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.     

Placental 11β-hydroxysteroid dehydrogenase and the programming of hypertension

Excessive foetal exposure to glucocorticoids retards growth and “programmes” adult hypertension in rats. Placental 11β-hydroxysteroid dehydrogenase (11β-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11β-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11β-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11β-HSD, by regulating foetal exposure to maternal glucocorticoids, crucially determines foeto-placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11β-HSD activity. Thus, deficiency of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11β-HSD (type 2) will aid the further study of these intriguing findings.     

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.     

Thermal environment and human birth weight

Human birth weight is known to be influenced by several factors, including maternal energy supply, maternal stature, disease status, smoking status and gestation length. This article proposes that the thermal environment may be a further factor influencing birth weight. Experimental animal studies demonstrate clear effects of thermal stress on placental function and birth weight, but may have limited relevance for humans due to between-species differences in pregnancy physiology. Observational studies suggest an inverse relationship between environmental temperature and birth weight within and between human populations. Variation in maternal size, body fatness, pregnancy weight gain and heat production is predicted to influence maternal thermoregulatory capacity, as are the size and composition of the foetus. These associations generate the hypothesis that low birth weight in hot environments may in part represent an adaptation to environmental heat stress.     

Some features of an ultrasonic study of bovine foetal kinesis

Following the use of doppler ultrasound to study equine foetal kinesis, further observations on this form of behaviour have been made on bovine subjects using similar apparatus. Pregnant cows were examined with an intrapelvic transducer probe introduced per rectum and directed over the dorsum of the gravid uterus. Examinations were conducted throughout the terminal two thirds of gestation. In the last week of gestation, frequent serial examinations were performed to monitor the prepartum increase in kinetic behaviour.Simple foetal movements occurred at a fairly consistent level throughout the second and third trimesters averaging approximately 800/day. Complex foetal movements occurred in the last 2 months of gestation. These increased markedly in incidence during the terminal week, reaching a peak approximately 77 h prepartum. This mass kinesis, involving approximately 3 500 movements, coincided with foetal “righting” actions and typically ceased 1–2 days before parturition when a phase of quiescent foetal behaviour developed and persisted till birth. Two cases of difficult birth were encountered which were related to a condition termed “foetal inertia”.It is speculated that the muscular “competence” necessary for full-scale foetal activity is acquired by intra-gestational foetal exercising. Attainment of the birth posture by the foetus is the apparent function of terminal foetal kinesis. Foetal care warrants restrictive management of pregnant cattle when calving is imminent.     

Up regulation of the maternal immune response in the placenta of cattle naturally infected with Neospora caninum

Neospora caninum is an intracellular protozoan parasite which is a major cause of abortion in cattle worldwide. It forms persistent infections which recrudesce during pregnancy leading to foetal infection and in a proportion of cases, abortion. The mechanisms underlying abortion are not understood. In this study, recrudescence of a persistent infection in eight naturally infected cows occurred between 20 and 33 weeks of gestation. Animals were killed at the time of recrudescence and parasites were detected in the placentae and foetuses. An active maternal immune response consisting of an infiltration of CD4+ and CD8+ T cells and a 46-49 fold increase in interferon-γ and interleukin-4 mRNA was detected. Other cytokines, notably interleukin-12 p40, interleukin-10 and tumour necrosis factor-α were also significantly increased and Major Histocompatibility Class II antigen was expressed on maternal and foetal epithelial and stromal fibroblastoid cells. Significantly, despite the presence of an active maternal immune response in the placenta, all the foetuses were alive at the time of maternal euthanasia. There was evidence of parasites within foetal tissues; their distribution was restricted to the central nervous system and skeletal muscle and their presence was associated with tissue necrosis and a non-suppurative inflammatory response involving lymphocytes and macrophages, irrespective of the gestational age of the foetus. Whilst an active maternal immune response to a pathogen in the placenta is generally considered to be damaging to the foetal trophoblast, our findings suggest that the presence of a parasite-induced maternal immune response in the placenta is not detrimental to foetal survival but may contribute to the control of placental parasitosis.     

Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

“Fetal programming” is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal development. Excessive fetal glucocorticoid exposure during pregnancy results in low birth weight and abnormalities in a number of tissues. The amount of fetal exposure to maternal glucocorticoids depends on the expression of HSD11B2, an enzyme predominantly produced by the syncytiotrophoblast in the placenta. This protects the fetus by converting active glucocorticoids into inactive forms. In this review we examine recent findings regarding placental HSD11B2 that suggest that its epigenetic regulation may mechanistically link maternal stress and long-term health consequences in affected 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.     

Non-cancer effects of chemical agents on children's health

This paper provides an overview about the non-cancer health effects for children from relevant chemical agents in our environment. In addition, a meta-analysis was conducted on the association between sudden infant death syndrome (SIDS) and maternal smoking during pregnancy as well as postnatal exposure to environmental tobacco smoke (ETS).In children, birth deformities, neurodevelopment, reproductive outcomes and respiratory system are mainly affected by chemical exposures. According to recent systematic reviews, evidence is sufficient for cognitive impairments caused by low lead exposure levels. Evidence for neurotoxicity from prenatal methylmercury exposure is sufficient for high exposure levels and limited for low levels. Prenatal exposure to polychlorinated biphenyls (PCB) and related toxicants results in cognitive and motor deficits.Maternal smoking during pregnancy is a risk factor for preterm birth, foetal growth deficit and SIDS. The meta-analytic pooled risk estimate for SIDS based on 15 studies is 2.94 (95% confidence interval: 2.43–3.57). Postnatal exposure to ETS was found to increase the SIDS risk by a factor of 1.72 (95% CI: 1.28–2.30) based on six studies which took into account maternal smoking during pregnancy. Additionally, postnatal ETS exposure causes acute respiratory infections, ear problems, respiratory symptoms, more severe asthma, and it slows lung growth. These health effects are also of concern for postnatal exposure to ambient and indoor air pollution.Children differ from adults with respect to several aspects which are relevant for assessing their health risk. Thus, independent evaluation of toxicity in childhood populations is essential.     

Litter-size-dependent intrauterine growth restriction in sheep

Regulation of foetal development in sheep depends on interactions between the intrinsic capacity of the foetus for growth and the maternal environment. Lambs born in multi-foetus litters have relatively small placentae with fewer cotelydons, and lower birth weights. Litter-size-dependent intrauterine growth restriction (IUGR) is evident at mid gestation when metabolic needs of the conceptus are moderate, and overnutrition of ewes with multiple foetuses does not promote growth of their foetuses to the size of singletons. Those observations suggest that placental and conceptus growth in multi-foetus pregnancies is reprogrammed at mid gestation by an as yet undefined mechanism to attenuate foetal growth. This may protect the foetus from severe nutritional insult during late gestation, when its daily growth rate is at a maximum. In that way, lambs born in large litters with relatively lower birth weights may not experience the long-term physiological insults that can be observed in small lambs born to undernourished ewes.     

Maternal-fetal immune tolerance, block by block

How difficult is to go from egg to implanted embryo? The evolution of placentation in eutherian mammals created enormous challenges, in particular to the maternal immune system, as the fetus expresses paternal antigens that are capable of triggering immune rejection. Samstein et al. reveal a role for inducible regulatory T cells in the enforcement of maternal-fetal immune tolerance.     

Failure of Neuraminidase to unmask Histocompatibility Antigens on Trophoblast

DURING outbred pregnancy the mother is exposed to genetically foreign tissue because the offspring inherits transplantation antigens from the father. The survival of the foetus is ensured by the intervention of the trophoblast which does not express transplantation antigens between mother and foetus: mouse trophoblast is not rejected even when transplanted into immune recipients^1,3. The mechanism of this failure to express histocompatibility antigens is not understood^1–4, but Kirby et al. have suggested that the extracellular fibrinoid surrounding trophoblast cells is involved^5,6. Currie has suggested that the thick sialomucinous glycocalyx of the trophoblast cell might “mask” the histocompatibility antigens on the trophoblast^7,8 and has demonstrated that neuraminidase unmasked these antigens⁸. Our experiments, however, show that trophoblast incubated with neuraminidase cannot sensitize allogeneic mice to donor histocompatibility antigens. Furthermore, pretreatment of trophoblastic implants with neuraminidase did not interfere with their proliferation and growth in highly immune allogeneic recipients.     

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.     

Antibody-Dependent Transplacental Transfer of Malaria Blood-Stage Antigen Using a Human Ex Vivo Placental Perfusion Model

Prenatal exposure to allergens or antigens released by infections during pregnancy can stimulate an immune response or induce immunoregulatory networks in the fetus affecting susceptibility to infection and disease later in life. How antigen crosses from the maternal to fetal environment is poorly understood. One hypothesis is that transplacental antigen transfer occurs as immune complexes, via receptor-mediated transport across the syncytiotrophoblastic membrane and endothelium of vessels in fetal villi. This hypothesis has never been directly tested. Here we studied Plasmodium falciparum merozoite surface protein 1 (MSP1) that is released upon erythrocyte invasion. We found MSP1 in cord blood from a third of newborns of malaria-infected women and in >90% following treatment with acid dissociation demonstrating MSP1 immune complexes. Using an ex vivo human placental model that dually perfuses a placental cotyledon with independent maternal and fetal circuits, immune-complexed MSP1 transferred from maternal to fetal circulation. MSP1 alone or with non-immune plasma did not transfer; pre-incubation with human plasma containing anti-MSP1 was required. MSP1 bound to IgG was detected in the fetal perfusate. Laser scanning confocal microscopy demonstrated MSP1 in the fetal villous stroma, predominantly in fetal endothelial cells. MSP1 co-localized with IgG in endothelial cells, but not with placental macrophages. Thus we show, for the first time, antibody-dependent transplacental transfer of an antigen in the form of immune complexes. These studies imply frequent exposure of the fetus to certain antigens with implications for management of maternal infections during pregnancy and novel approaches to deliver vaccines or drugs to the fetus.     

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.     

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.     

Early‐life environment,developmental immunotoxicology,and the risk of pediatric allergic disease including asthma

Incidence of childhood allergic disease including asthma (AD‐A) has risen since the mid‐20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid‐gestation until 2 years after birth is one of particular concern relative to DIT and AD‐A. Several prenatal‐perinatal risk factors have been identified as contributing to a DIT‐mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic‐related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT‐affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy‐relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children. Birth Defects Res (Part B) 2008. © 2008 Wiley‐Liss, Inc.     

Molecular and immunological characterization of allergens from the entomopathogenic fungus Beauveria bassiana

Background

The mechanisms for the association between birth by cesarean section and atopy and asthma are largely unknown.

Objective

To examine whether cesarean section results in neonatal secretion of cytokines that are associated with increased risk of atopy and/or asthma in childhood. To examine whether the association between mode of delivery and neonatal immune responses is explained by exposure to the maternal gut flora (a marker of the vaginal flora).

Methods

CBMCs were isolated from 37 neonates at delivery, and secretion of IL-13, IFN-γ, and IL-10 (at baseline and after stimulation with antigens [dust mite and cat dander allergens, phytohemagglutinin, and lipopolysaccharide]) was quantified by ELISA. Total and specific microbes were quantified in maternal stool. The relation between mode of delivery and cord blood cytokines was examined by linear regression. The relation between maternal stool microbes and cord blood cytokines was examined by Spearman's correlation coefficients.

Results

Cesarean section was associated with increased levels of IL-13 and IFN-γ. In multivariate analyses, cesarean section was associated with an increment of 79.4 pg/ml in secretion of IL-13 by CBMCs after stimulation with dust mite allergen (P < 0.001). Among children born by vaginal delivery, gram-positive anaerobes and total anaerobes in maternal stool were positively correlated with levels of IL-10, and gram-negative aerobic bacteria in maternal stool were negatively correlated with levels of IL-13 and IFN-γ.

Conclusion

Cesarean section is associated with increased levels of IL-13 and IFN-γ, perhaps because of lack of labor and/or reduced exposure to specific microbes (e.g., gram-positive anaerobes) at birth.     

Age paternel: apport des données épidémiologiques et d'AMP

Introduction

Maternal age over 35 years is a well known risk factor in reproduction. This effect of maternal age had been demonstrated on the risk of infertility and the risk of miscarriage on the basis of epidemiological data and ART data, especially AID sources. In contrast, the effect of paternal age has been rarely analysed. The objective of this study was to review the literature analysing the effect of paternal age on the risk of infertility and the risk of miscarriage.

Material and method

Sixteen publications analysing paternal age were selected by a MEDLINE search. Thirteen publications concerned epidemiological data, based on surveys in the general population, surveys in pregnant women, case-control studies, and birth and death certificates. Three publications concerned ART data, based on IVF with ovum donation. In IVF with ovum donation, there is no correlation between paternal age and age of the female gamete donor.

Results

Seven epidemiological studies analysed the effect of paternal age on the risk of infertility. After controlling for maternal age, five studies showed a paternal age effect, and one showed a very weak paternal age effect. The last study did not show any paternal age effect, but only considered men under the age of 33 years. Three studies analysed the effect of paternal age on pregnancy rates in IVF with ovum donation. Only one study showed a paternal age effect. The four studies analysing the effect of paternal age on the risk of miscarriage showed a paternal age effect and two of the three studies based on birth and death certificates showed a paternal age effect on late foetal death (>20 weeks of gestation).

Conclusion

There are concordant data in the literature showing an effect of paternal age on the risk of infertility and the risk of miscarriage. Paternal age over 40 years could therefore be a risk factor in reproduction in the same way as maternal age over 35 years. Moreover, the risk of infertility and the risk of miscarriage could be much higher when both partners are over the age of 35–40 years.