The SLC25A42 Transcript Is a Biomarker for Fetal Reprogramming in Response to Placental Insufficiency in Preterm Newborns Under 32 Weeks Gestation—A Pilot Study
Abstract:Introduction:
Timing of medical delivery of preterm newborns exposed to placental insufficiency is largely determined by umbilical artery blood flow and maternal clinical manifestations. There is a lack of tools to properly assess fetal body response to placental insufficiency before or upon delivery. Yet, short- and long-term comorbidities associated with placental insufficiency and the consequential intrauterine growth restriction may be a result of fetal response following prolonged stress. This … Show more
“…In fact, single-nucleotide polymorphisms near this gene have been associated with hypertension in some studies ( Fox et al, 2011 ), likely due to the role of CoA in beta oxidation in the mitochondrion. Interestingly, SLC25A42 expression has been shown to be upregulated in foetuses undergoing transcriptional reprogramming to adapt to placental insufficiency ( Box 1 ) ( Chou and Wang, 2020 ), suggesting that SLC25A42 upregulation may contribute to the metabolic reprogramming required for foetal survival in sub-optimal nutritional environments. Box 1.…”
Section: Structure Function and Physiological Roles Of Membrane Trans...mentioning
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
“…In fact, single-nucleotide polymorphisms near this gene have been associated with hypertension in some studies ( Fox et al, 2011 ), likely due to the role of CoA in beta oxidation in the mitochondrion. Interestingly, SLC25A42 expression has been shown to be upregulated in foetuses undergoing transcriptional reprogramming to adapt to placental insufficiency ( Box 1 ) ( Chou and Wang, 2020 ), suggesting that SLC25A42 upregulation may contribute to the metabolic reprogramming required for foetal survival in sub-optimal nutritional environments. Box 1.…”
Section: Structure Function and Physiological Roles Of Membrane Trans...mentioning
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
“…In the context of placental insufficiency, the signaling pathways instructing the evolution of gene expression profiles in proper fetal development is altered at least partly due to a state of chronic hypoxia and nutrient deprivation. Such fetal response to placental insufficiency, with resultant alteration in global expression, is viewed as "fetal reprogramming" [5,21]. In a sense, transcriptional regulation is "reprogrammed" in order for the body to cope with the environmental stress, with a goal of ensuring survival.…”
Section: Fetal Reprogrammingmentioning
confidence: 99%
“…In the past two years, several studies were published to report the use of highthroughput sequencing in characterizing fetal or placental reprogramming in response to gestational hypertensive disorders and/or placental insufficiency using human tissues (Table 1). Our group assessed transcriptomes of blood obtained at birth from 20 very preterm newborns (3 with preeclampsia, 6 with placental insufficiency, and 11 controls without any of the aforementioned diagnoses) [21]. In this pilot study, we characterized transcriptional regulation by conducting pairwise analyses among the three groups.…”
Section: High-throughput Sequencing Approach To Studying Fetal Reprogmentioning
confidence: 99%
“…Rational development of biomarkers for fetal reprogramming requires thorough considerations of tissue types. While blood collected at time of birth may provide a comprehensive picture of the sum of antenatal stress and is reasonable for use in neonatal outcome prediction, it does not provide an opportunity for assessing the dynamics of fetal reprogramming, nor does it provide any value for clinical decision making in terms of optimal timing of delivery [21]. The placental or umbilical cord tissues are likely the tissue types that are the most sensitive to deprivation of oxygen and/or nutrients, and therefore provide an opportunity to assess reprogramming at its earliest stage [32,33,37].…”
Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.
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