Maternal-fetal Interactions Research Articles

Fusarium Mycotoxins Disrupt the Barrier and Induce IL-6 Release in a Human Placental Epithelium Cell Line.

Deoxynivalenol, T-2 toxin, and zearalenone, major Fusarium mycotoxins, contaminate human food on a global level. Exposure to these mycotoxins during pregnancy can lead to abnormalities in neonatal development. Therefore, the aim of this study was to investigate the effects of Fusarium mycotoxins on human placental epithelial cells. As an in vitro model of placental barrier, BeWo cells were exposed to different concentrations of deoxynivalenol, zearalenone or T-2 toxin. Cytotoxicity, effects on barrier integrity, paracellular permeability along with mRNA and protein expression and localization of junctional proteins after exposure were evaluated. Induction of proinflammatory responses was determined by measuring cytokine production. Increasing mycotoxin concentrations affect BeWo cell viability, and T-2 toxin was more toxic compared to other mycotoxins. Deoxynivalenol and T-2 toxin caused significant barrier disruption, altered protein and mRNA expression of junctional proteins, and induced irregular cellular distribution. Although the effects of zearalenone on barrier integrity were less prominent, all tested mycotoxins were able to induce inflammation as measured by IL-6 release. Overall, Fusarium mycotoxins disrupt the barrier of BeWo cells by altering the expression and structure of junctional proteins and trigger proinflammatory responses. These changes in placental barrier may disturb the maternal–fetal interaction and adversely affect fetal development.

Effects of maternal-fetal transmission of viruses and other environmental agents on lung development.

New information is emerging concerning the influence of environmental factors (e.g., viruses, pollutants, nutrients) on fetal lung development and the prenatal modulation of cellular and molecular effectors essential to the control of airway function, which may shed new light into the pathogenesis of chronic obstructive pulmonary disease in childhood. In particular, recent studies have shown that nanosize biological and inorganic particles (e.g., respiratory viruses and pollutants) are able to spread hematogenously across the placenta from mother to offspring and interfere with lung development during critical “windows of opportunity”. Furthermore, the nutritional balance of maternal diet during pregnancy can affect postnatal lung structure and function. Adverse prenatal environmental conditions can predispose to increased airway reactivity by inducing aberrant cholinergic innervation of the respiratory tract, enhanced contractility of the airway smooth muscle, and impaired innate immunity. Such changes can persist long after birth and might provide a plausible explanation to the development of chronic airway dysfunction in children, even in the absence of atopic predisposition. Insight into maternal-fetal interactions will contribute to a better understanding of the pathogenesis of highly prevalent diseases like bronchiolitis and asthma, and may lead to more precise preventative and therapeutic strategies, or new indications for existing ones.

Experimental models of maternal-fetal interface and their potential use for nanotechnology applications.

During pregnancy, the placenta regulates the transfer of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams and is a key determinant of fetal exposure to xenobiotics from the mother. To study the disposition of substances through the placenta, various experimental models are used, especially the perfused placenta, placental villi explants, and cell lineagemodels. In this context, nanotechnology, an area of study that is on the rise, enables the creation of particles on nanometric scales capable of releasing drugs aimed at specific tissues. An important reason for furthering the studies on transplacental transfer is to explore the potential of nanoparticles (NPs), in new delivery strategies for drugs that are specifically aimed at the mother, the placenta, or the fetus and that involve less toxicity. Due to the fact that the placental barrier is essential for the interaction between the maternal and fetal organismsas well as the possibility of NPs being used in the treatment of various pathologies, the aim of this review is to present the main experimental models used in studying the maternal-fetal interaction and the action of NPs in the placental environment.

Investigation of Maternal Effects, Maternal-Fetal Interactions, and Parent-of-Origin Effects (Imprinting) for Candidate Genes Positioned on Chromosome 18q21, in Probands with Schizophrenia and their First-Degree Relatives.

ObjectiveA popular design for the investigation of such effects, including effects of parent-of-origin (imprinting), maternal genotype, and maternal-fetal genotype interactions, is to collect deoxyribonucleic acid (DNA) from affected offspring and their mothers and to compare with an appropriate control sample. We investigate the effects of estimation of maternal, imprinting and interaction effects using multimodal modeling using parents and their offspring with schizophrenia in Korean population. MethodsWe have recruited 27 probands (with schizophrenia) with their parents and siblings whenever possible. We analyzed 20 SNPs of 7 neuronal genes in chromosome 18. We used EMIM analysis program for the estimation of maternal, imprinting and interaction effects using multimodal modeling. ResultsOf analyzed 20 single nucleotide polymorphisms (SNPs), significant SNP (rs 2276186) was suggested in EMIM analysis for child genetics effects (p=0.0225438044) and child genetic effects allowing for maternal genetic effects (p=0.0209453210) with very stringent multiple comparison Bonferroni correction. ConclusionOur results are the pilot study for epigenetic study in mental disorder and help to understanding and use of EMIM statistical genetics analysis program with many limitations including small pedigree numbers.

Fetal-maternal interactions during the establishment of pregnancy in ruminants

This review integrates established information with new insights into molecular and physiological mechanisms responsible for events leading to pregnancy recognition, endometrial receptivity, and implantation with emphasis on sheep. After formation of the corpus luteum, progesterone acts on the endometrium and stimulates blastocyst growth and elongation to form a filamentous conceptus (embryo/fetus and associated extraembryonic membranes). Recurrent early pregnancy loss in the uterine gland knockout ewe model indicates that endometrial epithelial secretions are essential for peri-implantation blastocyst survival and growth. The elongating sheep conceptus secretes interferon tau (IFNT) that acts on the endometrium to inhibit development of the luteolytic mechanism by inhibiting transcription of the estrogen receptor alpha (ESR1) gene in the luminal (LE) and superficial ductal glandular (sGE) epithelia, which prevents estrogen-induction of oxytocin receptors (OXTR) and production of luteolytic prostaglandin F2-alpha pulses. Progesterone downregulates its receptors (PGR) in LE and then GE, correlating with a reduction of anti-adhesive MUC1 (mucin glycoprotein one) and induction of secreted LGALS15 (galectin 15) and SPP1 (secreted phosphoprotein one), that are proposed to regulate trophectoderm growth and adhesion. IFNT acts on the LE to induce WNT7A (wingless-type MMTV integration site family member 7A) and to stimulate LGALS15, CTSL (cathepsin L), and CST3 (cystatin C), which may regulate conceptus development and implantation. During the peri-implantation period, trophoblast giant binucleate cells (BNC) begin to differentiate from mononuclear trophectoderm cells, migrate and then fuse with the uterine LE as well as each other to form multinucleated syncytial plaques. Trophoblast giant BNC secrete chorionic somatomammotropin (CSH1 or placental lactogen) that acts on the endometrial glands to stimulate their morphogenesis and differentiated function. The interactive, coordinated and stage-specific effects of ovarian and placental hormones regulate endometrial events necessary for fetal-maternal interactions and successful establishment of pregnancy.

The Impact of Maternal Voice on the Fetus: A Systematic Review

Background: Studies have shown pre-natal memory underlining the ability of newborns to discriminate maternal vs. other voices and to recognize linguistic stimuli presented prenatally by the mother. The fetus reacts to maternal voice at the end of gestation but it is important to clarify the indicators and conditions of these responses. Objective: To understand the state of the art concerning: 1) indicators of fetal reactions to maternal voice vs. other voices; 2) conditions of maternal voice required to obtain fetal response, 3) neonatal recognition of maternal voice and of linguistic material presented prenatally and 4) obstetric and behavioral maternal conditions compromising fetal ability to discriminate between maternal and other female voices. Method: Systematic review using EBSCO, WEBSCIENCE and MEDLINE. Eligibility: studies with maternal voice delivered before birth as stimulus and with fetal or neonatal behavior as responses. Results: Fetal responses to maternal voice are observed through fetal cardiac, motor (fetal yawning decrease, mouth opening, fetal body movements) and brain responses (activation of the lower bank of the left temporal lobe). Newborns’ head orientation and non-nutritive sucking are shown as being neonatal indicators. Conclusion: Gestational age, baseline measures (fetal state, acoustic conditions and pre-stimulus time) and obstetrical conditions may enable or compromise fetal discrimination between maternal and other voices. The role of maternal voice for prenatal human bonding needs to be discussed according to different maternity conditions such as surrogate mothers. A new paradigm is suggested; the focus of research should be on maternal-fetal interaction under the presence of maternal voice.</P>

First person – Lauren Brilli Skvarca and Hwa Han

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Lauren Brilli Skvarca and Hwa Han are co-first authors on ‘Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish’, published in DMM. Lauren is a Pathologist Investigator Residency Research Training (PIRRT) Fellow at the University Pittsburgh Medical Center (UPMC), USA, in the lab of Carl Hubel, investigating maternal-fetal cell interactions contributing to placental vascular changes in preeclampsia and postpartum maternal cardiovascular risk. Hwa is a PhD graduate student in the lab of Neil Hukriede at the University of Pittsburgh School of Medicine, USA, and is involved in characterizing regenerative cellular mechanisms in gentamicin-induced acute kidney injury using larval zebrafish as a model organism.

Tacrolimus treatment for infertility related to maternal-fetal immune interactions.

Many approaches have been used to achieve successful pregnancies in patients with infertility, though existing treatments remain unsatisfactory in patients with infertility caused by abnormal maternal-fetal immunity. However, our understanding of the immunological aspects of infertility has steadily progressed, aided by recent research into organ transplantation and cancer. The results of these recent analyses have led to the development and evaluation of several candidate immunological treatments, but the use of immunological treatments remains a novel approach. The current paper presents the hypothesis that tacrolimus may have potential as a candidate agent for the treatment of maternal-fetal immunity-related infertility.

Murine trophoblast-derived and pregnancy-associated exosome-enriched extracellular vesicle microRNAs: Implications for placenta driven effects on maternal physiology.

The role of extracellular vesicles (EVs), specifically exosomes, in intercellular communication likely plays a key role in placental orchestration of pregnancy and maternal immune sensing of the fetus. While murine models are powerful tools to study pregnancy and maternal-fetal immune interactions, in contrast to human placental exosomes, the content of murine placental and pregnancy exosomes remains largely understudied. Using a recently developed in vitro culture technique, murine trophoblast stem cells derived from B6 mice were differentiated into syncytial-like cells. EVs from the conditioned media, as well as from pregnant and non-pregnant sera, were enriched for exosomes. The RNA composition of these murine trophoblast-derived and pregnancy-associated exosome-enriched-EVs (ExoE-EVs) was determined using RNA-sequencing analysis and expression levels confirmed by qRT-PCR. Differentially abundant miRNAs were detected in syncytial differentiated ExoE-EVs, particularly from the X chromosome cluster (mmu-miR-322-3p, mmu-miR-322-5p, mmu-miR-503-5p, mmu-miR-542-3p, and mmu-miR-450a-5p). These were confirmed to be increased in pregnant mouse sera ExoE-EVs by qRT-PCR analysis. Interestingly, fifteen miRNAs were only present within the pregnancy-derived ExoE-EVs compared to non-pregnant controls. Mmu-miR-292-3p and mmu-miR-183-5p were noted to be some of the most abundant miRNAs in syncytial ExoE-EVs and were also present at higher levels in pregnant versus non-pregnant sera ExoE-EVs. The bioinformatics tool, MultiMir, was employed to query publicly available databases of predicted miRNA-target interactions. This analysis reveals that the X-chromosome miRNAs are predicted to target ubiquitin-mediated proteolysis and intracellular signaling pathways. Knowing the cargo of placental and pregnancy-specific ExoE-EVs as well as the predicted biological targets informs studies using murine models to examine not only maternal-fetal immune interactions but also the physiologic consequences of placental-maternal communication.

Circulating microparticle proteins obtained in the late first trimester predict spontaneous preterm birth at less than 35 weeks’ gestation: a panel validation with specific characterization by parity

We have previously shown that protein biomarkers associated with circulating microparticles proteins (CMPs) obtained at the end of the first trimester may detect physiologic changes in maternal-fetal interaction such that the risk of spontaneous preterm delivery ≤35 weeks can be stratified. We present here a study extension and validation of the CMP protein multiplex concept using a larger sample set from a multicenter population that allows for model derivation in a training set and characterization in a separate testing set. Ethylenediaminetetraacetic acid (EDTA) plasma was obtained from 3 established biobanks (Seattle, Boston, and Pittsburgh). Samples were from patients at a median of 10-12 weeks' gestation, and the CMPs were isolated via size-exclusion chromatography followed by protein identification via targeted protein analysis using liquid chromatography-multiple reaction monitoring-mass (LC-MRM) spectrometry. A total of 87 women delivered at ≤35 weeks, and 174 women who delivered at term were matched by maternal age (±2 years) and gestational age at sample draw (±2 weeks). From our prior work, the CMP protein multiplex comprising F13A, FBLN1, IC1, ITIH2, and LCAT was selected for validation. For delivery at ≤35 weeks, the receiver operating characteristic (ROC) curve for a panel of CMP proteins (F13A, FBLN1, IC1, ITIH2, and LCAT) revealed an associated area under the ROC curve (AUC) of 0.74 (95% CI, 0.63-0.81). A separate panel of markers (IC1, LCAT, TRFE, and ITIH4), which stratified risk among mothers with a parity of 0, showed an AUC of 0.77 (95% CI, 0.61-0.90). We have identified a set of CMP proteins that provide, at 10-12 weeks gestation, a clinically useful AUC in an independent test population. Furthermore, we determined that parity is pertinent to the diagnostic testing performance of the biomarkers for risk stratification.

Immunological Homeostasis at the Ovine Placenta May Reflect the Degree of Maternal Fetal Interaction.

Successful mammalian pregnancies are a result of complex physiological, endocrinological, and immunological processes that combine to create an environment where the mother is tolerant to the semi-allogeneic fetus. Our knowledge of the mechanisms that contribute to maternal tolerance is derived mainly from human and murine studies of haemochorial placentation. However, as this is the most invasive type of placentation it cannot be assumed that identical mechanisms apply to the less invasive epitheliochorial placentation found in other species such as ruminants. Here, we examine three features associated with reproductive immune regulation in a transformed ovine trophoblast cell line and ex-vivo ovine reproductive tissues collected at term, namely: major histocompatibility complex (MHC) expression, Indoleamine 2,3 dioxygenase-1 (IDO-1) expression, and Natural Killer (NK) cell infiltration. High levels of MHC class I protein expression were detected at the surface of the trophoblast cell line using a pan-MHC class I specific monoclonal antibody. The majority of MHC class I transcripts isolated from the cell line clustered with classical MHC alleles. Transcriptional analysis of placental tissues identified only classical MHC class I transcripts. We found no evidence of constitutive transcription of IDO-1 in either the trophoblast cell line or placental tissues. Ex-vivo tissues collected from the materno-fetal interface were negative for cells expressing NKp46/NCR1. Collectively, these observations suggest that the relatively non-invasive synepitheliochorial placentation found in sheep has a more limited requirement for local immunoregulation compared to the more invasive haemochorial placentation of primates and rodents.

Biology of preeclampsia: Combined actions of angiogenic factors, their receptors and placental proteins

Although massive efforts have been undertaken to elucidate the etiology of the pregnancy syndrome preeclampsia, its developmental origin remains a mystery. Most efforts of the last decade have focused on biomarkers to predict and/or diagnose preeclampsia, including the anti-angiogenic factor sFlt-1 (soluble fms-like tyrosin kinase-1), the angiogenic factor PGF (placental growth factor) and PP13 (placental protein 13). The origins of these marker proteins are still under debate, and so far their actions have only been describe separate from each other. This study will focus on the origins and actions of all three markers during pregnancy and outside pregnancy and will describe a scenario where all three markers act synergistically to rescue the mother from the deleterious effects of the debris that is released from the placenta during preeclampsia. This more holistic approach may open new avenues to think about maternal-fetal interactions and putative therapies.

207 Cat oviductal exosomes as a tool to improve gamete rescue of endangered felids: effects on sperm capacitation and in vitro fertilization

Exosomes play important roles in reproduction, for example, facilitating fetal-maternal interaction and establishment of pregnancy. However, little is known about how oviductal exosomes affect sperm function. We investigated the effects of oviductal exosomes on sperm capacitation and fertilizing ability in domestic cats as a model for endangered felids. Oviducts were collected from cats (1-5 years) after elective spaying and flushed with 1mL of PBS. Exosomes (EX) were isolated using the Total Exosome Isolation kit (Invitrogen/Thermo Fisher Scientific, Waltham, MA, USA) and labelled with BODIPY dye (boron dipyrromethene). Unattached dye was removed by using Exosome Spin Columns (MW 3000, Invitrogen). Presence and purity of EX was confirmed by transmission electron microscopy (TEM). To investigate the effects of EX on sperm capacitation, semen was recovered from epididymis of 5 cats (3 replicates) after elective neutering. One million spermatozoa mL−1 were incubated with or without EX (1V sperm to 2V total exosomes from 2 oviducts) for 1h in PBS. The samples were then incubated at 38.5°C in 1 of the 2 conditions: (1) capacitation (SOF medium+1000IU of penicillin, 10μg mL−1 streptomycin, 10μg mL−1 heparin, 20 µM penicillamine, 10 µM hypotaurine, 1 µM epinephrine); and (2) non-capacitation (capacitation medium without heparin, penicillamine, or hypotaurine) for up to 24h. Total motility, hyperactive and progressive motility, and percentage of intact acrosomes (FITC-PNA) were assessed at 0, 1, 2, 18, and 24h. Data were analysed by using SPSS software (IBM Corp., Armonk, NY) using a paired samples t-test with 95% CI. Vesicles of 30-100nm were observed by TEM, indicating successful isolation of EX, which were found to bind to both acrosome and mid-piece (BODIPY labelling). Sperm incubated with EX exhibited higher motility than those without EX (P<0.05 for all comparisons) at 1h (capacitation: 80±3.7v. 70±3.5; non-capacitation: 78±1.6v. 66±2.5%), 2h (capacitation: 77±1.3v. 61±1.1; non-capacitation: 74±0.9v. 55±3.5%), 18h (capacitation: 53±1.5v. 40±4.7; non-capacitation: 30±1.2v. 21±3.7%), and 24h (capacitation: 30±2.5v. 12±1.1; non-capacitation: 21±2.1v. 8±0.9%). Regarding progressive and hyperactive motility and acrosome integrity, only hyperactive motility at 1h using capacitation medium was significantly higher in the presence of EX than without it (18±1.5v. 9±2.7%; P<0.05). Next, we performed IVF using sperm with or without 1h incubation with EX. After 18h IVF, presumptive zygotes were stained with Hoechst 33342 and observed under a fluorescence microscope to assess fertilization and polyspermy. Preliminary data (30 oocytes/group) revealed that sperm incubation with EX reduced polyspermy (6±4% v. 20±8%) and improved normal fertilization (28±14vs 8±4%), although the differences were not significantly different (P>0.05 for both groups). In conclusion, the findings indicate that oviductal EX play roles in regulating sperm function by enhancing sperm motility. Further studies are needed to confirm the impact of EX on fertilization and how this strategy can be applied to endangered felid conservation.

Trophoblast organoids as a model for maternal–fetal interactions during human placentation

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for both mother and child, our knowledge of the human placenta is limited due to lack of functional experimental models1. Upon implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, the proliferative villous cytotrophoblast cells (VCT) differentiate into two main sub-populations: syncytiotrophoblast (SCT), the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast (EVT) that anchor the placenta to the maternal decidua and transform the maternal spiral arteries2. Here, we describe the generation of long-term, genetically-stable organoid cultures of trophoblast cells that can differentiate to SCT and EVT. We used HLA-typing to confirm the organoids are fetally-derived, and verified their identity against four trophoblast-specific criteria3. The cultures organise into villous-like structures, and we detected secretion of placental-specific peptides and hormones, including hCG, GDF15, PSGs and PAPPA, by mass spectrometry. The organoids also differentiate to HLA-G+ EVT that vigorously invade in 3D. Analysis of the methylome reveals the organoids closely resemble normal first-trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.

Antibodies: The major participants in maternal-fetal interaction.

The aim of this study is to improve our understanding of the mechanisms involved in maternal-fetal immune tolerance. We searched the related literatures and overviewed the major antibodies associated with pregnancy and described in details their possible roles in mediating maternal-fetal interactions. Antibodies classified into different types based on their functional or structural characteristics were summarized, including immunoglobulin G, blocking antibody, nonprecipitating asymmetric antibody, antiphospholipid antibody, antitrophoblast antibody and antipaternal antibody. The presence and levels of various circulating antibodies in pregnancy may play a crucial role in the occurrence, development and termination of pregnancy.

Preliminary Evaluation of Fetal Congenital Heart Defects Changes on Fetal-Maternal Heart Rate Coupling Strength.

Monitoring fetal heart rate in an important aspect in evaluating fetal well being. Maternal-fetal interaction has shown evolution during fetal maturation. In this work, we studied maternal-fetal heart rate synchronization in early and late gestation fetuses. We also evaluated variations in the synchronization due to congenital heart defect (CHD). Maternal-fetal heart rate synchronization for 22 early gestation (Age < 32 weeks), $late gestation (Age >32 weeks) and 7 CHD fetuses (5 of them with gestational age < 32 weeks). The synchronization ratio between the mother and the fetus was more localized at certain fetus heart rate in the early gestation group while it was spreading over more fetal heart rate for the late group. For example, for maternal primary cycle of 3 beat- to-beat (m=3), the synchronization ratio of 5 fetus beats (n=5) contributed 60±30% of the whole coupling ratios for the early group while it contributed 30°30% for the late group (p< 0.01). On the other hand, the coupling ratio of m:n=3:7 contributed 4±17% of the early group and 13±24% for the late group (p< 0.05). The standard deviation of the phase coherence index $(\lambda_{-\mathrm{S}\mathrm{D}})$ for both the late and the CHD groups were significantly higher than the early group at different values. For example, $\lambda -\mathrm{S}\mathrm{D} was 0.006\pm 0.004$ for the early group while it was 0.009±0.008 for the late group (p< 0.01) and 0.01± 0.002 for the CHD group (p< 0.01) for m=3. The variation between the early and late normal groups might indicate a healthy development of the autonomic nervous system while the higher variation in the CHD group could be a good marker for impairment of the cardiac autonomic activity. Further coupling analysis with more abnormal cases is needed to verify these findings.

Fetal Sex, Need for Insulin, and Perinatal Outcomes in Gestational Diabetes Mellitus: An Observational Cohort Study

PurposeThis was a prospective observational cohort study that aimed to determine whether fetal sex influences the maternal and fetal outcomes of gestational diabetes mellitus (GDM). MethodsIn this study, 327 European primiparous women were consecutively recruited after diagnosis of GDM. AUC on the oral glucose tolerance test (OGTT), need for insulin therapy, maternal and obstetrical outcomes, and fetal fat mass (by measuring the thickness of the anterior abdominal subcutaneous tissue) were recorded and compared between the two subgroups of female and male fetuses. FindingsDespite the absence of differences in multiple comparisons of the OGTT, the AUC–OGTT was significantly higher in women carrying a male fetus (22.6 [3.2] mmol/L vs 19.7 [2.8] mmol/L). The abdominal fat thickness appeared to increase with gestational age, with higher growth in male fetuses than in female fetuses. The overall risk of need for insulin therapy was significantly higher in women carrying a male fetus (odds ratio = 1.837). At delivery, birthweight was higher in males than in females only if adjusted for gestational age, similarly for placental weight, otherwise there were no significant differences between the groups in total length of gestation, rates of cesarean delivery, and Apgar scores. ImplicationsOverall, our data propose an association between fetal sex and GDM outcomes, suggesting the hypothesis that in maternal–fetal interactions, the fetus can affect maternal glucose metabolism.

Genomic imprinting, growth and maternal-fetal interactions.

In the 1980s, mouse nuclear transplantation experiments revealed that both male and female parental genomes are required for successful development to term ( McGrath and Solter, 1983; Surani and Barton, 1983). This non-equivalence of parental genomes is because imprinted genes are predominantly expressed from only one parental chromosome. Uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith-Wiedemann and Silver-Russell syndromes (reviewed in Peters, 2014). More than 100 imprinted genes have now been discovered and the functions of many of these genes have been assessed in murine models. The first such genes described were the fetal growth factor insulin-like growth factor 2 (Igf2) and its inhibitor Igf2 receptor (Igf2r) ( DeChiara et al., 1991; Lau et al., 1994; Wang et al., 1994). Since then, it has emerged that most imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have been shown to affect postnatal growth and energy homeostasis. Given that abnormal birthweight correlates with adverse adult metabolic health, including obesity and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to fetal and postnatal growth, with implications for lifelong health and disease.

Use of field-portable ultrasonography reveals differences in developmental phenology and maternal egg provisioning in two sympatric viviparous snakes.

A thorough understanding of the life cycles underlying the demography of wild species is limited by the difficulty of observing hidden life‐history traits, such as embryonic development. Major aspects of embryonic development, such as the rate and timing of development, and maternal–fetal interactions can be critical features of early‐life fitness and may impact population trends via effects on individual survival. While information on development in wild snakes and lizards is particularly limited, the repeated evolution of viviparity and diversity of reproductive mode in this clade make it a valuable subject of study. We used field‐portable ultrasonography to investigate embryonic development in two sympatric garter snake species, Thamnophis sirtalis and Thamnophis elegans in the Sierra Nevada mountains of California. This approach allowed us to examine previously hidden reproductive traits including the timing and annual variation in development and differences in parental investment in young. Both species are viviparous, occupy similar ecological niches, and experience the same annual environmental conditions. We found that T. sirtalis embryos were more developmentally advanced than T. elegans embryos during June of three consecutive years. We also found that eggs increased in volume more substantially across developmental stages in T. elegans than in T. sirtalis, indicating differences in maternal provisioning of embryos via placental transfer of water. These findings shed light on interspecific differences in parental investment and timing of development within the same environmental context and demonstrate the value of field ultrasonography for pursuing questions relating to the evolution of reproductive modes, and the ecology of development.

Current model systems for the study of preeclampsia.

Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the values of blood pressure, urine protein concentrations, symptomatology, and onset of disease there is a wide range of phenotypes, from mild forms developing predominantly at the end of pregnancy to severe forms developing in the early stage of pregnancy. In the worst cases severe forms of PE could lead to systemic endothelial dysfunction, eclampsia, and maternal and/or fetal death. Worldwide the fetal morbidity and mortality related to PE is calculated to be around 8% of the total pregnancies. PE still being an enigma regarding its etiology and pathophysiology, in general a deficient trophoblast invasion during placentation at first stage of pregnancy, in combination with maternal conditions are accepted as a cause of endothelial dysfunction, inflammatory alterations and appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in vivo, and in silico models have been used to evaluate the PE pathophysiology as well as to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This review focuses on the most common models used for the study of PE, including those related to placental development, abnormal trophoblast invasion, uteroplacental ischemia, angiogenesis, oxygen deregulation, and immune response to maternal-fetal interactions. The advances in mathematical and computational modeling of metabolic network behavior, gene prioritization, the protein-protein interaction network, the genetics of PE, and the PE prediction/classification are discussed. Finally, the potential of these models to enable understanding of PE pathogenesis and to evaluate new preventative and therapeutic approaches in the management of PE are also highlighted. Impact statement This review is important to the field of preeclampsia (PE), because it provides a description of the principal in vitro, in vivo, and in silico models developed for the study of its principal aspects, and to test emerging therapies or biomarkers predicting the syndrome before their evaluation in clinical trials. Despite the current advance, the field still lacking of new methods and original modeling approaches that leads to new knowledge about pathophysiology. The part of in silico models described in this review has not been considered in the previous reports.