-driven behavior, among others. This review synthesizes human and animal data linking maternal obesity and high-fat diet consumption to abnormal fetal brain development, and neurodevelopmental and psychiatric morbidity in offspring. It highlights key mechanisms by which maternal obesity and maternal diet impact fetal and offspring development, and sex differences in offspring programming. In addition, we review placental effects of maternal obesity, and the role the placenta might play as an indicator vs mediator of fetal programming.     

Copy number analysis of meiotic and postzygotic mitotic aneuploidies in trophectoderm cells biopsied at the blastocyst stage and arrested embryos

Preimplantation genetic testing for aneuploidy (PGT-A) by copy number analysis is now widely used to select euploid embryos for transfer. Whole or partial chromosome aneuploidy can arise in meiosis, predominantly female meiosis, or in the postzygotic, mitotic divisions during cleavage and blastocyst formation, resulting in chromosome mosaicism. Meiotic aneuploidies are almost always lethal, however, the clinical significance of mitotic aneuploidies detected by PGT-A is not fully understood and healthy live births have been reported following transfer of mosaic embryos. Here, we used single nucleotide polymorphism genotyping of both polar bodies and embryo samples to identify meiotic aneuploidies and compared copy number changes for meiotic and presumed mitotic aneuploidies in trophectoderm cells biopsied at the blastocyst stage and arrested embryos. PGT-A detected corresponding full copy number changes (≥70%) for 36/37 (97%) maternal meiotic aneuploidies. The number of presumed mitotic copy number changes detected exceeded those of meiotic origin. Although mainly in the mosaic range, some of these mitotic aneuploidies had copy number changes ≥70% and would have been identified as full aneuploidies. Interestingly, many arrested embryos had multiple mitotic aneuploidies across a broad range of copy number changes, which may have arisen through tripolar spindle and other mitotic abnormalities.     

A novel cell division factor from tobacco 2B-13 cells that induced cell division in auxin-starved tobacco BY-2 cells

Effects of auxin as plant hormones are widespread; in fact in almost all aspects of plant growth and development auxin plays a pivotal role. Although auxin is required for propagating cell division in plant cells, its effect upon cell division is least understood. If auxin is depleted from the culture medium, cultured cells cease to divide. It has been demonstrated in this context that the addition of auxin to auxin-starved nondividing tobacco BY-2 cells induced semisynchronous cell division. On the other hand, there are some cell lines, named habituated cells, that can grow without auxin. The cause and reason for the habituated cells have not been clarified. A habituated cell line named 2B-13 is derived from the tobacco BY-2 cell line, which has been most intensively studied among plant cell lines. When we tried to find the difference between two cell lines of BY-2 and 2B-13 cells, we found that the addition of culture filtrated from the auxin-habituated 2B-13 cells induced semisynchronous cell division in auxin-starved BY-2 cells. The cell division factor (CDF) that is responsible for inducing cell division in auxin-starved BY-2 cells was purified to near-homogeneity by sequential passage through a hydroxyapatite column, a ConA Sepharose column and a Sephadex gel filtration column. The resulting purified fraction appeared as a single band of high molecular weight on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels by silver staining and was able to induce cell division in auxin-starved BY-2 cells. Identification of the protein by MALD-TOF-MS/MS revealed that it is structurally related to P-glycoprotein from Gossypioides kirkii, which belongs to ATP-binding cassette (ABC)-transporters. The significance of CDF as a possible ABC-transporter is discussed in relationship to auxin–autotrophic growth and auxin-signaling pathway.     

Cardiotocographic and sonographic findings in two cases of antenatally diagnosed intrauterine fetal brain death

Intrauterine fetal brain death is a rare cause of a fixed fetal heart rate pattern. Seven cases have been previously reported in the literature, but only two of them were diagnosed prenatally and all the newborns died soon after delivery. Two additional cases of antepartum diagnosis of intrauterine fetal brain death, managed expectantly, are reported. We had the unique opportunity to document progressive sonographic cerebral changes during the follow-up period, following the neurological event, while the fetus continued life and growth in utero. The cardiographic and sonographic findings suggesting intrauterine fetal brain death were a prolonged fixed fetal heart rate, even following a vibroacoustic and contraction stress test; an atonic fetus without breathing and body movement; and the appearance of hydramnios and the development of ventriculomegaly.     

石化企业苯类物质非密闭操作过程的职业暴露分析

采用职业卫生学调查和职业暴露风险评估方法,对选定的苯类物质非密闭操作过程较集中的芳烃装置进行职业暴露分析和评估,为石化企业苯类物质的健康风险控制提供依据。     

Detection and isolation of fetal cells from maternal blood using the flourescence-activated cell sorter (FACS)

The presence of fetal cells in the maternal circulation during pregnancy has been suggested by repeated observations of small numbers of cells containing Y chromatin or a Y chromosome in the blood of pregnant women. With the fluorescence-activitated cell sorter (FACS), we have used antibodies to a paternal cell surface (HLA) antigen, not present in the mother, to select fetal cells from the lymphocyte fractions of a series of maternal blood samples, collected as early as 15 weeks of gestation. These sorted cells have been examined for a second paternal genetic marker, Y chromatin. Y chromatin-containing cells were found among the sorted cells from prenatal maternal blood specimens in 8 pregnancies subsequently producing male infants whose lymphocytes reacted with the same antibodies to paternal antigen used for sorting with the FACS. In each of 17 pregnancies resulting in male infants who failed to inherit the antigen detected by the antibodies used for cell sorting, Y chromatin-containing cells were not found prenatally. The use of two paternal genetic markers, a cell surface antigen and nuclear Y chromatin, to identify fetal cells in maternal blood permits us to conclude that these cells are present in the mother's circulation, as early as 15 weeks gestation. Further development of the techniques reported here could lead to widespread screening of maternal blood samples during pregnancy for detection of fetal genetic abnormalities.     

Fetoplacental discrepancy involving structural abnormalities of chromosome 8 detected by prenatal diagnosis

We describe the finding of three cell lines involving different structural abnormalities of chromosome 8 detected in a prenatal diagnosis. Chorionic villi sampling (CVS) was performed on a pregnant woman because of advanced maternal age. Semidirect cytogenetic analysis showed a mos46,XX,i(8q)/46,XX,del(8)(p11.2) karyotype, confirmed by fluorescence in situ hybridization (FISH). Amniocentesis was subsequently performed, and the karyotype obtained was 46,XX,dup(8)(p23p11.2). The pregnancy was terminated; pathologic findings included clubfeet, clenched left hand, subcutaneous edema and bilateral hydrocephalus. Molecular studies using chromosome 8 microsatellites performed on parents' blood and fetal tissues revealed a maternal meiotic origin of the inv dup(8p) with deletion of the distal p23 region and duplication of the remaining 8p. We propose a model to explain the cytogenetic findings, which includes a first maternal meiotic error giving rise to a large dicentric isochromosome 8 present in the ovum, a second error in one of the first zygote divisions with misdivision of the dicentric 8 giving rise to a cell line with del(8p) confined to the trophoblast and another cell line with inv dup(8p) confined to the fetal tissue and a third error in the trophoblast giving rise to a further cell line with isochromosome 8q. Copyright © 2003 John Wiley & Sons, Ltd.