דו״ח מאומת

Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance that develops in the second or third trimester of pregnancy. GDM can lead to short-term and long-term complications both in the mother and in the offspring. Diagnosing and treating this condition is therefore of great importance to avoid poor pregnancy outcomes. There is increasing interest in finding new markers with potential diagnostic, prognostic and therapeutic utility in GDM. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, are critically involved in metabolic processes and their dysregulated expression has been reported in several pathological contexts. The aberrant expression of several circulating or placenta-related ncRNAs has been linked to insulin resistance and β-cell dysfunction, the key pathophysiological features of GDM. Furthermore, significant associations between altered ncRNA profiles and GDM-related complications, such as macrosomia or trophoblast dysfunction, have been observed. Remarkably, the deregulation of ncRNAs, which might be linked to a detrimental intrauterine environment, can lead to changes in the expression of target genes in the offspring, possibly contributing to the development of long-term GDM-related complications, such as metabolic and cardiovascular diseases. In this review, all the recent findings on ncRNAs and GDM are summarized, particularly focusing on the molecular aspects and the pathophysiological implications of this complex relationship.…

PMID: 32512799

Gestational diabetes mellitus (GDM), one of the most common complications during pregnancy, is associated with a high risk of short- and long-term adverse effects on the mother and offspring. Placenta-derived hormones and cytokines aggravate maternal insulin resistance (IR) during pregnancy, which in turn contribute to GDM. The hyperglycemia and IR in GDM result in aberrant placental structure and function adversely affecting fetal growth and well-being. Therefore, it is reasonable to assume that structural and functional alterations in the placenta contribute to the pathogenesis of GDM and GDM-related complications. Increasing evidence suggests that multiple non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are dysregulated in placentas of patients with GDM and linked to abnormal placental structure, metabolism, and function. Manipulation of ncRNA expression led to some key pathophysiological features of GDM, such as trophoblast dysfunction, changes in intracellular glucose metabolism, and inflammation. Moreover, placenta-specific ncRNAs may be potential diagnostic biomarkers and even therapeutic targets for GDM. This review summarizes data published on the involvement of aberrantly expressed placental ncRNAs in GDM and provides information on their role in the pathogenesis of GDM and GDM-associated complications.…

PMID: 34456579

Gestational diabetes mellitus (GDM) is a complex disorder that is defined by glucose intolerance with onset during pregnancy. The incidence of GDM is increasing worldwide. Pregnancies complicated with GDM have higher rates of maternal and fetal morbidity with short- and long-term consequences, including increased rates of cardiovascular disease and type II diabetes for both the mother and offspring. The pathophysiology of GDM still remains unclear and there has been interest in the role of small extracellular vesicles (sEVs) in the maternal metabolic adaptations that occur in pregnancy and GDM. Small EVs are nanosized particles that contain bioactive content, including miRNAs and proteins, which are released by cells to provide cell-to-cell communication. Pregnancy induces an increase in total and placental-secreted sEVs across gestation, with a further increase in sEV number and changes in the protein and miRNA composition of these sEVs in GDM. Research has suggested that these sEVs have an impact on maternal adaptations during pregnancy, including targeting the pancreas, skeletal muscle and adipose tissue. Consequently, this review will focus on the differences in total and placental sEVs in GDM compared to normal pregnancy, the role of sEVs in the pathophysiology of GDM and their clinical application as potential GDM biomarkers.…

PMID: 33714611

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition dur-ing pregnancy. Explanation of the GDM pathogenesis is important due to preventing gestational complications. During pregnancy there are significant changes in maternal metabolism. Many of these changes are influenced by different adi-pokines produced in the placenta and adipose tissue. The exact role of adipokines in the pathogenesis of GDM remains still unknown. Several adipokines have been analysed throughout gestation and their levels have been suggested as biomarkers of maternal-perinatal outcomes. Some of them have been postulated as significant in the pathogenesis of pregnancy complications like GDM. This report aims to review some of the recent topics of adipokine research that may be of particular importance in patho-physiology and diagnosis of gestational diabetes mellitus. Because of manuscript length limitations, after thorough literature review and in view of the recent evidence, we focus on the one of the most well-known adipokine: adiponectin, and not so well-studied: nesfatin-1, chemerin, ghrelin, and CTRP 1.…

PMID: 29781079

<h4>Problem</h4>Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with adverse maternal and fetal outcomes. Nevertheless, the molecular mechanism of placental dysfunction in GDM are still not clear, especially the role of ferroptosis and its interplay with oxidative stress, inflammation, and angiogenesis.<h4>Method of study</h4>Placental tissues from GDM pregnancies were examined to assess oxidative stress, antioxidant defense, ferroptosis regulation, inflammatory signaling, and angiogenic pathways. Expression levels of key molecular markers were evaluated, and correlation analyses were performed to identify mechanistic interrelationships.<h4>Results</h4>GDM placenta demonstrated elevated oxidative stress markers, including P22PHOX and TXNIP, accompanied by reduced antioxidant markers, such as HO-1, NQO1, SOD2, and CAT, indicating impaired cellular defense. Ferroptosis regulation was disrupted, as anti-ferroptotic markers GPX4, SLC7A11, and NRF2 were significantly downregulated, while pro-ferroptotic markers TFR1 and ACSL4 were increased, suggesting enhanced iron accumulation and lipid peroxidation. This was accompanied by heightened inflammation, evidenced by increased IL-6, IL-1β, TNF-α, and NF-κB activation, alongside reduced IL-10 expression. Furthermore, angiogenesis was impaired, reflected by decreased VEGFA, HIF-1α, and SDF-1α levels, highlighting poor vascular development in the placenta. Additionally, Correlation analyses demonstrated strong associations between ferroptosis markers and oxidative stress, inflammatory, and angiogenic pathways, suggesting the possible presence of an interconnected regulatory network.<h4>Conclusions</h4>These findings identify ferroptosis as a central regulator of GDM-associated placental dysfunction, through a possible interconnected network of oxidative stress, inflammation, and impaired angiogenesis. Targeting ferroptosis may offer a possible therapeutic option to restore placental function and improve maternal-fetal outcomes in GDM.…

PMID: 42464732

Our efforts to understand the developmental origins of birth defects and disease have primarily focused on maternal exposures and intrauterine stressors. Recently, research into non-genomic mechanisms of inheritance has led to the recognition that epigenetic factors carried in sperm also significantly impact the health of future generations. However, although researchers have described a range of potential epigenetic signals transmitted through sperm, we have yet to obtain a mechanistic understanding of how these paternally-inherited factors influence offspring development and modify life-long health. In this endeavor, the emerging influence of the paternal epigenetic program on placental development, patterning, and function may help explain how a diverse range of male exposures induce comparable intergenerational effects on offspring health. During pregnancy, the placenta serves as the dynamic interface between mother and fetus, regulating nutrient, oxygen, and waste exchange and coordinating fetal growth and maturation. Studies examining intrauterine maternal stressors routinely describe alterations in placental growth, histological organization, and glycogen content, which correlate with well-described influences on infant health and adult onset of disease. Significantly, the emergence of similar phenotypes in models examining preconception male exposures indicates that paternal stressors transmit an epigenetic memory to their offspring that also negatively impacts placental function. Like maternal models, paternally programmed placental dysfunction exerts life-long consequences on offspring health, particularly metabolic function. Here, focusing primarily on rodent models, we review the literature and discuss the influences of preconception male health and exposure history on placental growth and patterning. We emphasize the emergence of common placental phenotypes shared between models examining preconception male and intrauterine stressors but note that the direction of change frequently differs between maternal and paternal exposures. We posit that alterations in placental growth, histological organization, and glycogen content broadly serve as reliable markers of altered paternal developmental programming, predicting the emergence of structural and metabolic defects in the offspring. Finally, we suggest the existence of an unrecognized developmental axis between the male germline and the extraembryonic lineages that may have evolved to enhance fetal adaptation.…

PMID: 36468017

Early-life programming is a major determinant of lifelong metabolic health, yet current preventive strategies focus almost exclusively on maternal factors. Emerging experimental and preclinical data reveal that a father's diet before conception, particularly high-fat intake, also shapes offspring physiology. Here, we synthesize the latest evidence on how such diets remodel the sperm epigenome during two discrete windows of vulnerability: (i) testicular spermatogenesis, via DNA methylation and histone modifications, and (ii) post-testicular epididymal maturation, where small non-coding RNAs are selectively gained. We examine how these epigenetic signals influence pregnancy, placental development, and ultimately, metabolic trajectories in progeny. To extend published work, we sourced publicly available diet-induced sperm epigenome datasets and provide new potential connections of these changes to genes governing placental development, vascularization and size using the International Mouse Phenotyping Consortium data. Moreover, we further interrogate these overlaps with intricate in-silico analyses to examine their potential consequences. To foster meaningful interactions with these findings, we have developed a web application for ease (ShinySpermPlacenta). Collectively, these findings support a biparental model of preconception care and position the sperm epigenome as a promising tractable biomarker platform for personalized paternal nutrition counselling aimed at improving fertility and reducing intergenerational metabolic disease risk.…

PMID: 40913545

Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally induced effects on placenta development and function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm histone H3 lysine 4 tri-methylation signatures, the placenta transcriptome, and cellular composition. C57BL6/J male mice were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 at promoters of genes involved in metabolism and development. Notably, altered sperm H3K4me3 was also localized at placental enhancers. Bulk RNA-sequencing on placentas revealed paternal obesity-associated sex-specific changes in expression of genes involved in hypoxic processes such as angiogenesis, nutrient transport, and imprinted genes, with a subset of de-regulated genes showing changes in H3K4me3 in sperm at corresponding promoters. Paternal obesity was also linked to impaired placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity effects on placenta development and function as one potential developmental route to offspring metabolic disease.…

PMID: 39612469

The human placenta plays an important role in pregnancy and offspring health. The paternal genome contributes significantly to placental growth and development. While the maternal factors affecting gestational health are thoroughly investigated, the paternal factors are often overlooked. Thus, it is important to understand various paternal factors affecting placental development and function. To assess the effect of various paternal factors on placental development, function, and pregnancy-related disorders. This review was registered in PROSPERO (Registration number CRD420250634649). Literatures across databases like JSTOR, Scopus, Google Scholar, ScienceDirect, and PubMed were screened through a set of criteria. Forty-eight studies were selected that included low-to-moderate risk paternal factors like age, smoking, race/ethnicity/location, genetic, epigenetic factors, exposure to chemicals, seminal plasma, and lifestyle factors. Increased paternal age was reported to contribute towards higher risks of preeclampsia, spontaneous abortions, preterm birth, stillbirth, and higher placental and fetal birth weight. Paternal smoking, on the other hand, was found to be an associated risk factor for placental abruption and stillbirth. Exposure to various chemicals was found to be associated with changes in sperm epigenome and placental dysfunction. Paternal health, lifestyle, and exposure to chemicals may affect placental development and pregnancy. Paternal factors may alter seminal plasma proteome, cytokine profile, and abnormal sperm DNA methylation of imprinted genes which is associated with adverse pregnancy outcomes. Pre-conceptional health assessment of prospective fathers might be helpful in ensuring optimal placental development in pregnancies to follow, in addition to newborn health.…

PMID: 40699405

While maternal health has long been the focus of reproductive and developmental research, increasing attention is being given to the father's preconception health. Over the past two decades, growing evidence supports the Paternal Origins of Health and Disease (POHaD) paradigm, highlighting how paternal environmental factors prior to conception can significantly influence offspring development and long-term health. Rodent models have provided critical mechanistic insights into how paternal environmental exposure can alter the sperm epigenetic cargo. Emerging evidence indicates that paternal nutrition not only impacts the embryo but also the placenta. This review synthesizes current knowledge on how different types of paternal diet influence the sperm epigenome and the downstream consequences for the feto-placental unit and for pregnancy outcomes. We provide essential context: first, on the placenta's sensitivity to environmental influences, and second, on the variability across studies exploring paternal dietary exposures, highlighting key factors that may modulate paternal effects. We then examine how an altered diet affects the sperm epigenome and describe the physiological and molecular consequences on embryonic and placental development. Importantly, these modifications are linked to adverse outcomes including fetal growth restriction and placental insufficiency, and may therefore contribute to maternal complications such as preeclampsia, known for its long-term cardiovascular impact on women. Our review underscores the need to integrate paternal health into preconception care strategies, alongside maternal health, as it could significantly improve pregnancy outcomes and long-term health of both mothers and offspring.…

PMID: 41324420

In brief: Activation of ER signaling during spermatogenesis in rats alters sperm epigenetic marks and decreases male fertility. This study shows that altered sperm DNA methylation marks can be transmitted to the developing embryo and impede its development, thereby contributing to decreased male fertility. Abstract: Activation of estrogen receptors (ER) signaling in adult male rats leads to subfertility, and whole-genome bisulfite sequencing revealed large-scale genome-wide changes in sperm DNA methylation. In this study, we further probed the developmental consequences of altered sperm methylome. An enrichment map analysis of the differentially methylated genes revealed that clusters related to embryo development and its regulation were most enriched. Genes differentially methylated in sperm and implicated in embryo development were selected for validation in sperm by pyrosequencing. DNA methylation and expression levels of these developmental genes were evaluated in resorbed and normal embryos and placental tissues. The aberrant sperm DNA methylation pattern in developmental genes Cdkn1c, Tgfb1, Bmp4, Gab1, Peg3, Myc, Wt1, Sfmbt2, Sox5, and Hoxa3 was reflected in that of the resorbed embryos, along with their deregulated expression after paternal ER agonist treatment. In contrast, the methylation pattern and expression in normal embryos and placenta for most genes were comparable to those of the controls. Additionally, several key developmental pathways, including MAPK, Tgfβ, Wnt, Notch, Hedgehog, and Scf-cKit signaling, were also found to be affected in resorbed embryos sired by ERα agonist-treated male rats. The results indicate that activation of estrogen signaling during spermatogenesis causes aberrant sperm DNA methylation in developmental genes. These defects could be transmitted to embryos, altering the expression of these genes and pathways, thereby impeding embryonic development, reducing litter size and causing subfertility. The study provides a mechanism by which ERs epigenetically regulate male fertility and subsequent embryogenesis.…

PMID: 42275185

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking…

PMID: 38092039

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF family receptor alpha like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy (∼75-fold increase in macaques vs. ∼2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of…

PMID: 37584611

An efficient functioning placenta is essential for a healthy pregnancy and yet the way this is achieved has been the subject of much discussion and confusion, particularly with the occurrence of pathological conditions such as preeclampsia, morning sickness and hyperemesis/ptyalism gravidarum. We will attempt to explain the underlying physiology and the potential roles played by the placental tachykinins, neurokinin B and endokinin.…

PMID: 29212865

Nausea and emesis in early pregnancy is a common phenomenon affecting between 50% and 70% of pregnant women, but little is known about the etiology and possible function of this common and often incapacitating condition. Morning sickness has been reported to have a positive effect on pregnancy outcome and is associated with a decreased risk of miscarriage, preterm birth, low birth weight (LBW), and perinatal death. Both human and animal studies have shown that reduced energy intakes in early pregnancy are associated with increased placental weight. Based on evidence from the literature, a hypothesis is proposed that suggests a functional role for the nausea and emesis of pregnancy in stimulating early placental growth. It is suggested that morning sickness, resulting from secretion of hCG and thyroxine, reduces maternal energy intake. As a result, maternal levels of the anabolic hormones, insulin, and insulin growth factor-1 (IGF-1) are lowered. By suppressing maternal tissue synthesis in early pregnancy, we propose that nausea and vomiting in pregnancy helps ensure that nutrient partitioning favors the developing placenta. Evidence is also presented that suggests there may be a positive relationship between morning sickness and preconceptional body mass index (BMI), such that women who are underweight will experience less severe symptoms of morning sickness compared with women with normal preconceptional BMIs.…

PMID: 10775746

Evolutionary biologists have long been fascinated by pregnancy sickness, the heritable, stereotyped syndrome in early pregnancy that usually consists of benign nausea and vomiting and in around 1% of cases progresses to the pathological extreme hyperemesis gravidarum. Identification of the placental hormone GDF15 as a principal causal factor justifies reassessment of its proximate and ultimate causes. This Review synthesizes knowledge of pregnancy sickness at the four levels of analysis of classical ethology-mechanism, development, phylogeny, and adaptive function. Emerging insight into GDF15's role in innate sickness behaviors suggests pregnancy sickness is a heightened state of pre-existing behavioral defenses triggered by placental production of an emetogenic hormone which may hold a different primary function. Comparison of transcriptomes reveals that placental <i>GDF15</i> production rose 100- to 1000-fold to human-like levels in catarrhine primates, and is low or absent in New World monkeys, rodents, and other mammals, with the possible exception of elephants. This suggests that pregnancy sickness is phylogenetically restricted yet not human-specific, and associates with innovations in syncytiotrophoblast biology rather than diet. I re-evaluate leading adaptive hypotheses (prophylactic, metabolic rewiring, placental growth, and anti-rejection) and argue that the key to adjudicating among them hinges on whether GDF15 acts locally through non-canonical receptors and whether additional factors distinguish pregnancy sickness from sickness behavior. Finally, I evaluate explanations for the persistent risk of hyperemesis gravidarum in modern humans, including trade-offs, mismatch, and conflict. With recent advances, pregnancy sickness is not just a curiosity of human evolution, but a compelling opportunity to investigate the mechanistic bases of complex adaptive behaviors.…

PMID: 41132319

The article presents current views on maternal hyperhomocysteinemia (HHcy) as an important factor causing prenatal stress and impaired nervous system development in fetuses and newborns in early ontogenesis, as well as complications in adulthood. Experimental data demonstrate that prenatal HHcy (PHHcy) affects the morphological maturation of the brain and activity of its neurotransmitter systems. Cognitive deficit observed in the offspring subjected to PHHcy in experimental studies can presumably cause the predisposition to various neurodegenerative diseases, as the role of maternal HHcy in the pathogenesis such diseases has been proven in clinical studies. The review also discusses molecular mechanisms of the HHcy neurotoxic action on the nervous system development in the prenatal and early postnatal periods, which include oxidative stress, apoptosis activation, changes in the DNA methylation patterns and microRNA levels, altered expression and processing of neurotrophins, and neuroinflammation induced by an increased production of pro-inflammatory cytokines. Special attention is given to the maternal HHcy impact on the placenta function and its possible contribution to the brain function impairments in the offspring. Published data suggest that some effects of PHHcy on the developing fetal brain can be due to the disturbances in the transport functions of the placenta resulting in an insufficient supply of nutrients necessary for the proper formation and functioning of brain structures.…

PMID: 34225594

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.…

PMID: 28757456

Maternal immune activation (MIA) refers to a maternal immune system triggered by infectious or infectious-like stimuli. A cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes most notably in the central nervous system. Epidemiologic studies implicate maternal infections in a variety of neuropsychiatric disorders, most commonly autism spectrum disorders and schizophrenia. In animal models, MIA causes neurochemical and anatomic changes in the brain that correspond to those found in humans with the disorders. As our understanding of the interactions between environment, genetics, and immune system grows, the role of alternative, noninfectious risk factors, such as prenatal stress, obesity, and the gut microbiome also becomes clearer. This review considers how infectious and noninfectious etiologies activate the maternal immune system. Their impact on fetal programming and neuropsychiatric disorders in offspring is examined in the context of human and animal studies.…

PMID: 30430765

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother's immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood-brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior.…

PMID: 34768946