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Introduction: Disturbed paternal epigenetic status of imprinted genes has been observed in infertility and recurrent spontaneous abortions. Shallow placentation has been associated with early-onset preeclampsia. Hence, the present study aimed to investigate the methylation patterns of imprinted genes involved in placental development, in the spermatozoa of partners of women experiencing preeclampsia., Methods: The study involved recruitment of couples into preeclampsia (n = 14) and control (n = 25) groups. Methylation analysis of imprinted gene differentially methylated regions (DMRs) and LINE1 repetitive element was carried out by pyrosequencing in the spermatozoa and placental villi. Global 5 mC levels in the spermatozoa were measured through ELISA. Expression of imprinted genes was quantified in the placental villi by real time qPCR. Association of birth weight with DNA methylation and gene expression was assessed., Results: KvDMR, PEG3 DMR, PEG10 DMR and DLK1-GTL2 IG-DMR were differentially methylated in the spermatozoa and placental villi of preeclampsia group. Global 5 mC content and LINE1 methylation levels did not differ between the spermatozoa of the two groups. Increased transcript levels of PEG3, IGF2, DLK1, PHLDA2 and CDKN1C were observed in the preeclamptic placental villi. Birth weight showed significant association with KvDMR, PEG10 DMR, DLK1-GTL2 IG-DMR and LINE1 methylation levels in the spermatozoa. DLK1 expression levels showed a negative association with birth weight., Discussion: The study highlighted the paternal contribution to early-onset preeclampsia, in the form of disrupted sperm DNA methylation patterns at imprinted gene loci. These loci, after further evaluation in future studies, could serve as sperm-based preeclampsia predictive markers, for couples planning pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Polypeptide hormones and steroid hormones, either expressed by the placenta or dependant on the placenta for their synthesis, are key to driving adaptations in the mother during pregnancy that support growth in utero. These adaptations include changes in maternal behaviour that take place in pregnancy and after the birth to ensure that offspring receive appropriate care and nutrition. Placentally-derived hormones implicated in the programming of maternal caregiving in rodents include prolactin-related hormones and steroid hormones. Neuromodulators produced by the placenta may act directly on the fetus to support brain development. A number of imprinted genes function antagonistically in the placenta to regulate the development of key placental endocrine lineages expressing these hormones. Gain-in-expression of the normally maternally expressed gene Phlda2 or loss-of-function of the normally paternally expressed gene Peg3 results in fewer endocrine cells in the placenta, and pups are born low birth weight. Importantly, wild type dams carrying these genetically altered pups display alterations in their behaviour with decreased focus on nurturing (Phlda2) or heightened anxiety (Peg3). These same genes may regulate placental hormones in human pregnancies, with the potential to influence birth weight and maternal mood. Consequently, the aberrant expression of imprinted genes in the placenta may underlie the reported co-occurrence of low birth weight with maternal prenatal depression. [ABSTRACT FROM AUTHOR]

The placenta is a complex and poorly understood organ, which serves as the connection between the mother and the developing fetus. Genomic imprinting, defined as a regulatory process resulting in the expression of a gene in a parent-of-origin-specific manner, plays an important role in fetal development and placental function. Disturbances that occur during the establishment and maintenance of imprinting could compromise the placenta and fetus, and ultimately, offspring health. Assisted Reproductive Technologies (ART) have been widely used to overcome infertility, however experimental studies have shown that ART procedures affect placentation and the expression of imprinted genes. Here we briefly review the role of imprinted genes in placental development and the evidence from mouse and human studies suggesting ART disrupts imprinted gene regulation in the placenta. [ABSTRACT FROM AUTHOR]

Introduction: The increased maternal estradiol (E2) concentrations induced by assisted reproductive technology (ART) result in lower birth weight of offspring, which is associated with increased risk of adult diseases. However, the exact mechanism remains unknown. The present study investigated the effect of high E2 exposure on the expression of imprinted genes CDKN1C and IGF2 in human placentas and the DNA methylation status of their differential methylation regions (DMRs).Methods: The mRNA expression of CDKN1C and IGF2 in human placentas and the human trophoblast cells (HTR8) treated with E2 were investigated by reverse transcription-real time polymerase chain reaction (PCR). The DNA methylation of their DMRs were investigated by sodium bisulfite sequencing.Results: CDKN1C and IGF2 were significantly up-regulated in ART conceived placentas. The mean birth weight of ART singletons was significantly lower than that of naturally conceived (NC) ones, with the increased percentage of small-for-gestational-age (SGA) birth. The DNA methylation was significantly down-regulated in the DMR of CDKN1C (KvDMR1) and up-regulated in the DMR of IGF2 (H19 DMR) in ART placentas. The treatment of E2 altered the expression of the two genes and the DNA methylation of their DMRs in HTR8 to a similar tendency as in vivo.Discussion: The maternal high E2 levels after ART up-regulate the expression of imprinted genes in human placentas through epigenetic modifications, which influences the growth potential of the offspring. Further studies are needed to follow up the growth and development of the ART offspring. [ABSTRACT FROM AUTHOR]

Introduction: Placental imprinted genes appear to be sensitive indicators of an inappropriate pre-implantation environment. This study examined the effects of negative uterine asynchrony after embryo transfer (ET) on early horse embryo development, and yolk-sac membrane expression of DNA methyltransferases (DNMTs) and equine specific placental imprinted genes.Methods: Day 8 embryos were transferred to recipient mares on day 8 (synchronous) or day 3 (asynchronous) after ovulation, and conceptuses were recovered 6 or 11 days later (day 14 or 19 of development).Results: Day 14 conceptuses recovered from an asynchronous uterus had a smaller embryonic disc, in which primitive streak development was visibly retarded compared to conceptuses from a synchronous uterus. Similarly, length, somite number and organogenesis were retarded in day 19 embryos after asynchronous ET. Maternal (GRB10, H19, IGF2R, PHLDA2) and paternal (IGF2, INSR, PEG3, PEG10, DIO3, NDN, SNRPN) imprinted genes and DNMTs (DNMT1, 3A and 3B) were all up-regulated between day 14 and 19 of pregnancy and, for most, mRNA expression was higher in synchronous than asynchronous day 19 yolk-sac membrane. Expression of the paternally imprinted gene HAT1 increased between day 14 and 19 of pregnancy, but was not affected by the asynchrony.Discussion: Conceptus development and upregulation of DNMTs and imprinted genes were delayed rather than dysregulated after transfer into a negatively asynchronous uterus. We propose that this ability to 'reset' conceptus development to uterine stage is an adaptation that explains why horse embryos are unusually tolerant of asynchrony after ET. [ABSTRACT FROM AUTHOR]

Introduction: Imprinted genes play an important role in mammalian fetoplacental growth and development. We have evaluated whether the placental expression of two imprinted genes, growth factor receptor-binding protein 10 (GRB10) and pleckstrin homology-like domain, family A, member 2 (PHLDA2) correlate with human fetoplacental growth parameters.Methods: Placentae (n = 77) were collected from small- (SGA) and appropriate- (AGA) for gestational age full-term singleton pregnancies (n = 36 SGA and 41 AGA). Placentae and neonates were weighed at birth. Realtime quantitative PCR was performed to assess placental transcript abundance of GRB10 and PHLDA2 normalized to a panel of reference genes.Results: Placental GRB10 transcript abundance associated positively with placental weight (r = 0.307, P = 0.007), birth weight (r = 0.267, P = 0.019) and neonatal head circumference (r = 0.280, P = 0.014). Placental GRB10 transcript levels were significantly lower in male SGA placentae compared to the male AGA placentae. Placental PHLDA2 transcript abundance did not show any associations with maternal, placental or neonatal parameters.Discussion: Placental GRB10 expression was found to be associated positively with placental weight, birth weight, and neonatal head circumference, especially in males. Hence, we speculate that placental GRB10 plays a role in regulating fetoplacental growth and thereby in the pathophysiology of fetal growth restriction in the context of fetal gender. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to determine whether the gene expression and associated DNA methylation regulation of H19 and IGF2 are altered in placentas conceived by assisted reproductive technologies (ART) compared to natural conceptions.Methods: 113 pregnancies were recruited resulting in 119 placentas (83 singletons and 36 twins), where 56 were conceived via in vitro fertilization (IVF), 41 via intracytoplasmic sperm injection (ICSI), and 22 naturally. Regulation of imprinting of H19 and IGF2 was determined by the DNA methylation status at three CpG sites within the H19 imprinting control region 1 (ICR1) using bisulphite pyrosequencing. Expression of H19 and IGF2 in 45 of these placentas (17 IVF, 14 ICSI, and 14 NC) was measured by determining the relative mRNA transcript levels using RT-qPCR in placental villi.Results: Placental weight and birth weight were not significantly different between groups. H19 expression was significantly increased in both IVF and ICSI placentas when compared to controls (1.8 and 1.9 fold higher, respectively). Conversely, IGF2 was significantly decreased in both ART groups (0.8 and 0.7 fold lower, respectively). Mean DNA methylation at ICR1 was found to be similar between all groups. No correlation was found between DNA methylation at ICR1 and expression of either gene. However, a significant inverse relationship was found between H19 and IGF2 expression.Conclusion: We provide evidence of altered H19 and IGF2 expression in ART placentas. The altered expression pattern may suggest a loss of imprinting on the paternal allele. Furthermore, these alterations may not be entirely associated with DNA methylation at ICR1. We show further indirect evidence of the H19-IGF2 inverse expression pattern. [ABSTRACT FROM AUTHOR]

Imprinted genes, which are monoallelically expressed by virtue of an epigenetic process initiated in the germline, are known to play key roles in regulating fetal growth and placental development. Numerous studies are investigating the expression of these imprinted genes in the human placenta in relation to common complications of pregnancy such as fetal growth restriction and preeclampsia. This study aimed to determine whether placental sampling protocols or other factors such as fetal sex, gestational age and mode of delivery may influence the expression of imprinted genes predicted to regulate placental signalling. Methods Term placentas were collected from Caucasian women delivering at University Hospital of Wales or Royal Gwent Hospital within two hours of delivery. Expression of the imprinted genes PHLDA2 , CDKN1C , PEG3 and PEG10 was assayed by quantitative real time PCR. Intraplacental gene expression was analysed (N = 5). Placental gene expression was compared between male (N = 11) and female (N = 11) infants, early term (N = 8) and late term (N = 10) deliveries and between labouring (N = 13) and non-labouring (N = 21) participants. Results The paternally expressed imprinted genes PEG3 and PEG10 were resilient to differences in sampling site, fetal sex, term gestational age and mode of delivery. The maternally expressed imprinted gene CDKN1C was elevated over 2-fold (p < 0.001) in placenta from labouring deliveries compared with elective caesarean sections. In addition, the maternally expressed imprinted gene PHLDA2 was elevated by 1.8 fold (p = 0.01) in samples taken at the distal edge of the placenta compared to the cord insertion site. Conclusion These findings support the reinterpretation of existing data sets on these genes in relation to complications of pregnancy and further reinforce the importance of optimising and unifying placental collection protocols for future studies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Placental nutrient flow is the primary determinant of fetal growth. This key function of the placenta depends on several growth-promoting or -suppressing imprinted genes including Insulin-like growth factor [IGF] axis genes, which regulate nutrient transfer across the placenta. However whether changes in the placental expression of these genes parallel increased fetal growth observed in the second and third trimester remains unknown. Objective: The aim of our study was to determine the ontogeny of key IGF axis genes and other growth regulating imprinted genes in the placenta and to characterize patterns of placental gene expression associated with intrauterine growth restriction (IUGR). Study design: Real time RT-PCR analysis of 11 genes using specific probes were performed in the placental tissue collected at the time of delivery from 63 subjects with live birth pregnancies from 24 to 40 weeks gestation between 2009 -2010. Results: We found that paternally expressed gene ZNF127 (p < 0.001) was upregulated whereas IGF1 (p = 0.001) and maternally expressed gene PHLDA2 (p = 0.001) were downregulated with advancing gestational age. ROC analysis revealed a significant change in the expression of the above genes early in the third trimester. When compared to age-matched appropriate for gestational age (AGA) infants, expression of PHLDA2 (p = 0.03) IGF2R (p < 0.05) was upregulated in IUGR infants. Maternal age was also a significant predictor for IUGR (p = 0.05). Conclusion: We found increased placental expression of growth-promoting imprinted genes and decreased expression of growth-suppressive imprinted genes with advancing gestational age. These changes in placental gene expression could potentially explain accelerated fetal growth seen in the third trimester. Upregulation of maternally expressed imprinted genes in IUGR population supports the “parental conflict hypothesis”. [Copyright &y& Elsevier]

Abstract: Cloning in mammals suffers from high rates of pregnancy losses associated with abnormal placentation, mainly placentomegaly, leading to fetal death. Placental growth is dependent on the regulated expression of many genes of which imprinted genes play a fundamental role. Among them, the Phlda2 gene is expressed from the maternal allele and acts to limit placental growth in mouse and human. Here we used Northern blots, quantitative RT-PCR and in situ hybridization to analyze the expression patterns of bovine PHLDA2 and to compare its expression levels in normal and somatic cell nuclear transfer (SCNT) placentas over a range of gestational stages. PHLDA2 is not expressed in extra-embryonic tissues before d32 of gestation but the level of expression increases throughout pregnancy until term in the placental villi collected from pregnancy obtained by artificial insemination (AI). At all stages of pregnancy, PHLDA2 mRNA are specifically localized in the trophoblast mononucleated cells contrasting with lack of expression in the binucleated cells and uterine tissues. In SCNT placentas, a similar pattern of expression was observed during early pregnancy. In contrast the level of expression is significantly reduced around d200 of gestation in the placental villi from pathological clones. The reduced expression of PHLDA2 was obvious particularly in the placental villi anchored within the uterine crypts with expression confined to the trophoblast of the chorionic plate. Altogether, these results highlight a similarity in expression patterns for PHLDA2 bovine and human where expression is localized to the trophoblast throughout pregnancy and parallels the continuous growth of the placenta. Moreover, the lack of expression in the fetal villi from oversized bovine cloned placenta is consistent with the function of PHLDA2 in restraining placental growth and underlines an aberrant expression of this gene after somatic cloning. [Copyright &y& Elsevier]

Genomic imprinting is a remarkable process that causes genes to be expressed or repressed depending on their parental-origin. Imprinted genes play important roles in prenatal growth and organ development. Postnatally, imprinted genes can contribute to the regulation of metabolic pathways and behaviour associated with the control of resources. One of the most important sites of imprinted gene action is the placenta. During this workshop at the 11th meeting of the International Federation of Placenta Associations/European Placenta Group held in Glasgow, a series of short talks were presented providing an overview of the evolution, function and mechanisms of imprinting in mammals with particular reference to the placenta. In addition, epigenetic control of trophoblast development and function were considered. This report summarises the contributions to the workshop. [Copyright &y& Elsevier]

Intrauterine growth and development can impact upon the long-term health of an individual. The fetus is dependent upon the placenta for its supply of nutrients and oxygen from the mother. In turn, the functional capacity of the placenta to supply that demand is under the control of the fetal and maternal genomes. Recent evidence suggests that imprinted genes, a class of genes found in placental mammals whose expression depends on their parental origin, have multiple roles in the placenta. The imprinted genes regulate the growth and transport capacity of the placenta, thereby controlling the supply of nutrients. They may also regulate the growth rate of fetal tissues directly, thereby controlling nutrient demand by the fetus. Recent studies using mice with deletions or disruption of imprinted genes with an altered balance between placental and fetal growth and changes in placental efficiency are indicative of feto-placental signalling of fetal nutrient demand. We propose that signalling mechanisms involving growth demand signals and nutrient transporters are likely to occur and are important for fine tuning normal fetal growth. [Copyright &y& Elsevier]

Abstract: Pregnancy is generally a co-operative interaction between mother and fetus in which the evolutionary genetic interests of both benefit from production of healthy offspring. While this view is largely supported by empirical data, Kinship Theory predicts that mother and fetus will disagree over the optimum level of maternal investment that maximises their respective fitnesses. This conflict will be more evident with polyandrous than monogamous mating systems, when resources are scarce and in late gestation when the fetus is growing maximally, particularly if conceptus mass is large relative to maternal mass. As the site of nutrient transfer, the placenta is pivotal in the tug-of-war between mother and fetus over resource allocation. It responds to both fetal signals of nutrient demand and maternal signals of nutrient availability and, by adapting its phenotype, regulates the distribution of available resources. These adaptations involve changes in placental size, morphology, transport characteristics, metabolism and hormone bioavailability. They are mediated by key growth regulatory, endocrine and nutrient supply genes responsive to mismatches between nutrient availability and the fetal genetic drive for growth. Indeed, evolution of genomic imprinting and placental secretion of hormones are believed to have been driven by maternal-fetal conflict over resource allocation. Although many of the specific mechanisms involved still have to be identified, the placenta confers optimal fitness on the offspring for its developmental environment by balancing conflict and cooperation in the allocation of resources through generation of nutrient transport phenotypes specific to the prevailing nutritional conditions and/or fetal genotype. [Copyright &y& Elsevier]