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Fowden, Abigail L., and Colin P. Sibley. "Placental phenotype and fetal growth." Journal of Physiology 587, no. 14 (July 14, 2009): 3429. http://dx.doi.org/10.1113/jphysiol.2009.175968.
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Waddell, B. J., C. S. Wyrwoll, D. P. Hewitt, and P. J. Mark. "037. Impact of glucocorticoids on fetal-placental growth and the postnatal phenotype." Reproduction, Fertility and Development 17, no. 9 (2005): 72. http://dx.doi.org/10.1071/srb05abs037.
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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.
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Vaughan, O. R., A. N. Sferruzzi-Perri, P. M. Coan, and A. L. Fowden. "Environmental regulation of placental phenotype: implications for fetal growth." Reproduction, Fertility and Development 24, no. 1 (2012): 80. http://dx.doi.org/10.1071/rd11909.
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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.
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Kuchma, M., V. Shablii, V. Kyryk, A. Onishchenko, Yu Shablii, L. Lukash, and G. Lobintseva. "Phenotypic heterogenecity of hematopoietic progenitor cells from placental tissue: comarative analysis with umbilical cord blood and fetal liver." Cell and Organ Transplantology 1, no. 1 (November 3, 2013): 70–73. http://dx.doi.org/10.22494/cot.v1i1.52.
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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.
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Xiang, R., C. A. S. Estrella, C. J. Fitzsimmons, Z. A. Kruk, D. A. Thomsen, D. L. Rutley, K. L. Kind, C. T. Roberts, and S. Hiendleder. "97 MAGNITUDE AND SPECIFICITY OF EFFECTS OF MATERNAL AND PATERNAL GENOMES ON THE FETO-PLACENTAL UNIT." Reproduction, Fertility and Development 27, no. 1 (2015): 141. http://dx.doi.org/10.1071/rdv27n1ab97.
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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.
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Buresova, Martina, Vaclav Zidek, Alena Musilova, Miroslava Simakova, Alena Fucikova, Vlasta Bila, Vladimir Kren, Ludmila Kazdova, Robert Di Nicolantonio, and Michal Pravenec. "Genetic relationship between placental and fetal weights and markers of the metabolic syndrome in rat recombinant inbred strains." Physiological Genomics 26, no. 3 (August 2006): 226–31. http://dx.doi.org/10.1152/physiolgenomics.00056.2006.
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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.
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Freedman, Alexa A., Lauren S. Keenan-Devlin, Ann Borders, Gregory E. Miller, and Linda M. Ernst. "Formulating a Meaningful and Comprehensive Placental Phenotypic Classification." Pediatric and Developmental Pathology 24, no. 4 (April 19, 2021): 337–50. http://dx.doi.org/10.1177/10935266211008444.
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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 ).
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Fowden, Abigail L., Owen R. Vaughan, Andrew J. Murray, and Alison J. Forhead. "Metabolic Consequences of Glucocorticoid Exposure before Birth." Nutrients 14, no. 11 (May 30, 2022): 2304. http://dx.doi.org/10.3390/nu14112304.
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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.
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Rousseau-Ralliard, D., A. Tarrade, R. Thieme, R. Brat, MC Aubrière, M. Dahirel, A. Rolland, et al. "119 A SHORT PERICONCEPTIONAL MATERNAL HYPERGLYCEMIA IS SUFFICIENT TO DISRUPT THE FETO-PLACENTAL PHENOTYPE IN A RABBIT MODEL." Reproduction, Fertility and Development 27, no. 1 (2015): 151. http://dx.doi.org/10.1071/rdv27n1ab119.
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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.
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Kusinski, Laura C., Joanna L. Stanley, Mark R. Dilworth, Cassandra J. Hirt, Irene J. Andersson, Lewis J. Renshall, Bernadette C. Baker, et al. "eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 1 (July 1, 2012): R86—R93. http://dx.doi.org/10.1152/ajpregu.00600.2011.
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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.
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Latendresse, Gwen. "Perinatal Genomics." Annual Review of Nursing Research 29, no. 1 (December 2011): 331–51. http://dx.doi.org/10.1891/0739-6686.29.331.
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Significant maternal, fetal, and newborn morbidity and mortality can be attributed to complications of pregnancy. There are direct links between perinatal complications and poor fetal/newborn development and impaired cognitive function, as well as fetal, newborn, and maternal death. Many perinatal complications have pathophysiologic mechanisms with a genetic basis. The objective of this chapter is to focus on perinatal genomics and the occurrence of two specific complications: preterm birth and dysfunctional placental phenotype. This chapter includes discussions of genetic variation, mutation and inheritance, gene expression, and genetic biomarkers in relation to preterm birth, in addition to the impact of maternal tobacco smoke exposure on placental phenotype. The concept of epigenetics is also addressed, specifically the regulation of gene expression in the placenta and fetal origins of adult health and disease. There is great potential for nurse-researchers to make valuable contributions to perinatal genomics investigations, but this requires perseverance, increased genetics-based understanding and skills, as well as multidisciplinary mentorship.
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Fowden, A. L., E. J. Camm, and A. N. Sferruzzi-Perri. "Effects of Maternal Obesity On Placental Phenotype." Current Vascular Pharmacology 19, no. 2 (December 30, 2020): 113–31. http://dx.doi.org/10.2174/1570161118666200513115316.
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: The incidence of obesity is rising rapidly worldwide with the consequence that more women are entering pregnancy overweight or obese. This leads to an increased incidence of clinical complications during pregnancy and of poor obstetric outcomes. The offspring of obese pregnancies are often macrosomic at birth although there is also a subset of the progeny that are growth-restricted at term. Maternal obesity during pregnancy is also associated with cardiovascular, metabolic and endocrine dysfunction in the offspring later in life. As the interface between the mother and fetus, the placenta has a central role in programming intrauterine development and is known to adapt its phenotype in response to environmental conditions such as maternal undernutrition and hypoxia. However, less is known about placental function in the abnormal metabolic and endocrine environment associated with maternal obesity during pregnancy. This review discusses the placental consequences of maternal obesity induced either naturally or experimentally by increasing maternal nutritional intake and/or changing the dietary composition. It takes a comparative, multi-species approach and focusses on placental size, morphology, nutrient transport, metabolism and endocrine function during the later stages of obese pregnancy. It also examines the interventions that have been made during pregnancy in an attempt to alleviate the more adverse impacts of maternal obesity on placental phenotype. The review highlights the potential role of adaptations in placental phenotype as a contributory factor to the pregnancy complications and changes in fetal growth and development that are associated with maternal obesity.
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Almeida-Toledano, Laura, Vicente Andreu-Fernández, Rosa Aras-López, Óscar García-Algar, Leopoldo Martínez, and María Dolores Gómez-Roig. "Epigallocatechin Gallate Ameliorates the Effects of Prenatal Alcohol Exposure in a Fetal Alcohol Spectrum Disorder-Like Mouse Model." International Journal of Molecular Sciences 22, no. 2 (January 13, 2021): 715. http://dx.doi.org/10.3390/ijms22020715.
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Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.
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Odorizzi, Pamela M., Prasanna Jagannathan, Tara I. McIntyre, Rachel Budker, Mary Prahl, Ann Auma, Trevor D. Burt, et al. "In utero priming of highly functional effector T cell responses to human malaria." Science Translational Medicine 10, no. 463 (October 17, 2018): eaat6176. http://dx.doi.org/10.1126/scitranslmed.aat6176.
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Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, we assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. We found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.
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Coan, P. M., O. R. Vaughan, Y. Sekita, S. L. Finn, G. J. Burton, M. Constancia, and A. L. Fowden. "Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice." Journal of Physiology 588, no. 3 (January 29, 2010): 527–38. http://dx.doi.org/10.1113/jphysiol.2009.181214.
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Yamaleyeva, Liliya M., Victor M. Pulgar, Sarah H. Lindsey, Larissa Yamane, Jasmina Varagic, Carolynne McGee, Mauro daSilva, Paula Lopes Bonfa, Susan B. Gurley, and K. Bridget Brosnihan. "Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity." American Journal of Physiology-Endocrinology and Metabolism 309, no. 1 (July 1, 2015): E84—E94. http://dx.doi.org/10.1152/ajpendo.00596.2014.
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Angiotensin-converting enzyme 2 (ACE2) knockout is associated with reduced fetal weight at late gestation; however, whether uteroplacental vascular and/or hemodynamic disturbances underlie this growth-restricted phenotype is unknown. Uterine artery reactivity and flow velocities, umbilical flow velocities, trophoblast invasion, and placental hypoxia were determined in ACE2 knockout (KO) and C57Bl/6 wild-type (WT) mice at day 14 of gestation. Although systolic blood pressure was higher in pregnant ACE2 KO vs. WT mice (102.3 ± 5.1 vs. 85.1 ± 1.9 mmHg, n = 5–6), the magnitude of difference was similar to that observed in nonpregnant ACE2 KO vs. WT mice. Maternal urinary protein excretion, serum creatinine, and kidney or heart weights were not different in ACE2 KO vs. WT. Fetal weight and pup-to-placental weight ratio were lower in ACE2 KO vs. WT mice. A higher sensitivity to Ang II [pD2 8.64 ± 0.04 vs. 8.5 ± 0.03 (−log EC50)] and greater maximal contraction to phenylephrine (169.0 ± 9.0 vs. 139.0 ± 7.0% KMAX), were associated with lower immunostaining for Ang II receptor 2 and fibrinoid content of the uterine artery in ACE2 KO mice. Uterine artery flow velocities and trophoblast invasion were similar between study groups. In contrast, umbilical artery peak systolic velocities (60.2 ± 4.5 vs. 75.1 ± 4.5 mm/s) and the resistance index measured using VEVO 2100 ultrasound were lower in the ACE2 KO vs. WT mice. Immunostaining for pimonidazole, a marker of hypoxia, and hypoxia-inducible factor-2α were higher in the trophospongium and placental labyrinth of the ACE2 KO vs. WT. In summary, placental hypoxia and uterine artery dysfunction develop before major growth of the fetus occurs and may explain the fetal growth restricted phenotype.
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Bobetsis, Y. A., S. P. Barros, D. M. Lin, J. R. Weidman, D. C. Dolinoy, R. L. Jirtle, K. A. Boggess, J. D. Beck, and S. Offenbacher. "Bacterial Infection Promotes DNA Hypermethylation." Journal of Dental Research 86, no. 2 (February 2007): 169–74. http://dx.doi.org/10.1177/154405910708600212.
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Maternal oral infection, caused by bacteria such as C. rectus or P. gingivalis, has been implicated as a potential source of placental and fetal infection and inflammatory challenge, which increases the relative risk for pre-term delivery and growth restriction. Intra-uterine growth restriction has also been reported in various animal models infected with oral organisms. Analyzing placental tissues of infected growth-restricted mice, we found down-regulation of the imprinted Igf2 gene. Epigenetic modification of imprinted genes via changes in DNA methylation plays a critical role in fetal growth and development programming. Here, we assessed whether C. rectus infection mediates changes in the murine placenta Igf2 methylation patterns. We found that infection induced hypermethylation in the promoter region-P0 of the Igf2 gene. This novel finding, correlating infection with epigenetic alterations, provides a mechanism linking environmental signals to placental phenotype, with consequences for development.
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Seveau, Stephanie. "Inflammatory responses to Listeria monocytogenes infection in the placenta." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 50.46. http://dx.doi.org/10.4049/jimmunol.208.supp.50.46.
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Abstract The immunological defense of the developing fetus is crucial for a successful pregnancy. The placenta plays key roles in protecting the fetus against rejection by the maternal immune system, while it ensures its defense against most pathogens. The mechanisms that orchestrate the placental immune functions are still poorly understood. The bacterial pathogen Listeria monocytogenes (Lm) breaches the maternal/fetal barrier, infects the placental chorionic villi, and reaches the fetus resulting in poor pregnancy outcomes. We studied the interplay between Lm and key players of the placental antimicrobial defense: trophoblasts (TCs), which are epithelial cells covering placental chorionic villi at the maternal/fetal interface, and placental macrophages (Hofbauer cells, or HBCs), which are the only leukocytes residing in chorionic villi. Both cell types form a critical immune barrier protecting the fetus from infection. We isolated human primary TCs and HBCs from healthy term placentas to study the Lm intracellular lifecycle as well as the cellular responses to infection (RNAseq and cytokine arrays). We found that both cell types were permissive to Lm infection and mounted a pro-inflammatory response to the pathogen including HBCs repolarization towards a pro-inflammatory phenotype favoring the innate immune responses. However, consistent with their placental homeostatic functions, TCs and repolarized HBCs maintained the expression of tolerogenic factors known to prevent maternal anti-fetal adaptive immunity. We will discuss our published studies (PMID 34399615 and 34367171) and recent data that teased apart the role of the Lm virulence factors in the inflammatory responses of placental cells. Supported by NIH (R01AI157205, R21AI105588, R03AI149371)
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Garcia-Contreras, Consolación, Marta Vazquez-Gomez, Alicia Barbero, José Pesantez, Angelo Zinellu, Fiammetta Berlinguer, Pedro Gonzalez-Añover, et al. "Polyphenols and IUGR Pregnancies: Effects of Maternal Hydroxytyrosol Supplementation on Placental Gene Expression and Fetal Antioxidant Status, DNA-Methylation and Phenotype." International Journal of Molecular Sciences 20, no. 5 (March 8, 2019): 1187. http://dx.doi.org/10.3390/ijms20051187.
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The use of polyphenols is a promising strategy for preventing or alleviating intrauterine growth restriction (IUGR) because polyphenol supplementation increases plasma antioxidant capacity and improves oxidative stress at the feto-placental unit; which are recognized as main issues in IUGR. However, there is a scarcity of experimental data on both realistic benefits and potential hazards of polyphenol supplementation during gestation. Hence, we aimed to use a swine model of IUGR pregnancy to determine possible effects of maternal supplementation with polyphenols (hydroxytyrosol) on placental expression of genes involved in antioxidant homeostasis, vascularization and fetal growth and thus on antioxidant status, DNA-methylation and phenotypic traits (morphology and homeostasis) of the fetus. Hydroxytyrosol improves placental gene expression and fetal antioxidant status and glucose metabolism in a sex-dependent manner, in which males were favored in spite of developmental failures. Concomitantly, hydroxytyrosol prevented hypomethylation of DNA associated with oxidative stress. Finally, no major deleterious effects of hydroxytyrosol supplementation on constriction of the ductus arteriosus, a possible secondary effect of polyphenols during pregnancy, were found.
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Scott, Hailey, Lilian M. Martinelli, David Grynspan, Enrrico Bloise, and Kristin L. Connor. "Preterm Birth Associates With Increased Placental Expression of MDR Transporters Irrespective of Prepregnancy BMI." Journal of Clinical Endocrinology & Metabolism 107, no. 4 (November 8, 2021): 1140–58. http://dx.doi.org/10.1210/clinem/dgab813.
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Abstract Context Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition; however, few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected proinflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. Objective To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and proinflammatory cytokine levels are altered by PTB and maternal BMI. Methods A cross-sectional study was conducted to assess the effect of PTB (with/without chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin (IL)-6 and -8 expression in 60 preterm and 36 term pregnancies. Results ABCB1 expression was increased in preterm compared to term placentae (P = .04). P-gp (P = .008) and BCRP (P = .01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, P = .007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (P = .0005) and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. Conclusion PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.
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Cetin, I., F. Parisi, C. Berti, C. Mandò, and G. Desoye. "Placental fatty acid transport in maternal obesity." Journal of Developmental Origins of Health and Disease 3, no. 6 (June 14, 2012): 409–14. http://dx.doi.org/10.1017/s2040174412000414.
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Pregestational obesity is a significant risk factor for adverse pregnancy outcomes. Maternal obesity is associated with a specific proinflammatory, endocrine and metabolic phenotype that may lead to higher supply of nutrients to the feto-placental unit and to excessive fetal fat accumulation. In particular, obesity may influence placental fatty acid (FA) transport in several ways, leading to increased diffusion driving force across the placenta, and to altered placental development, size and exchange surface area. Animal models show that maternal obesity is associated with increased expression of specific FA carriers and inflammatory signaling molecules in placental cotyledonary tissue, resulting in enhanced lipid transfer across the placenta, dislipidemia, fat accumulation and possibly altered development in fetuses. Cell culture experiments confirmed that inflammatory molecules, adipokines and FA, all significantly altered in obesity, are important regulators of placental lipid exchange. Expression studies in placentas of obese–diabetic women found a significant increase in FA binding protein-4 expression and in cellular triglyceride content, resulting in increased triglyceride cord blood concentrations. The expression and activity of carriers involved in placental lipid transport are influenced by the endocrine, inflammatory and metabolic milieu of obesity, and further studies are needed to elucidate the strong association between maternal obesity and fetal overgrowth.
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Sferruzzi-Perri, Amanda N., Jorge López-Tello, Abigail L. Fowden, and Miguel Constancia. "Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation." Proceedings of the National Academy of Sciences 113, no. 40 (September 12, 2016): 11255–60. http://dx.doi.org/10.1073/pnas.1602012113.
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Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.
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Nadkarni, Suchita, Joanne Smith, Amanda N. Sferruzzi-Perri, Agata Ledwozyw, Madhav Kishore, Robert Haas, Claudio Mauro, et al. "Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy." Proceedings of the National Academy of Sciences 113, no. 52 (December 12, 2016): E8415—E8424. http://dx.doi.org/10.1073/pnas.1611944114.
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Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil–T cell interactions in the regulation of vascularization at the maternal–fetal interface.
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Bassols, Judit, Anna Prats-Puig, Pilar Soriano-Rodríguez, María Mar García-González, Joanna Reid, María Martínez-Pascual, Fátima Mateos-Comerón, Francis de Zegher, Lourdes Ibáñez, and Abel López-Bermejo. "Lower Free Thyroxin Associates with a Less Favorable Metabolic Phenotype in Healthy Pregnant Women." Journal of Clinical Endocrinology & Metabolism 96, no. 12 (December 1, 2011): 3717–23. http://dx.doi.org/10.1210/jc.2011-1784.
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Context: A lower free T4 (fT4), within the euthyroid range, has been shown in adults to associate with an adverse metabolic phenotype. Thyroid physiology changes significantly during gestation and affects maternal and fetal well-being. Objective: The aim of the study was to test the hypothesis that a lower serum fT4 in healthy euthyroid pregnant women is related to a less favorable metabolic phenotype and to fetal or placental weight. Design, Setting, Patients, and Outcome Measures: We examined associations of thyroid function tests (TSH and fT4) and the free T3 (fT3)-to-fT4 ratio (as a proxy of deiodinase activity) with a metabolic profile [preload and postload glucose, glycosylated hemoglobin (HbA1c), high molecular-weight (HMW)-adiponectin, homeostasis model of assessment for insulin resistance (HOMA-IR), and serum lipids] in 321 healthy pregnant women. All women were euthyroid and had negative anti-thyroid peroxidase antibodies. None received thyroid hormone replacement. Blood tests were performed in women between 24 and 28 wk gestation. Placentas and newborns were weighed at birth. Results: Circulating TSH did not relate to metabolic parameters, but decreasing fT4 and increasing fT3-to-fT4 ratio associated with a less favorable metabolic phenotype, as judged by higher postload glucose, HbA1c, fasting insulin, HOMA-IR, and triglycerides, and by a lower HMW-adiponectinemia (all P ≤ 0.005). In multiple regression analyses, fT4 was independently associated with HbA1c (β = −0.135; P = 0.038), HMW-adiponectin (β = 0.218; P < 0.001), and placental weight (β = −0.185; P < 0.005), whereas the fT3-to-fT4 ratio was independently associated with maternal body mass index (β = 0.265; P < 0.001), HMW-adiponectinemia (β = −0.237; P < 0.002), HOMA-IR (β = 0.194; P = 0.014), and placental weight (β = 0.174; P = 0.020). Conclusion: In pregnant women without a history of thyroid dysfunction, lower concentrations of fT4 and a higher conversion of fT4 to fT3, as inferred by changes in the fT3-to-fT4 ratio, were found to be associated with a less favorable metabolic phenotype and with more placental growth.
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Sferruzzi-Perri, Amanda N., Ionel Sandovici, Miguel Constancia, and Abigail L. Fowden. "Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth." Journal of Physiology 595, no. 15 (May 23, 2017): 5057–93. http://dx.doi.org/10.1113/jp273330.
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Simoni, G., S. M. Sirchia, and M. Fraccaro. "Aneuploid Correction and Confined Placental Mosaicism." Acta geneticae medicae et gemellologiae: twin research 45, no. 1-2 (April 1996): 153–61. http://dx.doi.org/10.1017/s0001566000001240.
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Uniparental disomy (UPD) can be caused by various genetic mechanisms such as gamete complementation, chromosome duplication in a monosomic zygote or postzygotic aneuploid correction. This latter mechanism has been recently well documented in human reproduction and seems to be strictly related to placental mosaicism. We have therefore studied some aspects of confined placental mosaicism (CPM) which are useful to clarify one of the most common sources of UPD in humans.Abnormal distribution of chromosomes in postzygotic mitotic cell divisions may result in a mosaic condition with two or more cell lines showing different chromosome constitutions. The effects on fetal phenotype and pregnancy development depend on the chromosomes involved, the distribution of the abnormal cells among tissues and on the precise stage at which chromosome mutation occurs.As shown in Fig. 1, when the mutational event occurs in the blastocyst, prior to the differentiation of embryonic and chorionic compartments, the mosaicism is found in both the placental and fetal tissues. In contrast, when the chromosome mutation occurs at a later stage, after embryonic and chorionic compartment separation, the abnormal cells may be confined to the placenta or to the embryo, and are not necessarily found in both.
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Gillis-Buck, Eva, Haleigh Miller, Marina Sirota, Stephan J. Sanders, Vasilis Ntranos, Mark S. Anderson, James M. Gardner, and Tippi C. MacKenzie. "Extrathymic Aire-expressing cells support maternal-fetal tolerance." Science Immunology 6, no. 61 (July 16, 2021): eabf1968. http://dx.doi.org/10.1126/sciimmunol.abf1968.
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Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire+) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire+ cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.
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Vaughan, O. R., H. M. Phillips, A. J. Everden, A. N. Sferruzzi-Perri, and A. L. Fowden. "Dexamethasone treatment of pregnant F0 mice leads to parent of origin-specific changes in placental function of the F2 generation." Reproduction, Fertility and Development 27, no. 4 (2015): 704. http://dx.doi.org/10.1071/rd14285.
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Dexamethasone treatment of F0 pregnant rodents alters F1 placental function and adult cardiometabolic phenotype. The adult phenotype is transmitted to the F2 generation without further intervention, but whether F2 placental function is altered by F0 dexamethasone treatment remains unknown. In the present study, F0 mice were untreated or received dexamethasone (0.2 µg g–1 day–1, s.c.) over Days 11–15 or 14–18 of pregnancy (term Day 21). Depending on the period of F0 dexamethasone treatment, F1 offspring were lighter at birth or grew more slowly until weaning (P < 0.05). Glucose tolerance (1 g kg–1, i.p.) of adult F1 males was abnormal. Mating F1 males exposed prenatally to dexamethasone with untreated females had no effect on F2 placental function on Day 19 of pregnancy. In contrast, when F1 females were mated with untreated males, F2 placental clearance of the amino acid analogue 14C-methylaminoisobutyric acid was increased by 75% on Day 19 specifically in dams prenatally exposed to dexamethasone on Days 14–18 (P < 0.05). Maternal plasma corticosterone was also increased, but F2 placental Slc38a4 expression was decreased in these dams (P < 0.05). F0 dexamethasone treatment had no effect on F2 fetal or placental weights, regardless of lineage. Therefore, the effects of F0 dexamethasone exposure are transmitted intergenerationally to the F2 placenta via the maternal, but not paternal, line.
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Loewendorf-Snead, Andrea, Tina Nguyen, Maria Yesayan, and Daniel Kahn. "Uterine integrity is required to maintain human fetal immunologic naiveté (MUC7P.770)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 197.22. http://dx.doi.org/10.4049/jimmunol.192.supp.197.22.
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Abstract Introduction: In healthy pregnancy, maternal and fetal compartments are physically separated by multiple cell layers and the fetal immune system displays an ‘in-experienced’ phenotype in utero. The uterus as an immunologic barrier contributing to the naïve state of the fetal immune system has not been explored thus far. Methods: A prospective cohort study of fetuses born to mothers with prior uterine scar was undertaken (UCLA IRB # 11-002962). Cord blood lymphocytes were analyzed for memory status of the T regulatory cells (CD4+FoxP3+RO/RA) and blinded from placental location prior to final analysis. Results: In this prospective cohort study, we identified placental implantation in apposition to a uterine scar as a sufficient factor for fetal in utero immune activation (CD45RO+), specifically in the regulatory T cell compartment. Our results (N=20) identify a risk difference of 90% with a relative risk of 10 (p<0.05) of activation (RO+) of the FoxP3+ regulatory T cells when the placenta was implanted over the prior uterine scar. Discussion: Our study demonstrates that intrauterine formation of tolerogenic fetal responses is caused by fetal exposure to a scarred uterus. Our results highlight the role that uterine integrity plays as an immunologic barrier.
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Slutsky, Rebecca, Roberto Romero, Yi Xu, Jose Galaz, Derek Miller, Bogdan Done, Adi L. Tarca, et al. "Exhausted and Senescent T Cells at the Maternal-Fetal Interface in Preterm and Term Labor." Journal of Immunology Research 2019 (May 23, 2019): 1–16. http://dx.doi.org/10.1155/2019/3128010.
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Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4+ T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4+ and CD8+ T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4+ T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8+ T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4+ and CD8+ T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFNγ and TNFα upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.
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Kretschmer, Tobias, Merle Schulze-Edinghausen, Eva-Maria Turnwald, Ruth Janoschek, Inga Bae-Gartz, Peter Zentis, Marion Handwerk, et al. "Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis." Nutrients 12, no. 2 (January 22, 2020): 296. http://dx.doi.org/10.3390/nu12020296.
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Obesity during pregnancy is a known health risk for mother and child. Since obesity is associated with increased inflammatory markers, our objectives were to determine interleukin-6 (IL-6) levels in obese mice and to examine the effect of IL-6 on placental endothelial cells. Placentas, blood, and adipose tissue of C57BL/6N mice, kept on high fat diet before and during pregnancy, were harvested at E15.5. Serum IL-6 levels were determined and endothelial cell markers and IL-6 expression were measured by qRT-PCR and western blot. Immunostaining was used to determine surface and length densities of fetal capillary profiles and placental endothelial cell homeostasis. Human placental vein endothelial cells were cultured and subjected to proliferation, apoptosis, senescence, and tube formation assays after stimulation with hyperIL-6. Placental endothelial cell markers were downregulated and the percentage of senescent endothelial cells was higher in the placental exchange zone of obese dams and placental vascularization was strongly reduced. Additionally, maternal IL-6 serum levels and IL-6 protein levels in adipose tissue were increased. Stimulation with hyperIL-6 provoked a dose dependent increase of senescence in cultured endothelial cells without any effects on proliferation or apoptosis. Diet-induced maternal obesity led to an IUGR phenotype accompanied by increased maternal IL-6 serum levels. In the placenta of obese dams, this may result in a disturbed endothelial cell homeostasis and impaired fetal vasculature. Cell culture experiments confirmed that IL-6 is capable of inducing endothelial cell senescence.
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Sferruzzi-Perri, A. N., O. R. Vaughan, P. M. Coan, M. C. Suciu, R. Darbyshire, M. Constancia, G. J. Burton, and A. L. Fowden. "Placental-Specific Igf2 Deficiency Alters Developmental Adaptations to Undernutrition in Mice." Endocrinology 152, no. 8 (June 14, 2011): 3202–12. http://dx.doi.org/10.1210/en.2011-0240.
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The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.
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Raasch, Lauren E., Keisuke Yamamoto, Christina M. Newman, Jenna R. Rosinski, Phoenix M. Shepherd, Elaina Razo, Chelsea M. Crooks, et al. "Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus." PLOS Neglected Tropical Diseases 16, no. 8 (August 4, 2022): e0010623. http://dx.doi.org/10.1371/journal.pntd.0010623.
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Countermeasures against Zika virus (ZIKV), including vaccines, are frequently tested in nonhuman primates (NHP). Macaque models are important for understanding how ZIKV infections impact human pregnancy due to similarities in placental development. The lack of consistent adverse pregnancy outcomes in ZIKV-affected pregnancies poses a challenge in macaque studies where group sizes are often small (4–8 animals). Studies in small animal models suggest that African-lineage Zika viruses can cause more frequent and severe fetal outcomes. No adverse outcomes were observed in macaques exposed to 1x104 PFU (low dose) of African-lineage ZIKV at gestational day (GD) 45. Here, we exposed eight pregnant rhesus macaques to 1x108 PFU (high dose) of African-lineage ZIKV at GD 45 to test the hypothesis that adverse pregnancy outcomes are dose-dependent. Three of eight pregnancies ended prematurely with fetal death. ZIKV was detected in both fetal and placental tissues from all cases of early fetal loss. Further refinements of this exposure system (e.g., varying the dose and timing of infection) could lead to an even more consistent, unambiguous fetal loss phenotype for assessing ZIKV countermeasures in pregnancy. These data demonstrate that high-dose exposure to African-lineage ZIKV causes pregnancy loss in macaques and also suggest that ZIKV-induced first trimester pregnancy loss could be strain-specific.
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Swieboda, Dominika, Erica Johnson, Ioanna Skountzou, and Rana Chakraborty. "Baby’s First Macrophage: How do placental macrophages (Hofbauer Cells, HCs) contribute to immune tolerance and infection response during pregnancy?" Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 126.28. http://dx.doi.org/10.4049/jimmunol.202.supp.126.28.
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Abstract Placental immunity is dichotomous: tolerance of the semiallogenic fetus is balanced with limiting transmission of maternal pathogens. HCs are the major fetal immune cell at the placenta, but mechanisms responsible for maintaining immune homeostasis while preventing infection require elucidation. We determined the phenotype of human HCs throughout gestation and analyzed stimulation response. Activated HCs were present in early pregnancy and reduced in number by term while maintaining similar phenotypes. Tolerant HC numbers were highest in midgestation, after a relatively intolerant phenotype early in gestation. We saw a significant shift in macrophage polarization as gestation progressed. Transcription of ARG2 exceeded iNOS at all points, reaching 10-fold higher at term. Following treatment with IL4+IL13 or IFNγ+LPS midgestation HCs underwent significant phenotype change and activation. Basal expression of antiviral IFN stimulated genes (ISGs) was lowest at midgestation and was enhanced by IFN-α and IFN-λ1 with a 10-fold stronger response to IFN-α. RIG-I agonism induced HC activation, 10-fold iNOS upregulation and enhanced transcription of IFNs, MDA5, RIG-I, and ISGs. Response to stimulation by IFNγ+LPS, IL4+IL13, IL1β+HAGG was limited to loss of tolerance at term. IL-10 treatment increased numbers of CD163+ HCs, and IFNγ+LPS caused loss of discernible polarization patterns. Basal expression of RIG-I, MDA5 and ISGs was highest in term HCs, but IFN-α did not activate them. RIG-I agonism reduced markers of tolerance. HCs are variable macrophages, with phenotype and immune capacity strongly dependent on gestational age. Understanding placental immunobiology is fundamental to addressing key pregnancy morbidities.
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Schäffers, Olivier J. M., Catherine Dupont, Eric M. Bindels, Diane Van Opstal, Dick H. W. Dekkers, Jeroen A. A. Demmers, Joost Gribnau, and Bas B. van Rijn. "Single-Cell Atlas of Patient-Derived Trophoblast Organoids in Ongoing Pregnancies." Organoids 1, no. 2 (October 2, 2022): 106–15. http://dx.doi.org/10.3390/organoids1020009.
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Trophoblast organoids (TOs) hold great promise for elucidating human placental development and function. By deriving TOs in ongoing pregnancies using chorionic villus sampling (CVS), we established a platform to study trophoblast differentiation and function in early pregnancy, including pregnancies with different fetal genetic abnormalities. We addressed cellular heterogeneity of CVS-derived TOs by providing a single-cell transcriptomic atlas and showed that CVS-TOs recapitulate key aspects of the human placenta, including syncytial fusion and hormone synthesis. This study demonstrates the utility of trophoblast organoids for investigating genetic defects in the placenta and describes an experimental platform for future personalized placental medicine approaches, including genotype–phenotype mapping.
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Sparnaaij, Michelle, Peter Chedraui, Kim H. Liem, Gustavo S. Escobar, Jasson Espinoza-Caicedo, Boris W. Kramer, Johan S. H. Vles, and Antonio W. D. Gavilanes. "Fetal asphyctic preconditioning in rats results in a preserved placental inflammatory phenotype at birth." Placenta 38 (February 2016): 84–92. http://dx.doi.org/10.1016/j.placenta.2015.12.016.
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Wallace, Jacqueline M. "Competition for nutrients in pregnant adolescents: consequences for maternal, conceptus and offspring endocrine systems." Journal of Endocrinology 242, no. 1 (July 2019): T1—T19. http://dx.doi.org/10.1530/joe-18-0670.
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The competition for nutrients that arises when pregnancy coincides with continuing or incomplete growth in young adolescent girls increases the risk of preterm delivery and low birthweight with negative after-effects for mother and child extending beyond the perinatal period. Sheep paradigms involving nutritional management of weight and adiposity in young, biologically immature adolescents have allowed the consequences of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented, and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood, whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young adolescents before and during pregnancy, and their offspring thereafter.
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Tanner, Amelia R., Asghar Ali, Quinton A. Winger, Paul J. Rozance, and Russell V. Anthony. "152 Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 121. http://dx.doi.org/10.1093/jas/skaa278.220.
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Abstract Chorionic somatomammotropin (CSH) is one of the most abundant hormones produced by the sheep placenta, yet the exact function of CSH has been elusive. Previously we reported the use of in vivo RNA interference (RNAi) to assess the impact of CSH deficiency on placental and fetal growth in sheep. Near-term (135 dGA), there are two distinct CSH RNAi phenotypes: 1) pregnancies with intrauterine growth restriction (IUGR), and 2) pregnancies with normal fetal and placental weights. This study describes physiological changes in the latter phenotype. To generate the CSH RNAi pregnancies, the trophectoderm of hatched blastocysts (9 dGA) were infected with lentiviral-constructs expressing either a scrambled control (NTS) or CSH-specific shRNA (CSH RNAi), prior to transfer into synchronized recipient ewes. At 120 dGA, 6 NTS and 6 CSH RNAi pregnancies were fitted with maternal and fetal catheters. Uterine and umbilical blood flows were measured utilizing the 3H2O transplacental diffusion technique at 132 dGA, and nutrient uptakes were calculated by the Fick principle. Resulting data were analyzed by Student’s t-test and significance was set at P ≤ 0.05. CSH RNAi tended (P ≤ 0.10) to reduce placentome weight with no effect on fetal weight. Absolute (ml/min) and relative (ml/min/kg fetus) uterine blood flows were reduced (P ≤ 0.05) in CSH RNAi pregnancies, but umbilical flows were not impacted. The uterine artery-to-vein glucose gradient (mmol/l) was significantly (P ≤ 0.05) increased, whereas the gradients for taurine and glycine were reduced (P ≤ 0.05). Uteroplacental glucose uptake (mmol/min/kg placenta) was increased 27% (P ≤ 0.05), whereas umbilical glucose uptake (mmol/min/kg fetus) was reduced 13%. This cohort demonstrates that even in the absence of IUGR, CSH deficiency has significant physiological ramifications, and the investigation of CSH RNAi pregnancies exhibiting both IUGR and non-IUGR phenotypes may help determine the direct effects of CSH and its potential impact on fetal programming. Supported by NIH R01 HD093701.
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Bergamelli, Mathilde, Hélène Martin, Yann Aubert, Jean-Michel Mansuy, Marlène Marcellin, Odile Burlet-Schiltz, Ilse Hurbain, et al. "Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro." Viruses 14, no. 9 (September 13, 2022): 2030. http://dx.doi.org/10.3390/v14092030.
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Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.
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Juma, Edwin Omondi, Margaret Keraka, and Anthony Wanyoro. "Clinical Phenotypes Associated With Preterm Births at Jaramogi Oginga Odinga Teaching and Referral Hospital in Kisumu County, Kenya." International Journal of Current Aspects 3, no. III (June 28, 2019): 175–86. http://dx.doi.org/10.35942/ijcab.v3iiii.38.
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Preterm birth is a global health problem. It is the leading cause of child and neonatal mortality globally including Kenya. Preterm birth is the birth occurring before 37 completed weeks of gestation. In Kenya, preterm birth is the leading cause of neonatal mortality as it contributes to 35% of deaths among the neonates while Kisumu County is among the county’s leading with child under-five mortality rate at 133 deaths per 1000 live births. The main objective of this study was to identify the clinical phenotypes associated with preterm birth in JOOTRH in Kisumu County. It was a cross sectional study based on women who had a preterm birth alive or stillbirth at JOORTH in Kisumu County. Purposive sampling technique was used to select 178 respondents who met the inclusion criteria. Interviewer administered questionnaire was used to collect both qualitative and quantitative data. Data was analyzed by computer software SPSS version 23; descriptive statistics was used together with inferential statistics (Chi-square and Fisher’s Exact test) to help in the identification of the statistical significance of any association between the variables. A p value of < 0.05 was used. Bivariate analysis was utilized to measure the strength of associations. Data presented by use of frequency tables and narrative description. Ethical clearance was sought from Kenyatta University Ethics and Review Committee, permit sought from NACOSTI, consent and assent from the respondents. Results showed that maternal age (p=0.011) to be statistical significant with preterm births. Clinical phenotypes based on maternal, fetal and placental conditions; preeclampsia/eclampsia (p=0.016), extrauterine infections which includes malaria, UTI and HIV (p=0.030), severe maternal conditions that includes DM, anaemia, cardiac disease, hypertension prior to pregnancy and TB (p=0.001), multiple gestations (p=0.013), fetal anomaly (0.048), IUGR (p=0.049), antepartum stillbirth (p=0.046) and APH/early bleeding that include placenta previa and placenta abruption (p=0.025) were all significantly associated with preterm births. On bivariate analysis between clinical phenotypes and preterm births, all except multiple gestation (p=0.416) and APH (p=0.660) remained statistically significant. All clinical phenotypes (maternal, fetal and placental conditions) were significantly associated with preterm births. All clinical phenotypes except multiple gestations and APH/early bleeding remained statistically significant after bivariate analysis. The study recommends the use of Barro’s classifications system of clinical phenotypes to phenotype all preterm births in JOOTRH. Early identification of maternal, fetal and placental conditions identified in this study to be associated with preterm births by adopting Barros’ phenotyping of preterm births as a strategy to help prevent the occurrence of PTBs and eventually reduce neonatal deaths and under-five mortality.
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Fitzsimmons, C., Z. Kruk, D. Lines, C. Roberts, and S. Hiendleder. "101 PLACENTAL DEVELOPMENT IN A BOVINE HETEROSIS MODEL." Reproduction, Fertility and Development 20, no. 1 (2008): 131. http://dx.doi.org/10.1071/rdv20n1ab101.
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Heterosis or hybrid vigor is a biological phenomenon referring to the phenotypic superiority of hybrids over their parents. Despite its economic importance, the mechanisms of heterosis are still poorly understood. Reciprocal cross Brahman (B) � Angus (A) calves display significant heterosis in birth weight, but this effect is almost entirely due to the dramatic fetal overgrowth observed in Brahman male � Angus female offspring. The reciprocal is much less affected and similar to purebred Brahman calves (Brown et al. 1993 J. Anim. Sci. 71, 3273–3279). We have generated a defined A � A (n = 20), B � A (n = 21), A � B (n = 13), and B � B (n = 15; male parent listed first) day 153 (term = 280) fetal/placental resource from artificially inseminated, estrous cycle synchronized heifers to identify components and mechanisms of heterotic fetal growth regulation. An ANOVA showed that full uterus weight (P < 0.001), fetal weight (P = 0.01), umbilical cord length (P = 0.003) and weight (P = 0.04), placenta fetalis weight (P < 0.001), total caruncle weight (P = 0.002), empty uterus weight (P < 0.001), and combined amniotic/allantoic fluid weight (P < 0.001) were significantly affected by the 4 genetic groups after adjustment for fetal sex and dam weight where required. The weight of reciprocal hybrid fetuses was intermediate to the purebred fetuses and thus did not display heterosis defined as the difference between reciprocal cross and parental means. Full uterus weight and combined amniotic/allantoic fluid weight, in contrast, displayed heterosis of 6.6% (P = 0.02) and 9.0% (P = 0.01). As in neonate calves, the heterosis effects were due to the B � A group. The t-tests demonstrated that full uterus weight in B � A was significantly greater (19.84 � 0.43 kg) than in A � B (16.23 � 0.47 kg; P < 0.001), A � A (17.41 � 0.35 kg; P < 0.001), and B � B (16.76 � 0.49 kg; P = 0.001) crosses. Combined amniotic/allantoic fluids were 12.58 � 0.31 kg in B � A as compared to 10.93 � 0.39 kg in A � B (P = 0.001), 10.75 � 0.29 kg in A � A (P < 0.001), and 11.48 � 0.36 kg in B � B (P = 0.02) crosses. We found similar superiority of the B � A group for parameters that did not fulfil the formal heterosis criterion. These include umbilical cord, placenta fetalis, empty uterus, and total caruncle weights. All but 1 of these (combined amniotic/allantoic fluid weight) were significantly correlated (r = 0.43–0.70; P < 0.001) with fetal weight. We conclude that massive changes in placental parameters underly and precede the heterosis effects in birth weight observed in Brahman � Angus crosses. Although formally designated heterosis, placental and fetal overgrowth is present in only 1 of the hybrids (B � A). This natural overgrowth phenotype is clearly distinct from the early onset overgrowth phenotypes observed after IVF and nuclear transfer cloning (Hiendleder et al. 2004 Biol. Reprod. 71, 217–223) and will be useful in the dissection of factors contributing to fetal growth and development.
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Ford, S. P., and N. M. Long. "Evidence for similar changes in offspring phenotype following either maternal undernutrition or overnutrition: potential impact on fetal epigenetic mechanisms." Reproduction, Fertility and Development 24, no. 1 (2012): 105. http://dx.doi.org/10.1071/rd11911.
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The goal of this review is to shed light on the role of maternal malnutrition in inducing epigenetic changes in gene expression, leading to alterations in fetal growth and development, and to altered postnatal phenotype and the development of metabolic disease. We present evidence supporting the concept that both maternal undernutrition and overnutrition can induce the same cadre of fetal organ and tissue abnormalities and lead to the same postnatal metabolic changes in the resulting offspring. Furthermore, we present evidence that in both overnourished and undernourished ovine pregnancies, fetuses experience a period of nutrient restriction as a result of alterations in placental delivery of maternal nutrients into the fetal compartment. We argue that this bout of reduced fetal nutrition in undernourished and overnourished pregnancies leads to the development of a thrifty phenotype in which the fetus attempts to alter the function of its tissues and organs to maximise its chances of survival in a postnatal environment that is deficient in nutrients. Importantly, we present evidence to support the concept that these phenotypic changes in offspring quality resulting from maternal malnutrition are transmitted to subsequent generations, independent of their maternal nutritional inputs.
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Burton, Graham J., Abigail L. Fowden, and Kent L. Thornburg. "Placental Origins of Chronic Disease." Physiological Reviews 96, no. 4 (October 2016): 1509–65. http://dx.doi.org/10.1152/physrev.00029.2015.
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Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.
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Sferruzzi-Perri, Amanda, Jaspreet Khaira, Abigail Fowden, and Miguel Constancia. "The role of the phosphoinositol kinase (PI3K) p110α in regulating placental phenotype and fetal growth." Placenta 35, no. 9 (September 2014): A26. http://dx.doi.org/10.1016/j.placenta.2014.06.087.
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Binder, Natalie, Stephen Tong, David Gardner, and Natalie Hannan. "Paternal diet induced obesity has a fetal/placental growth restricted phenotype in a mouse model." Placenta 35, no. 9 (September 2014): A32. http://dx.doi.org/10.1016/j.placenta.2014.06.106.
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Chung, Douglas, Emily Wong, SeongJun Han, Alisha Elford, Carlos Garcia-Batres, and Pamela S. Ohashi. "The Role of Innate Lymphoid Cells in Immune Regulation and Fetal Protection During Allogeneic Pregnancies." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 84.14. http://dx.doi.org/10.4049/jimmunol.204.supp.84.14.
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Abstract Maternal immune tolerance against paternal alloreactive antigens expressed by the fetus is essential in the development of successful pregnancies. Disturbances of immunoregulatory mechanisms by genetic modifications or viral infections results in aberrant placental development, intrauterine growth restriction (IUGR), and fetal loss. Mechanisms of immune regulation during pregnancy has not been fully elucidated. Our lab and others were the first to uncover a novel subset of regulatory innate lymphoid cells (ILCregs) that suppressed immune responses in chronic viral infections, organ transplant rejection, and cancer. In this study, we identified a subset of decidual NK1.1+ ILC1s in healthy murine pregnancies that expressed surface markers and intracellular cytokines reminiscent of an ILCreg phenotype. Interestingly, these characteristics were more abundant early in gestation compared to mid-late gestation. Furthermore, depletion of NK1.1+ ILC1s using neutralizing antibodies induced fetal destruction in allogeneic (C57BL/6J female X BALB/c male), but not in syngeneic pregnancies (C57BL/6J female X C57BL/6J male). This highlights the importance of allogenicity in fetal destruction in the absence of NK1.1+ ILC1s. Decidual ILC1s have been shown to promote trophoblast invasion, placental angiogenesis, and in utero fetal growth during pregnancy. However, we are one of the first groups to thoroughly investigate potential immunosuppressive role of decidual ILC1s to prevent immune-mediated fetal destruction. Further elucidation of immune tolerance mechanisms during pregnancy may uncover novel therapeutic targets for pregnancy-related complications such as preeclampsia and spontaneous miscarriages.
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Sanches, Ana Paula Varela, Josilene Lopes de Oliveira, Maíra Schuchter Ferreira, Bruna de Souza Lima, Josiane Érica Miyamoto, Laís Angélica de Paula Simino, Márcio Alberto Torsoni, Adriana Souza Torsoni, Marciane Milanski, and Letícia Ignácio-Souza. "Obesity phenotype induced by high-fat diet leads to maternal-fetal constraint, placental inefficiency, and fetal growth restriction in mice." Journal of Nutritional Biochemistry 104 (June 2022): 108977. http://dx.doi.org/10.1016/j.jnutbio.2022.108977.
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Boehmer, Brit H., Sean W. Limesand, and Paul J. Rozance. "The impact of IUGR on pancreatic islet development and β-cell function." Journal of Endocrinology 235, no. 2 (November 2017): R63—R76. http://dx.doi.org/10.1530/joe-17-0076.
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Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.
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Bronson, Stefanie L., and Tracy L. Bale. "Prenatal Stress-Induced Increases in Placental Inflammation and Offspring Hyperactivity Are Male-Specific and Ameliorated by Maternal Antiinflammatory Treatment." Endocrinology 155, no. 7 (July 1, 2014): 2635–46. http://dx.doi.org/10.1210/en.2014-1040.
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Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress-induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress-induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress.
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Frost, Elizabeth L., Catherine R. Lammert, David M. Johanson, Eli R. Zunder, and John R. Lukens. "Sex bias in maternal immune activation-induced neurodevelopmental disease begins at the maternal-fetal interface." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 79.13. http://dx.doi.org/10.4049/jimmunol.204.supp.79.13.
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Abstract Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to an ASD-like phenotype in the offspring, consisting of deficits in socialization and communication as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines, specifically IL-6 and IL-17, contributes to alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits manifest only in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA that have deleterious impacts on fetal neurodevelopment originate there. Our preliminary findings show that MIA leads to sexually dimorphic alterations in placental pathology. To further characterize responses to MIA at the maternal-fetal interface over the course of gestation, we conducted bulk RNA-sequencing of the placenta/decidua from polyI:C- and saline-treated embryos at several time points post-injection. Sex of the embryos was determined by PCR genotyping for comparison of male and female placental transcriptomes. We find previously undescribed signatures related to myeloid cells in placentas from MIA males, as well as sex-based differences under homeostasis. This data set will shed light on the immune mechanisms that impact fetal brain health.