Academic literature on the topic 'Placental-fetal phenotype'

Glucocorticoids are recognised as a key fetal programming signal, with excess glucocorticoid exposure in utero linked to various adverse outcomes in offspring including delayed puberty onset, hyperleptinemia and hypertension. Fetal glucocorticoid exposure is controlled by the placental glucocorticoid barrier, whereby two 11β-hydroxysteroid dehydrogenase enzymes regulate transplacental passage of active glucocorticoids (cortisol and corticosterone). Fetal programming by glucocorticoids is likely due to their actions in several fetal tissues, but may also be mediated via effects exerted within the placenta. Indeed, in our model of fetal programming, treatment of pregnant rats with dexamethasone inhibits both fetal and placental growth, and dose–response experiments suggest that the placenta is more susceptible than the fetus to this growth inhibition. Moreover, glucocorticoid treatment stimulates placental apoptosis and reduces expression of several placental gene products, including PPARγ, Muc1 and VEGF. This down-regulation of gene expression occurs specifically within the labyrinth zone, the region of maternal–fetal exchange, and is associated with a marked reduction in placental vascularity. These data indicate that excess placental glucocorticoid exposure is likely to compromise fetal nutrient supply, which in turn could result in adverse fetal programming effects. Subsequent, long-term effects of fetal programming in offspring can either be amplified or attenuated by the postnatal environment. Thus, while programmed hyperphagia and adiposity are exacerbated by a high-energy diet in postnatal life, we have demonstrated that programmed hyperleptinemia and hypertension are prevented by a postnatal diet enriched with omega-3 fatty acids. These effects are mediated, in part, by changes in the adipocyte phenotype, most notably in relation to leptin mRNA expression. In conclusion, fetal programming by glucocorticoids is likely to be mediated, in part, by their detrimental effects on placental growth and vascularity. Postnatally, adverse outcomes of glucocorticoid-induced fetal programming can be prevented by dietary manipulations, thus raising the possibility of preventative, therapeutic interventions.

Environmental conditions during pregnancy determine birthweight, neonatal viability and adult phenotype in human and other animals. In part, these effects may be mediated by the placenta, the principal source of nutrients for fetal development. However, little is known about the environmental regulation of placental phenotype. Generally, placental weight is reduced during suboptimal conditions like maternal malnutrition or hypoxaemia but compensatory adaptations can occur in placental nutrient transport capacity to help maintain fetal growth. In vivo studies show that transplacental glucose and amino acid transfer adapt to the prevailing conditions induced by manipulating maternal calorie intake, dietary composition and hormone exposure. These adaptations are due to changes in placental morphology, metabolism and/or abundance of specific nutrient transporters. This review examines environmental programming of placental phenotype with particular emphasis on placental nutrient transport capacity and its implications for fetal growth, mainly in rodents. It also considers the systemic, cellular and molecular mechanisms involved in signalling environmental cues to the placenta. Ultimately, the ability of the placenta to balance the competing interests of mother and fetus in resource allocation may determine not only the success of pregnancy in producing viable neonates but also the long-term health of the offspring.

The study of placental hematopoietic progenitor cells (HPCs) and comparison of their properties with other fetal and adult HPCs is necessary for assessing of their possible clinical application. It has been shown that HPCs from placenta are heterogeneous by phenotype: placental tissue contains three populations with different level of CD34 expression such as CD34+++CD45low/-, CD34++CD45low/- and CD34+/lowCD45low/-. Similar to fetal liver placenta contains both, population of CD34++CD45low/- and CD34+CD45low/-cells, suggesting hematopoiesis in placental tissue. CD34++CD45low/- population also expressed CD133, almost negative for lineage markers, and had lymphocyte-like morphology conforming the presence of primitive HPCs in this population. Additionally, we found later progenitors with phenotype CD34+/lowCD45+ in placental tissueas the majority of these cells expressed hematopoietic lineage markers. Population with phenotype CD34+++CD45low was observed in the placenta that may evidence for their generation in the placental tissue or migration from the other sites of hematopoiesis and changing phenotype under placental microenvironment.

The placenta, a major determinant of fetal growth in eutherians, facilitates maternal-fetal cross talk and mediates programming of postnatal phenotype via genetic and epigenetic mechanisms. However, magnitude and specificity of effects of maternal and paternal genomes on placental and fetal phenotype and their relationships are unclear. Using an outbred bovine intra-species model with well-defined Bos taurus taurus and Bos taurus indicus maternal and paternal genetics, we generated purebred and reciprocal cross fetuses (Animal Ethics No. S-094-2005) to dissect and quantify effects of parental genomes, fetal sex, and nongenetic maternal effects (maternal weight and post-conception maternal weight gain) on 41 gross and histomorphological feto-placental parameters. Analysis of data from 73 fetuses recovered at midgestation (Day 153) with general linear models (Xiang et al. 2014 JBMR http://dx.doi.org/10.1002/jbmr.2263) using the GLM procedure of R version 22.14 (R Development Core Team, Vienna, Austria) revealed that maternal and paternal genome combined explained the highest proportion of variation (47.2–99.5%) in 30 investigated parameters with significant (P < 0.05–0.0001) models. Fetal sex accounted for up to 32.2% (P < 0.05–0.0001) and nongenetic maternal effects for up to 25.1% (P < 0.05–0.001) of variation in 11 and 14 parameters, respectively. Partitioning of parental (epi)genome variation showed that the maternal genome predominantly contributed to variation in gross (80.3–95.7%; P < 0.05–0.0001) and histomorphological (51.5–82.1%; P < 0.05–0.0001) placental parameters, fetal weight (54.1%; P < 0.0001), and fetal organ weights (43.7–73.1%; P < 0.05–0.0001), whereas the paternal genome predominantly contributed to fetal fluids weight (73.0%; P < 0.001), umbilical cord weight (73.9%; P < 0.05) and length (73.2%; P < 0.01), and placental (69.6%; P < 0.05) and umbilical cord (83.2%; P < 0.0001) efficiency. Our finding that the maternal genome determined placental phenotype (i.e. nutrient source) and the paternal genome determined umbilical cord and fetal fluid phenotype (i.e. nutrient flow) is in line with predicted expression patterns of genomic imprinting effects by both maternal-offspring coadaptation (Wolf and Hager 2006 PLoS Biol. 4, e380) and conflict-of-interest (Moore and Haig 1991 Trends Genet 7, 45–49) hypotheses in the feto-placental unit. Furthermore, there were 4 maternal genome determined relationships between placental weights and umbilical cord phenotype (P < 0.05–0.0001) and 28 paternal genome and/or fetal sex-determined relationships between fetus-, organ- and fetal fluid weights and umbilical cord phenotype (P < 0.05–0.0001). The finding of specific relationships between placenta and fetus merging in clusters differentiated by maternal and paternal genome effects suggests the existence of (epi)genetic-regulated morphological modules within the feto-placental unit.Funded by the JS Davies Bequest.

Epidemiological studies have shown a clear link between fetal growth retardation and an increased propensity for later cardiovascular disease in adults. It has been hypothesized that such early fetal deprivation “programs” individuals toward a life-long metabolical “thrifty phenotype” that predisposes adults to such diseases. Here we test this hypothesis, and its possible genetic basis, in rat recombinant inbred (RI) strains that uniquely allow the longitudinal studies necessary for its testing. Placental and fetal weights were determined on day 20 of pregnancy in (at least) 6 litters from each of 25 available BXH/HXB RI strains and from their SHR and BN-Lx progenitors and were correlated with metabolic traits determined in adult rats from the same inbred lines. Quantitative trait loci (QTLs) associated with placental and fetal weights were identified by total genome scanning of RI strains using the Map Manager QTX program. Heritabilities of placental and fetal weights were 56% and 62%, respectively, and total genome scanning of RI strains revealed QTLs near the D1Rat266 marker on chromosome 1 and near the D15Rat101 marker on chromosome 15 that were significantly associated with fetal and placental weights respectively. Placental weights correlated with fetal weights ( r = 0.60, P = 0.001), while reduced fetal weights correlated with increased insulin concentrations during glucose tolerance test ( r = −0.71, P = 0.0001) and with increased serum triglycerides ( r = −0.54, P = 0.006) in adult rats. Our results suggest that predisposition toward a thrifty phenotype associated with decreased placental weight and restricted fetal growth is in part genetically determined.

Introduction While many placental lesions have been identified and defined, the significance of multiple overlapping lesions has not been addressed. The purpose of our analysis was to evaluate overlapping patterns of placental pathology and determine meaningful phenotypes associated with adverse birth outcomes. Methods Placental pathology reports were obtained from a single hospital between 2009 and 2018. Placental lesions were grouped into four major categories: acute inflammation (AI), chronic inflammation (CI), maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM). Within each category, lesions were classified as not present, low grade or high grade. Combinations of pathologies were evaluated in relation to preterm birth (<37 weeks) and small for gestational age (SGA) infant (birthweight <10th percentile). Results During the study period, 19,027 placentas were reviewed by pathologists. Results from interaction models indicate that MVM and MVM in combination with CI and/or FVM are associated with the greatest odds of SGA infant and PTB. When incorporating grade, we identified 21 phenotype groups, each with characteristic associations with the SGA infant and patterns of PTB. Discussion We have developed a comprehensive and meaningful placental phenotype that incorporates severity and multiplicity of placental lesions. We have also developed a web application to facilitate phenotype determination ( https://placentaexpression.shinyapps.io/phenotype ).

Glucocorticoids have an important role in development of the metabolic phenotype in utero. They act as environmental and maturational signals in adapting feto-placental metabolism to maximize the chances of survival both before and at birth. They influence placental nutrient handling and fetal metabolic processes to support fetal growth, fuel storage and energy production with respect to nutrient availability. More specifically, they regulate the transport, utilization and production of a range of nutrients by the feto-placental tissues that enables greater metabolic flexibility in utero while minimizing any further drain on maternal resources during periods of stress. Near term, the natural rise in fetal glucocorticoid concentrations also stimulates key metabolic adaptations that prepare tissues for the new energy demanding functions after birth. Glucocorticoids, therefore, have a central role in the metabolic communication between the mother, placenta and fetus that optimizes offspring metabolic phenotype for survival to reproductive age. This review discusses the effects of maternal and fetal glucocorticoids on the supply and utilization of nutrients by the feto-placental tissues with particular emphasis on studies using quantitative methods to assess metabolism in rodents and sheep in vivo during late pregnancy. It considers the routes of glucocorticoid overexposure in utero, including experimental administration of synthetic glucocorticoids, and the mechanisms by which these hormones control feto-placental metabolism at the molecular, cellular and systems levels. It also briefly examines the consequences of intrauterine glucocorticoid overexposure for postnatal metabolic health and the generational inheritance of metabolic phenotype.

Pre-gestational type 1-diabetes (T1D) increases the risk of miscarriage and congenital malformations and programs the offspring to develop metabolic syndrome in adulthood. Management of maternal diabetes is essential during gestation but could be also highly important around the time of conception. Using a rabbit model, the effects of maternal T1D during the periconceptional period on pre-implantation blastocysts have been well documented, but the effects on feto-placental phenotype at 28 dpc (term = 31 days) has not been explored. Diabetes was induced by Alloxan in dams 7 days before mating. Glycemia was maintained at 15 to 20 mmol L–1 with exogenous insulin injections. At 4 dpc, embryos were collected and transferred into nondiabetic recipients. At 28 dpc, control (C) and diabetic (D) fetuses were collected for biometric records, placental analyses including stereology and gene expression, and lipid profiles of feto-placental tissues by gas chromatography. Lipid data were analysed by principal component analysis. D-fetuses were growth retarded, hyperglycemic, and dyslipidemic compared with C fetuses. Moreover, placental efficiency was much higher in D- than in C-fetuses. The volume density of fetal vessels was significantly decreased in D-placentas compared to C-placentas, whereas the volume density of trophoblast tended to increase (P = 0.051). This morphometric disruption was associated with a deregulation of the expression of genes related to nutrient supply and lipid metabolism. In fetal plasma, a specific fatty acid signature was observed in D- and C-groups. Moreover, the composition of placental and fetal liver membranes differed according to maternal status and fetal sex. Tissues from D-fetuses contained significantly more n-6 polyunsaturated fatty acids compared with C. Docosahexaenoic acid decreased whereas linoleic acid increased in the cardiac membranes of D-fetuses, indicating a higher risk of ischemia. This study demonstrates that exposure to high plasma glucose during the short periconceptional period is sufficient to adversely program fetal phenotype by reducing fetal growth, altering placental function and lipid profiles in all fetal tissues.

Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to “placental insufficiency”: inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS−/−) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS−/− fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS−/− dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS−/− fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal 14C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent 14C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS−/− fetuses, indicating diminished placental nutrient transport. eNOS−/− mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS−/− mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates “uteroplacental hypoxia,” providing a new framework for understanding the etiology of FGR in human pregnancy.

Lifelong development is largely programmed prenatally. Genetic and epigenetic factors, such as mitochondrial (mt) DNA variation and parent-of-origin effects, significantly contribute to variation in important prenatal phenotypes that determine lifetime development, including placenta and fetal musculoskeletal system. Such effects initially impact on transcriptome expression levels and eventually give rise to altered phenotypic traits. However, data regarding the overall magnitude and specificity of maternal and paternal genome effects in mammalian prenatal development is lacking. The present study aimed to dissect and quantify differential maternal and paternal genome effects on specific placental and fetal traits, and associated transcriptomic events which drive prenatal development. A large bovine fetal resource (n=73), consisting of both purebreds and reciprocal hybrids with Bos taurus taurus (Angus) and Bos taurus indicus (Brahman) (epi) genetics, was used in this study. We examined 41 gross- and histo-morphological placental and fetal traits, 51 fetal bone weight and geometry parameters, and 22 myofibre characteristics and muscle mass parameters using morphometrical and/or immunohistochemical methods. Expression of the long non-coding RNA H19 in fetal muscle was determined by real time quantitative PCR. Profiles of mRNA and microRNA expression were obtained with microarrays that contained 24,027 and 13,133 mammalian probe sets, respectively, to assess transcript abundances in fetal liver. Phenotypic data were analysed by Analysis of Variance (ANOVA) using general linear models with nested effects and transcriptome data were analysed with microarray ANOVA procedures. The analyses identified 49 significant placental and fetal traits, including five principal components representing 51 bone parameters, and H19 gene expression levels in muscle, with ANOVA model significance levels (P) ranging from 3×10⁻²-9×10⁻¹⁷. We showed that parental genomes contributed to the largest proportion of variation explained by linear models for a majority of placental and fetal traits. Fetal sex was the next most significant factor to explain variation in these traits and non-genetic maternal effects, such as post-conception weight gain and final maternal weight, explained the least amount of variation. Significant effects of the maternal genome (P<5×10⁻²-5×10⁻¹³) predominantly contributed to genetic variation in: (i) Gross- and histo-morphological placental traits and fetal organ weights (59.6−99.9%,); (ii) most extracted principle components (PCs) representing bone weight and geometry traits, including PC1/bone mass (74%), PC3/limb elongation (73%), PC4/flat bone elongation (74%) and PC5/axial skeletal growth (97%) and (iii) most myofibre characteristics including fast myofibre cross-sectional area (CSA, 93%), total cell CSA (82%), absolute mass of studied muscles (59-88%) and H19 transcript abundance in fetal muscle (76%). Conversely, significant paternal genome (P<4×10⁻²-7×10⁻⁸) predominantly contributed to genetic variation in: (i) Fetal fluids weight (73%), umbilical cord weight and length (73%), maternal placenta (70%) and umbilical cord (83%) efficiencies; (ii) PC2/limb ossification (95%) and (iii) Relative mass of studied muscles to fetal weight (54-97%). Further, using nested effects in ANOVA, we found that maternal genome strongly determined regressions between placental weights and umbilical cord traits (P<4×10⁻²-2×10⁻⁶), whereas paternal genome and/or fetal sex determined regressions between weight of fetus, fetal organ and fetal fluid s and umbilical cord traits (P<5×10⁻²-10×10⁻⁸). For fetal liver transcription profiles, maternal genome strongly affected expression levels of: (i) Twenty-four mRNA transcripts (false discovery rate, FDR adjusted P<4×10⁻²-10×10⁻⁶), 13 of which were located in the mt genome and (ii) ten autosomal non-coding RNA transcripts including mammalian SNORD113-9, small nucleolar (sno)RNA, MIR187 and MIR1973 microRNA (FDR adjusted P<5×10⁻²-8×10⁻³). Paternal genome moderately affected expression levels of: (i) Forty-seven autosomal mRNA transcripts (FDR adjusted, P<5×10⁻²-4×10⁻²) (ii) MIR184 microRNA transcripts in five mammalian species (FDR adjusted, P<5×10⁻²-4×10⁻²). Two significant coexpression networks, between 86 significant mRNAs and non-coding RNA transcripts, were also identified for differential maternal and paternal genome effects. Our results show, for the first time, that a wide range of phenotypic and molecular traits within the placental-fetal system are affected by differential maternal and paternal genome and fetal sex effects. Identified differential maternal and paternal genome effects on specific placental and fetal traits are consistent with expression patterns of parent-of-origin effects predicted by both conflict-of-interest and maternal-offspring coadapdation hypotheses, thereby providing important insights to accommodate both hypotheses that explain the evolutionary basis of genomic imprinting effects. Observed complex, and predominantly maternal genome, effects are suggested to result from interaction between epigenetic factors from nuclear and mt genomes via RNA interference. This is further evidence for complex epigenetic crosstalk and coordination that contributes to mammalian prenatal development. Identified morphological and transcriptional modules within the placental-fetal system help to provide a new level of understanding prenatal development, i.e., systematic integration of omics data. Detailed molecular profiles of all core tissues and organs are now required to elucidate genetic, epigenetic and non-genetic components and interactions that control variation in placental and fetal phenotype. Future studies linking genome and epigenome with phenome data covering the complete placental-fetal system will provide a new multi-layer picture of understanding coordination for molecular and phenotypic events driving mammalian prenatal development.
Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences , 2014.

Prenatal growth is influenced by bidirectional exchange between the fetal and maternal systems that programme birth weight and postnatal phenotype. Fetal fluids are essential but unexplored areas for prenatal growth. This study examined allantoic and amniotic fluids and maternal blood in a Bos taurus, Bos indicus bovine model to provide fundamental information that is lacking regarding (i) changes in clinico-chemical parameters of maternal blood in early and midgestation and their relationships with placental-embryo/fetal weights (ii) differences in clinico-chemical parameters of allantoic and amniotic fluids of bovine concepti in early and midgestation, (iii) effects of genetics and sex on clinico-chemical parameters of fetal fluids and their relationships with feto-placental phenotype, and (iv) the effects of conceptus sex and genetics on maternal blood parameters. Purebred and reciprocal cross Bos taurus, (Bt) and Bos taurus indicus, (Bi) concepti were recovered in early gestation (Day 48, n = 60), and midgestation (Day 153, n = 72), (term ~ 280 days). Fetal fluids and maternal blood were sampled and analysed for clinico-chemical parameters. Insulin-like growth factors and thyroid hormones were assessed in maternal blood. Effects of genetics and sex on the measured parameters were determined using general linear models, and relationships with feto-placental phenotype assessed by linear regression. Breed effects on maternal electrolytes, metabolites and enzymes and their relationships with placental-embryo/fetal weights provide evidence of differences in maternal mineral metabolism, liver and kidney functions that influence conceptus growth. Stage- and genetic-specific differences were seen in clinico-chemical parameters of fetal fluids, which likely reflect differences in feto-placental phenotype. Greater maternal genome effects on fetal fluid in early gestation reflect the significance of placenta and maternal environment and represent maternal-offspring coadaptation. Paternal genome and maternal by paternal genome interactions exert stronger effects on amniotic fluid suggesting greater fetal influence and (epi)genetic regulation in line with the conflict-of-interest hypothesis. Conceptus sex had strong effects on fetal fluid metabolites in early gestation, while parental genome by sex effects influence amniotic fluid parameters at both stages. Furthermore, paternal genome and sex interacted with non-genetic maternal effects to affect fetal fluid parameters at both stages. Significant relationships between maternally controlled allantoic fluid parameters and embryo-placental weights suggest a critical role of allantoic fluid for embryonic development. In midgestation, paternally controlled amniotic fluid Na/K ratio showed significant relationships with fetal weight and fetal fluid volume, suggesting a paternal influence on amniotic fluid water and nutrient transfer. Conceptus sex and genetics affected maternal physiology in a maternal genetics dependent manner by influencing key parameters of maternal mineral metabolism, liver function and thyroid status. In conclusion, this study provides reference values for clinico-chemical parameters of fetal fluids and maternal serum in Bt and Bi concepti in early and midgestation. Results support the hypothesis that fetal fluid parameters are affected by genetics and sex, and are related to feto-placental phenotype, demonstrating their critical role in prenatal growth. This study highlights the importance of considering conceptus sex, genetics and maternal genetics as factors that impact maternal physiology and demonstrates the need for genetic background-specific maternal assessment.
Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2020

Folate is a coenzyme in multiple biochemical pathways involving one-carbon metabolism, including amino acid metabolism, DNA and RNA synthesis, homocysteine metabolism, and methylation of DNA. The most overt consequence of folate deficiency is megaloblastic anaemia caused by the inhibition of DNA synthesis in red blood cell production. Folate deficiency may also influence the ability to maintain DNA methylation patterns in replicating cells, resulting in lasting phenotypic changes. Embryogenesis and fetal growth require higher levels of folate, which must be supplied maternally during pregnancy. A link between low maternal folate levels and the occurrence of neural tube defects has long been recognized. Other effects in pregnancy include increased risks of pre-eclampsia and placental vascular disorders. The general recommendation is for supplementation prior to conception and throughout pregnancy with 400 #amp;#x03BC;g of folic acid in tablet form, in addition to dietary sources, which can reduce the risk of neural tube defects.