Phosphate metabolism and foetal growth in the rat. II. Net transfer of 31P and 32P inorganic phosphate from the maternal plasma to the normal foetus

Net transfer of 31P and 32P inorganic phosphate from the maternal plasma to the rat foetus has been studied after intraperitoneal injection of [32P] ortho-phosphate in primigravid females at the 12th day or later stages of gestation. The concentration per unit weight of foetus of the inorganic phosphate (P1) fraction increases markedly with increasing foetal weight; labelling data [inverse relationship between P1 concentration and specific activity, absence of precursor/product relationship between P1 and acid-soluble organic-bound phosphates (POAS)] show this increase to result in part from the formation of a relatively inert metabolic pool, presumably in mineralized tissue. The foetal concentrations of calcium and inorganic phosphate show a strong positive correlation, both increasing markedly with foetal weight. The progressive accumulation of calcium does not, however, account entirely for the rising concentration of inorganic phosphate. The concentration per unit weight of foetus of the POAS fraction remains stable for foetuses smaller than 2 000 mg. In heavier foetuses (greater than 2 000 mg) the POAS concentrations are, with an abrupt transition, distinctly lower, rising however slightly with increasing foetal weight. The concentration per unit weight of foetus of the acid-insoluble organic-bound phosphate (POAIS) fraction decreases slightly with increasing foetal weight. The label uptake per unit weight of foetus of both POAS and POAIS fractions is negatively correlated with increasing foetal weight. The amount and label uptake per whole foetus of the P1, POAS and POAIS fractions are positively correlated with increasing foetal weight. Phosphate transfer to the foetus increases continuously, being maximal at or near birth.     

Endocrine regulation of phosphorus and calcium metabolism during pregnancy in domestic ruminants

In pregnant domestic ruminants (cows, ewes, goats) foetal plasma calcium and inorganic phosphorus concentrations are higher than those measured in the dam. The foetus regulates its own calcaemia and phosphataemia. Changes in maternal plasma calcium levels have no significant effect on foetal calcaemia. Calcium and phosphorus are transported from the dam to the foetus according to a one-way process, the transport from the foetus to the dam being negligible. An important part of the calcium transferred to the foetus comes from the maternal skeleton. The true molecular mechanisms involved in placental transport of calcium are still unknown. This is an active transport, stimulated by vitamin D metabolites (of maternal, foetal or placental origin) and maternal prolactin. Maternal calcitonin protects the skeleton of the pregnant (and lactating) female ruminant against excessive demineralization, partly by modulating placental transport of calcium during periods of intense mineralization of foetal skeleton.     

Foetal distribution of inhaled mercury vapor in normal and acatalasaemic mice

Levels of mercury distribution in placenta, amniotic sac and foetus and those in brain and liver of maternal acatasaemic mice were higher than those of normal, respectively. The levels of mercury distribution in the blood and lungs of maternal acatalasaemic mice exposed to metallic mercury vapor were also lower than those of normal. Mercury concentrations in placenta and foetus of acatalasaemic mice following exposure to metallic mercury vapor were higher than those of normal. Maternal acatalasaemic mice had decreased levels of mercury in the blood than those of normal mice. Thus, the placenta/blood or foetus/blood ratio of mercury concentration in acatalasaemic mice was significantly higher than that in normal mice. Similarly the brain/blood or liver/blood ratio of maternal acatalasaemic mice was higher than that of normal mice. These results suggest that metallic mercury in the blood readily passed through the blood-brain, blood-foetus barriers. In contrast to the results on exposures of mice to metallic mercury, the foetus/maternal blood ratio of mercuric concentration in the acatalasaemic mice following injection of mercuric chloride was similar to that in the normal mice. Moreover, the foetus/maternal blood ratio of mercury concentration in acatalasaemic or normal mice injected with mercuric chloride was lower than those in acatalasaemic or normal mice exposed to metallic mercury.     

Foetomaternal relationships of serum bile acid pattern estimated by high-pressure liquid chromatography.

The bile acid patterns in the maternal and umbilical vein and artery serum samples were analysed by a two-step chromatographic method involving group separation by piperidinohydroxypropyl-Sephadex LH-20 and high-pressure liquid chromatography using immobilized 3 alpha-hydroxy steroid dehydrogenase. Glycochenodeoxycholate predominates in the maternal blood and taurochenodeoxycholate in the umbilical blood. In cases where a free bile acid was detected in the maternal blood, the same bile acid was also demonstrated in the corresponding cord blood. The concentrations of taurocholate and taurochenodeoxycholate were found to be significantly higher in the umbilical artery than in the corresponding umbilical vein. Our data suggest that there is a bidirectional placental transfer of free bile acids and that there is a transfer of taurine-conjugated primary bile acids from the foetus to the mother.     

Maternal exposure to paternal antigens can modulate the foetus immune system and is associated with reduced atopy in the childhood

The influence of the maternal immune system on pregnancy and on the foetus immune system have given rise to a variety of observations and interesting hypotheses. For example, the higher prevalence of atopy in first-born children as compared to their brotherhood is known as the “birth order effect”. The “hygienic hypothesis” states that more hygienic live conditions, and consequently reduced exposure to pathogens in young age (included the period of foetal development), increases the risk of atopy. Here we review the ideas concerning maternal exposure to paternal antigens and immunomodulation. In particularly, we discuss the idea that this phenomenon may induce a regulatory environment in women that interfere with the developing foetal immune system. This regulatory environment could be responsible for protecting children to the development of atopy during adulthood. We propose that maternal exposure to paternal antigens through different situations, such as pregnancy, repeated exposure to sperm or Paternal Leukocyte Immunization (PLI) would combine the “birth order effect” and the “hygienic hypothesis” and thus lower the risk to atopy in children through the transference of a regulatory environment to the foetus.     

Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig.

Biliverdin was reduced to bilirubin in pregnant and foetal guinea pigs, and the 100000 g supernatant from homogenates of foetal liver, placenta and maternal liver showed high biliverdin reductase activity. The placental transport of unconjugated bilirubin and biliverdin was compared by injecting unlabelled and radiolabelled pigments into the foetal or maternal circulation and analysing blood collected from the opposite side of the placenta. Injected bilirubin crossed the placenta from foetus to mother and vice versa, but injected biliverdin did not appear to cross without prior reduction to bilirubin. The guinea-pig placenta is apparently more permeable to bilirubin than biliverdin. Reduction of biliverdin to bilirubin in the foetus may, therefore, be essential for efficient elimination of haem catabolites from the foetus in placental mammals.     

DNA methylation changes in genes coding for leptin and insulin receptors during metabolic-altered pregnancies

The overwhelming rates of obesity worldwide are a major concern due to the elevated medical costs associated and the poor quality of life of obese patients. In the recent years, it has become evident that the intrauterine milieu can have a long-term impact on the foetus health. The placenta is a highly dynamic organ; whose primary function is to carry nutrients from the mother to the foetus and to remove waste products from the foetus. Any alteration in maternal circulating metabolites elicits a response in order to ensure the developing foetus an adequate growth environment. This response can be translated into epigenetic modifications in coding genes for metabolic-related receptors located in the placenta and foetal tissues. The most studied receptors involved in the metabolic sensing are the leptin and the insulin receptors. A maternal metabolic disease-like state can alter the expression of these receptors in different organs, including placenta. There is evidence that these alterations not only affect the expression level of these receptors, but there are also differences in epigenetic marks in regulatory elements of these genes that may become permanent despite the mother's treatment. This review provides evidence about possible mechanisms involved in the foetal programming of metabolic diseases originated from the pre-natal environment that could contributive to increasing levels of obesity in the world.     

t(Y; 15) translocation in a fertile male, detected at the time of amniocentesis

Cytogenetic studies on a phenotypically normal fertile male revealed an unbalanced Y; 15 translocation. His wife referred for a prenatal diagnosis because of maternal age. The foetus was male and carried the same translocation.     

Enzymic basis of deranged foetal flavin-nucleotide metabolism consequent on immunoneutralization of maternal riboflavin carrier protein in the pregnant rat.

A comparison of the kinetic and other parameters of enzymes of flavin-nucleotide metabolism in the whole foetus vis-à-vis the maternal liver in the pregnant rat revealed relatively lower activities of foetal flavokinase and FAD pyrophosphorylase. Passive immunoneutralization of the maternal riboflavin carrier protein suppresses foetal FAD pyrophosphorylase rather selectively. Additionally, although the activities of foetal nucleotide pyrophosphatase and FMN phosphatase were unchanged owing to immunoneutralization, higher activities of these enzymes in the whole foetus as compared with the maternal liver may be responsible for the drastic depletion of FAD levels that precipitates foetal degeneration.     

Ultrastructural studies of the placenta of the ewe: phagocytosis of erythrocytes by the chorionic epithelium at the central depression of the cotyledon.

Extravasated maternal blood, which escapes from capillaries and larger blood vessels within the tips of the maternal septa, is responsible for the characteristic pigmentation of the central depression of the ovine cotyledon in the last third of pregnancy. The chorionic epithelium of this region is actively engaged in the uptake and subsequent breakdown of maternal erythrocytes, which may represent an important source of iron for the foetus during the period of maximum intra-uterine growth.     

Non-invasive prenatal diagnosis by massively parallel sequencing of maternal plasma DNA

The presence of foetal DNA in the plasma of pregnant women has opened up new possibilities for non-invasive prenatal diagnosis. The use of circulating foetal DNA for the non-invasive prenatal detection of foetal chromosomal aneuploidies is challenging as foetal DNA represents a minor fraction of maternal plasma DNA. In 2007, it was shown that single molecule counting methods would allow the detection of the presence of a trisomic foetus, as long as enough molecules were counted. With the advent of massively parallel sequencing, millions or billions of DNA molecules can be readily counted. Using massively parallel sequencing, foetal trisomies 21, 13 and 18 have been detected from maternal plasma. Recently, large-scale clinical studies have validated the robustness of this approach for the prenatal detection of foetal chromosomal aneuploidies. A proof-of-concept study has also shown that a genome-wide genetic and mutational map of a foetus can be constructed from the maternal plasma DNA sequencing data. These developments suggest that the analysis of foetal DNA in maternal plasma would play an increasingly important role in future obstetrics practice. It is thus a priority that the ethical, social and legal issues regarding this technology be systematically studied.     

Mosaicism for FMR1 gene full mutation and intermediate allele in a female foetus: A postzygotic retraction event

Fragile X syndrome is caused by the expansion of an unstable CGG repeat in the 5′UTR of FMR1 gene. The occurrence of mosaicism is not uncommon, especially in male patients, whereas in females it is not so often reported. Here we report a female foetus that was subject to prenatal diagnosis, because of her mother being a premutation carrier. The foetus was identified as being a mosaic for an intermediate allele and a full mutation of FMR1 gene, in the presence of a normal allele. The mosaic status was confirmed in three different tissues of the foetus – amniotic fluid, skin biopsy and blood – the last two obtained after pregnancy termination. Karyotype analysis and X-chromosome STR markers analysis do not support the mosaicism as inheritance of both maternal alleles. Oligonucleotide array-CGH excluded an imbalance that could contain the primer binding site with a different repeat size. The obtained results give compelling evidence for a postzygotic expansion mechanism where the foetus mosaic pattern originated from expansion of the mother's premutation into a full mutation and consequent regression to an intermediate allele in a proportion of cells. These events occurred in early embryogenesis before the commitment of cells into the different tissues, as the three tested tissues of the foetus have the same mosaic pattern. The couple has a son with Fragile X mental retardation syndrome and choose to terminate this pregnancy after genetic counselling.     

Nongenomic memory of foetal history in chronic diseases development

Foetal growth from conception to birth is a complex process predetermined by the genetic configuration of the foetus, the availability of nutrients and oxygen to the foetus, maternal nutrition and various growth factors and hormones of maternal, foetal and placental origin. Maintenance of the optimal foetal environment is the key factor of the future quality of life. Such conditions like inadequate nutrition and oxygen supply, infection, hypertension, gestational diabetes or drug abuse by the mother, expose the foetus to nonphysiological environment. In conditions of severe intrauterine deprivation, there is a potential loss of structural units within the developing organ systems affecting their functionality and efficiency. Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The studies reviewed in this article show how environmental factors influence a diverse array of molecular mechanisms and consequently alter disease risk including diseases such as metabolic syndrome and cardiovascular diseases, insulin resistance and diabetes mellitus, neuropsychiatric disorders, osteoporosis, asthma and immune system diseases.     

Ultrastructural changes in the placenta of the ewe following foetal infusion of cortisol.

The placental changes which followed continuous infusion of cortisol into the sheep foetus in the later stages of gestation were, like the hormonal changes, broadly similar to those of spontaneous parturition. There was, however, a premature separation of foetal and maternal tissues in certain areas of the placental cotyledons, and this separation appeared to protect the foetal epithelium from the degenerative changes which normally take place in the short space of time between the birth of the lamb and the delivery of the foetal membranes. The results suggest that an experimental model in which premature labour is induced by the administration of cortisol to the foetus is probably incomplete, and that additional factors almost certainly contribute to the cascade phenomenon of spontaneous parturition.     

Cardiorespiratory effects of nifedipine in pregnant sheep

Four concentrations of nifedipine (AdalatR, Bayer) were infused into 25 pregnant sheep of 123-140 days of gestation (term, 147 days) and the effects on the ewe and the foetus have been studied. At all doses of nifedipine infused, maternal diastolic pressure fell by about 15% and maternal heart rate increased by 33%. There was no change in blood gases or pH. Uterine activity, as measured by uterine electromyographic recordings, was reduced due to an increase in the interval between periods of activity. The duration of a burst of activity remained unaffected. The effects of nifedipine on the foetus, were similar. Mean foetal arterial pressure fell by 4-5 mmHg and heart rate rose by 15 to 50%, both changes being maintained for the duration of the infusion and the increased heart rate for longer. The electrocorticogram of the foetal sheep was unaffected by nifedipine. The effects on foetal breathing movements were small. At the concentration of 5 micrograms/kg/min for either 2 or 4 hours the breathing pattern changed so that the episodes of breathing were shorter and more frequent. The total amount of breathing per hour was unaffected. Control infusion of ethanol had little effect on the ewe except for a significant increase in lactate production. In the foetus breathing was reduced at the highest concentration used.     

Mild iodine deficiency in pregnancy in Europe and its consequences for cognitive and psychomotor development of children: A review

Despite the introduction of salt iodization programmes as national measures to control iodine deficiency, several European countries are still suffering from mild iodine deficiency (MID). In iodine sufficient or mildly iodine deficient areas, iodine deficiency during pregnancy frequently appears in case the maternal thyroid gland cannot meet the demand for increasing production of thyroid hormones (TH) and its effect may be damaging for the neurodevelopment of the foetus. MID during pregnancy may lead to hypothyroxinaemia in the mother and/or elevated thyroid-stimulating hormone (TSH) levels in the foetus, and these conditions have been found to be related to mild and subclinical cognitive and psychomotor deficits in neonates, infants and children. The consequences depend upon the timing and severity of the hypothyroxinaemia. However, it needs to be noted that it is difficult to establish a direct link between maternal iodine deficiency and maternal hypothyroxinaemia, as well as between maternal iodine deficiency and elevated neonatal TSH levels at birth. Finally, some studies suggest that iodine supplementation from the first trimester until the end of pregnancy may decrease the risk of cognitive and psychomotor developmental delay in the offspring.     

The existence during gestation of an immunological buffer zone at the interface between maternal and foetal tissues.

In mammalian pregnancy the trophoblast normally constitutes an uninterrupted boundary of foetal tissue in immediate contact with maternal tissue, including blood in some species, and is the decisive immunological barrier to rejection of the foetus as an allograft. The ability of the trophoblast to function as a barrier evidently results from its capacity to resist immunological attack by either alloantibody or alloimmune cells and to prevent immunocompetent cells from reaching and damaging the foetus but, as yet, there is no general agreement regarding the means by which it exercises these functions. In view of the dramatic hormonal changes that occur during pregnancy and the undisputed involvement of trophoblast in these endocrine events, the possibility exists of an interaction between the hormones of pregnancy and the immunological phenomena. The present account furnishes evidence that endocrine activity at the maternal surface of the trophoblast, the presumptive site of the immunological frontier between foetus and mother, may be a factor in its local survival at implantation. The placental hormones so far known that are capable of blocking the antigen receptor sites of the mother's lymphocytes and thus preventing the latter from reacting with the foetal antigens are the glycoprotein, human chorionic gonadotrophin (HCG) and the polypeptide hormone, human chorionic somatomammotrophin (HCS) or human placental lactogen (HPL), both of which are specific to the human placenta. The origin of these hormones, their spatial distribution and their probable interaction with placental steroid hormones are discussed. It is argued that the place of highest concentration of these hormones is on the surface of the syncytial microvilli and the adjacent caviolae of the apical plasma membrane, as well as on the surfaces of the persisting cytotrophoblastic cells of the basal plate (cytotrophoblastic shell), the cell islands and the septa-precisely where the immunological challenge of the foetal allograft to the maternal host occurs. An explanation is offered for the continuing production of the voluminous quantities of these hormones during human pregnancy.     

Mammalian viviparity: a complex niche in the evolution of genomic imprinting

Evolution of mammalian reproductive success has witnessed a strong dependence on maternal resources through placental in utero development. Genomic imprinting, which has an active role in mammalian viviparity, also reveals a biased role for matrilineal DNA in its regulation. The co-existence of three matrilineal generations as one (mother, foetus and post-meiotic oocytes) has provided a maternal niche for transgenerational co-adaptive selection pressures to operate. In utero foetal growth has required increased maternal feeding in advance of foetal energetic demands; the mammary glands are primed for milk production in advance of birth, while the maternal hypothalamus is hormonally primed by the foetal placenta for nest building and post-natal care. Such biological forward planning resulted from maternal–foetal co-adaptation facilitated by co-expression of the same imprinted allele in the developing hypothalamus and placenta. This co-expression is concurrent with the placenta interacting with the adult maternal hypothalamus thereby providing a transgenerational template on which selection pressures may operate ensuring optimal maternalism in this and the next generation. Invasive placentation has further required the maternal immune system to adapt and positively respond to the foetal allotype. Pivotal to these mammalian evolutionary developments, genomic imprinting emerged as a monoallelic gene dosage regulatory mechanism of tightly interconnected gene networks providing developmental genetic stability for in utero development.     

A possible role for imprinted genes in inbreeding avoidance and dispersal from the natal area in mice

The expression of a subset of mammalian genes is subject to parent of origin effects (POE), most of which can be explained by genomic imprinting. Analysis of mutant animals has demonstrated that a number of imprinted genes influence brain development and behaviour. Here we provide evidence for POE on olfactory related behaviour and sensitivity to maternal odour cues. This was investigated by examining the odour preference behaviour of reciprocal cross F(1) mice made by embryo transfer to genetically unrelated foster parents. We determined that both adult males and females show an avoidance of female urinary odours of their genetic maternal but not paternal origin. This was found not to be due to any previous exposure to these odours or due to self-learning, but may be related to direct effects on the olfactory system, as reciprocal F(1) males show differential sensitivity to female odour cues. Currently the most robust theory to explain the evolution of imprinting is the conflict hypothesis that focuses on maternal resource allocation to the developing foetus. Kinship considerations are also likely to be important in the selection of imprinted genes and we discuss our findings within this context, suggesting that imprinted genes act directly on the olfactory system to promote post-weaning dispersal from the natal area.