RESUMO
Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.
Assuntos
Metabolômica , Gravidez , Animais , Feminino , Humanos , Gravidez/metabolismo , Corticosterona/metabolismo , Metaboloma/fisiologia , Placenta/metabolismo , Pré-Eclâmpsia , Primatas/metabolismoRESUMO
Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (ß=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (ß=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.
Assuntos
Peso ao Nascer , Desenvolvimento Fetal , Gravidez de Gêmeos , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez/sangue , Gravidez/metabolismo , Betaína/sangue , Betaína/metabolismo , Peso ao Nascer/fisiologia , Colina/sangue , Colina/metabolismo , Estudos de Coortes , Desenvolvimento Fetal/fisiologia , Peso Fetal/fisiologia , Homocisteína/sangue , Homocisteína/metabolismo , Metionina/sangue , Metionina/metabolismo , Gravidez de Gêmeos/sangue , Gravidez de Gêmeos/fisiologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Trimestres da Gravidez/sangue , Trimestres da Gravidez/fisiologia , Resultado da GravidezRESUMO
Prenatal exposure to single chemicals belonging to the per- and polyfluoroalkyl substances (PFAS) family is associated with biological perturbations in the mother, fetus, and placenta, plus adverse health outcomes. Despite our knowledge that humans are exposed to multiple PFAS, the potential joint effects of PFAS on the metabolome remain largely unknown. Here, we leveraged high-resolution metabolomics to identify metabolites and metabolic pathways perturbed by exposure to a PFAS mixture during pregnancy. Targeted assessment of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS), along with untargeted metabolomics profiling, were conducted on nonfasting serum samples collected from pregnant African Americans at 6-17 weeks gestation. We estimated the overall mixture effect and partial effects using quantile g-computation and single-chemical effects using linear regression. All models were adjusted for maternal age, education, parity, early pregnancy body mass index, substance use, and gestational weeks at sample collection. Our analytic sample included 268 participants and was socioeconomically diverse, with the majority receiving public health insurance (78%). We observed 13.3% of the detected metabolic features were associated with the PFAS mixture (n = 1705, p < 0.05), which was more than any of the single PFAS chemicals. There was a consistent association with metabolic pathways indicative of systemic inflammation and oxidative stress (e.g., glutathione, histidine, leukotriene, linoleic acid, prostaglandins, and vitamins A, C, D, and E metabolism) across all metabolome-wide association studies. Twenty-six metabolites were validated against authenticated compounds and associated with the PFAS mixture (p < 0.05). Based on quantile g-computation weights, PFNA contributed the most to the overall mixture effect for γ-aminobutyric acid (GABA), tyrosine, and uracil. In one of the first studies of its kind, we demonstrate the feasibility and utility of using methods designed for exposure mixtures in conjunction with metabolomics to assess the potential joint effects of multiple PFAS chemicals on the human metabolome. We identified more pronounced metabolic perturbations associated with the PFAS mixture than for single PFAS chemicals. Taken together, our findings illustrate the potential for integrating environmental mixture analyses and high-throughput metabolomics to elucidate the molecular mechanisms underlying human health.
Assuntos
Negro ou Afro-Americano , Poluentes Ambientais , Fluorocarbonos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Gravidez/metabolismo , Ácidos Alcanossulfônicos , Poluentes Ambientais/toxicidade , Feto/metabolismo , Fluorocarbonos/toxicidade , Placenta/metabolismo , Georgia , MetabolômicaRESUMO
INTRODUCTION: Obesity during pregnancy can contribute to hypertensive complications through changes in glucose utilization. We investigated the impact of vascular glucose uptake, GLUT4 density, and endothelium on agonist-induced vasoconstriction in the aortas of overweight pregnant rats. METHODS: Isolated aortic rings with or without endothelium from pregnant or nonpregnant rats fed a standard (SD) or hypercaloric diet (HD) were contracted with phenylephrine or serotonin (10-9 to 10-4
Assuntos
Sobrepeso , Gravidez , Vasoconstrição , Animais , Feminino , Gravidez/metabolismo , Ratos , Aorta , Glicemia/metabolismo , Endotélio Vascular , Sobrepeso/metabolismo , Fenilefrina/farmacologia , Fenilefrina/metabolismo , Serotonina/farmacologia , Serotonina/metabolismoRESUMO
Since the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigations have expanded our understanding of obstetric pharmacology. Many of the basic physiologic changes that occur during pregnancy impact on drug absorption, distribution, or clearance. Activities of hepatic metabolizing enzymes are variably altered by pregnancy, resulting in concentrations sufficiently different for some drugs that efficacy or toxicity may be affected. Understanding these unique pharmacologic changes will better inform our use of medications for our pregnant patients.
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Farmacocinética , Gravidez , Feminino , Humanos , Gravidez/metabolismo , Obstetrícia , FígadoRESUMO
INTRODUCTION: Despite its recent reputation as prosocial neurohormone, the most important physiological role of oxytocin (OT) is stimulating uterine contractions. Though it is well known that plasma OT concentrations change drastically during delivery, it remains unexplored whether and how OT receptors in the maternal brain are activated. We examined whether the responses of cells in the central amygdala (CeA), an OT receptor-rich limbic site involved in pain and fear memory regulation, to exogenously applied OT analogue, Thr-Gly-OT (TGOT), vary depending on delivery. METHODS: Intracellular Ca2+ dynamics of the CeA cells were visualized in brain slices from female rats at virgin (VG), during pregnancy term (PT) days 16-21, within 24 h after delivery (G0), and within 1-3 days after delivery (G3). The Ca2+ responses to 1 µM TGOT, 20 mM KCl (high K), and 300 µM ADP were compared. RESULTS: We found that fraction of cells responding to TGOT, high K, and ADP differed significantly between the four delivery-associated terms. In particular, the fraction of cells responding to TGOT (TGOT responders) significantly increased from VG and PT at G0 and G3. Furthermore, the significant positive correlation between TGOT and high K response in TGOT and high K responders was reduced at G0, while that between TGOT and ADP responses in TGOT and ADP responders was increased at G0. CONCLUSION: These results indicate that the responses of CeA cells to an OT receptor agonist markedly change around delivery, which might play a role in controlling the labor-related pain and post-delivery emotional complications.
Assuntos
Núcleo Central da Amígdala , Ocitocina , Período Periparto , Receptores de Ocitocina , Animais , Feminino , Gravidez/metabolismo , Gravidez/psicologia , Ratos , Cálcio/metabolismo , Núcleo Central da Amígdala/metabolismo , Medo/fisiologia , Medo/psicologia , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Dor/metabolismo , Dor/psicologia , Período Periparto/metabolismo , Período Periparto/psicologia , Receptores de Ocitocina/metabolismoRESUMO
Myometrial contraction is stringently controlled throughout pregnancy and parturition. Progesterone signaling, effecting through the progesterone receptor (PR), is pivotal in modulating uterine activity. Evidence has shown that two major PR isoforms, PR-A and PR-B, have distinct activities on gene regulation, and the ratio between these isoforms determines the contractility of the myometrium at different gestational stages. Herein, we focus on the regulation of PR activity in the myometrium, especially the differential actions of the two PR isoforms, which maintain uterine quiescence during pregnancy and regulate the switch to a contractile state at the onset of labor. To demonstrate the PR regulatory network and its mechanisms of actions on myometrial activity, we summarized the findings into three parts: Regulation of PR Expression and Isoform Levels, Progesterone Receptor Interacting Factors, and Biological Processes Regulated by Myometrial Progesterone Receptor Isoforms. Recent genomic and epigenomic data, from human specimens and mouse models, are recruited to support the existing knowledge and offer new insights and future directions in myometrial biology.
Assuntos
Contração Muscular , Miométrio , Parto , Gravidez , Receptores de Progesterona , Animais , Feminino , Humanos , Camundongos , Gravidez/genética , Gravidez/metabolismo , Miométrio/metabolismo , Parto/genética , Parto/metabolismo , Progesterona/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Contração Muscular/genéticaRESUMO
Prolactin, a pituitary hormone that was discovered about 80 years ago and is primarily known for its functions in mammary gland development and lactation, is now known to participate in numerous functions across different phylogenetic groups. Fundamentally known for its secretion from lactotroph cells in adenohypophysis region of pituitary gland, newer studies have demonstrated a number of extrapituitary sites which secrete prolactin, where it acts in an autocrine, paracrine, and endocrine manner to regulate essential physiological and biochemical processes. These sites include lymphocytes, epithelial cells of lactating mammary glands, breast cancer cells of epithelial origin, and the placenta. The placenta is one of the most important organs secreting prolactin; however, its role in placental biology has not to date been reviewed comprehensively. This review elaborates upon the various facets of prolactin hormone, including prolactin production and its post-translational modifications and signaling. Major emphasis is placed on placental prolactin and its potential roles, ranging from the role of prolactin in angiogenesis, preeclampsia, maternal diabetes, and anti-apoptosis, among others.
Assuntos
Placenta , Prolactina , Feminino , Humanos , Lactação , Hipófise/metabolismo , Hipófise/fisiologia , Placenta/metabolismo , Placenta/fisiologia , Gravidez/metabolismo , Gravidez/fisiologia , Prolactina/metabolismo , Prolactina/fisiologia , Transdução de SinaisRESUMO
Neutrophils, which extensively infiltrate maternal systemic blood vessels in preeclampsia, express protease-activated receptor 1 (PAR-1) but only during pregnancy. Neutrophils are generally considered to be non-specific in their response, but the pregnancy-specific expression of PAR-1 could result in a gene expression profile unique to pregnancy, which could help explain why the maternal inflammatory response in preeclampsia is systemic rather than localized. We sought to determine if gene expression of pregnancy neutrophils would differ if stimulated by a protease versus bacterial lipopolysaccharide (LPS). We isolated neutrophils from normal pregnant women at 30 weeks' gestation and cultured them with elastase or LPS. We used elastase because it is a protease elevated in women with preeclampsia, and it activates pregnancy neutrophils via PAR-1. RNA was isolated from the neutrophils for sequencing of the transcriptomes. We discovered many differences in the gene expression profiles. For example, exposure to elastase resulted in three times more uniquely expressed genes than LPS, and the number of significantly differentially upregulated and downregulated genes was greater for elastase. Analysis of canonical pathways revealed similarities for innate immunity but also differences. LPS treatment enriched more pathways, but elastase activated more genes in each pathway. Elastase treatment enriched the MAPK signaling pathway, whereas LPS did not. This is significant because MAPK is a key mediator of transcriptional responses. These findings indicate that protease stimulation of pregnancy neutrophils results in a different profile than stimulation with LPS, which may help explain why the sterile inflammatory response of preeclampsia is systemic and unique to pregnancy.
Assuntos
Lipopolissacarídeos , Neutrófilos , Peptídeo Hidrolases , Pré-Eclâmpsia , Feminino , Expressão Gênica , Humanos , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Neutrófilos/metabolismo , Elastase Pancreática/metabolismo , Elastase Pancreática/farmacologia , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/farmacologia , Pré-Eclâmpsia/metabolismo , Gravidez/metabolismo , Gravidez/fisiologia , Receptor PAR-1/metabolismoRESUMO
Maternal lipid metabolism status during pregnancy may have pivotal effects on a healthy pregnancy, the progression of labor, and childbirth. Based on evidence, changes in maternal lipid profile and metabolism is related to various alterations in fetal metabolic status, fat mass, birth weight and can result in serious maternal and fetal complications. 15-lipoxygenase accounts as a key enzyme in metabolizing polyunsaturated fatty acids that generate various inflammatory lipid metabolites. The possible involvement of 15- lipoxygenase and its metabolites in the inflammatory process, cell proliferation and death, and immune response has been postulated. The indicative role of the 15- lipoxygenase enzymatic pathway in the implantation process, stages of pregnancy, embryogenesis, organogenesis, progression of labor, pregnancy period, and pregnancy-associated complications is remarkable. Accordingly, this study will review the research conducted on the role of 15- lipoxygenase in different reproductive tissues, and its pathological role in pregnancy-related diseases to provide more insight regarding the emerging role of 15-lipoxygenase in normal pregnancy.
Assuntos
Araquidonato 15-Lipoxigenase , Complicações na Gravidez , Gravidez , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Ácidos Graxos Insaturados/metabolismo , Feminino , Feto , Humanos , Metabolismo dos Lipídeos , Gravidez/metabolismo , Complicações na Gravidez/enzimologia , Complicações na Gravidez/metabolismoRESUMO
Angiogenesis is vital during pregnancy for remodeling and enhancing vasodilation of maternal uterine arteries, and increasing uterine blood flow. Abnormal angiogenesis is associated with decreased uteroplacental blood flow and development of pregnancy disorders such as gestational hypertension, preeclampsia, fetal growth restriction, preterm delivery, stillbirth, and miscarriage. The mechanisms that contribute to normal angiogenesis remain obscure. Our previous studies demonstrated that expression of the angiotensin type 2 receptor (AT2R) is increased while the angiotensin type 1 receptor (AT1R) is unchanged in the endothelium of uterine arteries, and that AT2R-mediated pregnancy adaptation facilitates enhanced vasodilation and uterine arterial blood flow. However, the role of AT2R in regulating angiogenesis during pregnancy has never been studied. This study examines whether or not AT2R activation induces angiogenesis and, if so, what mechanisms are involved. To this end, we used primary human uterine artery endothelial cells (hUAECs) isolated from pregnant and nonpregnant women undergoing hysterectomy. The present study shows that Compound 21, a selective AT2R agonist, induced proliferation of pregnant-hUAECs, but not nonpregnant-hUAECs, in a concentration-dependent manner, and that this C21-induced mitogenic effect was blocked by PD123319, a selective AT2R antagonist. The mitogenic effects induced by C21 were inhibited by blocking JNK-but not ERK, PI3K, and p38-signaling pathways. In addition, C21 concentration dependently increased cell migration and capillary-like tube formation in pregnant-hUAECs. The membrane-based antibody array showed that C21 increased expression of multiple angiogenic proteins, including EGF, bFGF, leptin, PLGF, IGF-1, and angiopoietins. Our qPCR analysis demonstrates that C21-induced increase in expression of these angiogenic proteins correlates with a proportional increase in mRNA expression, indicating that AT2R activates angiogenic proteins at the transcriptional level. In summary, the present study shows that AT2R activation induces angiogenesis of hUAECs in a pregnancy-specific manner through JNK-mediated pathways with associated transcriptional upregulation of multiple proangiogenic proteins.
Assuntos
Células Endoteliais , Neovascularização Fisiológica , Gravidez , Receptor Tipo 2 de Angiotensina , Artéria Uterina , Proteínas Angiogênicas/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Feminino , Humanos , Imidazóis , Recém-Nascido , Gravidez/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sulfonamidas , Tiofenos , Artéria Uterina/citologia , Artéria Uterina/metabolismoRESUMO
Galectin-1 (gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, is differentially expressed at the feto-maternal interface and appears to be functionally polyvalent, with a wide range of biological activities. However, the contributions of maternal and/or feto-placental gal-1 to the signaling networks promoting a healthy pregnancy are still being elucidated. This chapter discusses the methods commonly employed to study the maternal or feto-placental contribution of gal-1 during pregnancy in mice. The methods described here can be used to decipher the specific role of each source, e.g., maternal and/or feto-placental derived gal-1 in the orchestration of pregnancy-associated processes.
Assuntos
Galectina 1 , Placenta , Gravidez , Animais , Família , Feminino , Galectina 1/genética , Galectina 1/metabolismo , Camundongos , Placenta/metabolismo , Gravidez/metabolismo , Resultado da GravidezRESUMO
Physiological changes that occur during pregnancy in the maternal body can lead to alterations in the response to drugs in the mother. Pregnancy modifies the volume of distribution of drugs, their binding to plasma proteins, the activity of their metabolizing enzymes, and their elimination. However, to date, due to the dynamic and complex processes involved, adjustments to the dosage regimen during pregnancy remain impossible to standardize. Knowledge of these modifications will help to better understand the possible loss of drug efficacy during pregnancy, as well as anticipating the clinical and plasma monitoring of drugs with a low therapeutic margin.
Assuntos
Preparações Farmacêuticas , Farmacocinética , Feminino , Humanos , Gravidez/metabolismoRESUMO
Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.
Assuntos
Aborto Espontâneo/metabolismo , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Gravidez/metabolismo , Trofoblastos/metabolismo , Adulto , Animais , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Transdução de Sinais , Quinases da Família src/metabolismoRESUMO
The cell-free transcriptome in amniotic fluid (AF) has been shown to be informative of physiologic and pathologic processes in pregnancy; however, the change in AF proteome with gestational age has mostly been studied by targeted approaches. The objective of this study was to describe the gestational age-dependent changes in the AF proteome during normal pregnancy by using an omics platform. The abundance of 1310 proteins was measured on a high-throughput aptamer-based proteomics platform in AF samples collected from women during midtrimester (16-24 weeks of gestation, n = 15) and at term without labor (37-42 weeks of gestation, n = 13). Only pregnancies without obstetrical complications were included in the study. Almost 25% (320) of AF proteins significantly changed in abundance between the midtrimester and term gestation. Of these, 154 (48.1%) proteins increased, and 166 (51.9%) decreased in abundance at term compared to midtrimester. Tissue-specific signatures of the trachea, salivary glands, brain regions, and immune system were increased while those of the gestational tissues (uterus, placenta, and ovary), cardiac myocytes, and fetal liver were decreased at term compared to midtrimester. The changes in AF protein abundance were correlated with those previously reported in the cell-free AF transcriptome. Intersecting gestational age-modulated AF proteins and their corresponding mRNAs previously reported in the maternal blood identified neutrophil-related protein/mRNA pairs that were modulated in the same direction. The first study to utilize an aptamer-based assay to profile the AF proteome modulation with gestational age, it reveals that almost one-quarter of the proteins are modulated as gestation advances, which is more than twice the fraction of altered plasma proteins (~ 10%). The results reported herein have implications for future studies focused on discovering biomarkers to predict, monitor, and diagnose obstetrical diseases.
Assuntos
Líquido Amniótico/metabolismo , Idade Gestacional , Gravidez/metabolismo , Proteoma , Adulto , Estudos Transversais , Feminino , Humanos , Estudos Retrospectivos , Adulto JovemRESUMO
The plasma pool of the hormone 1,25-dihydroxyvitamin D (1,25(OH)2D) is increased throughout most of human pregnancy. Mechanisms behind this adaptation are unclear, in part due to limited data on vitamin D kinetics during pregnancy. Stable isotopes make it possible to study vitamin D kinetics in vulnerable study populations like pregnant women. We conducted a pilot study of vitamin D kinetics in nonpregnant and pregnant women. We evaluated a clinical protocol and developed analytical methods to assess the serum appearance and disappearance of trideuterated vitamin D3 (d3-vitamin D3) and trideuterated 25-hydroxyvitamin D3 (d3-25(OH)D3) after a single oral dose of 25 µg of [6,19,19-2H]-vitamin D3 (d3-vitamin D3). Blood was collected at baseline and 2, 4, 6, 24, 168, 264, and 456 hours post-dosing. We then described the serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 in nonpregnant and pregnant women. Serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 followed a time course in line with previous pharmacokinetic studies. There was marked variability between participants in the area under the concentration-time curve (AUC) of d3-25(OH)D3 over the 20-day study period. This AUC of d3-25(OH)D3 was positively correlated with the serum vitamin D binding protein (DBP) concentration, which was higher in pregnant compared with nonpregnant women. The mean serum half-life of 25(OH)D3 was longer but not significantly different in pregnant women (18.8 days) compared with nonpregnant women (13.6 days). Our pilot study demonstrated that a single oral dose of 25 µg of d3-vitamin D3 can be used to study vitamin D kinetics. Serum DBP concentration is an important predictor of vitamin D kinetics, and more research is needed to fully understand the significance of elevated DBP concentration during pregnancy.
Assuntos
Calcitriol/metabolismo , Colecalciferol/farmacocinética , Gravidez/metabolismo , Administração Oral , Adulto , Calcitriol/sangue , Colecalciferol/administração & dosagem , Colecalciferol/sangue , Deutério/administração & dosagem , Deutério/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Projetos Piloto , Gravidez/sangue , Vitamina D/sangue , Adulto JovemRESUMO
Circulating miRNA may contribute to the development of adverse birth outcomes. However, few studies have investigated extracellular vesicle (EV) miRNA, which play important roles in intercellular communication, or compared miRNA at multiple time points in pregnancy. In the current study, 800 miRNA were profiled for EVs from maternal plasma collected in early (median: 12.5 weeks) and late (median: 31.8 weeks) pregnancy from 156 participants in the MADRES Study, a health disparity pregnancy cohort. Associations between miRNA and birth weight, birth weight for gestational age (GA), and GA at birth were examined using covariate-adjusted robust linear regression. Differences by infant sex and maternal BMI were also investigated. Late pregnancy measures of 13 miRNA were associated with GA at birth (PFDR<0.050). Negative associations were observed for eight miRNA (miR-4454+ miR-7975, miR-4516, let-7b-5p, miR-126-3p, miR-29b-3p, miR-15a-5p, miR-15b-5p, miR-19b-3p) and positive associations for five miRNA (miR-212-3p, miR-584-5p, miR-608, miR-210-3p, miR-188-5p). Predicted target genes were enriched (PFDR<0.050) in pathways involved in organogenesis and placental development. An additional miRNA (miR-107), measured in late pregnancy, was positively associated with GA at birth in infants born to obese women (PFDR for BMI interaction = 0.011). In primary analyses, the associations between early pregnancy miRNA and birth outcomes were not statistically significant (PFDR≥0.05). However, sex-specific associations were observed for early pregnancy measures of 37 miRNA and GA at birth (PFDR for interactions<0.050). None of the miRNA were associated with fetal growth measures (PFDR≥0.050). Our findings suggest that EV miRNA in both early and late pregnancy may influence gestational duration.
Assuntos
Vesículas Extracelulares , MicroRNAs , Complicações na Gravidez , Gravidez , Metilação de DNA , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , MicroRNAs/sangue , MicroRNAs/metabolismo , Placenta/metabolismo , Placentação , Gravidez/genética , Gravidez/metabolismo , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismoRESUMO
Both disturbed sleep and lack of exercise can disrupt metabolism in pregnancy. Accelerometery was used to objectively assess movement during waking (physical activity) and movement during sleeping (sleep disturbance) periods and evaluated relationships with continuous blood glucose variation during pregnancy. Data was analysed prospectively. 15-women without pre-existing diabetes mellitus wore continuous glucose monitors and triaxial accelerometers from February through June 2018 in Sweden. The relationships between physical activity and sleep disturbance with blood glucose rate of change were assessed. An interaction term was fitted to determine difference in the relationship between movement and glucose variation, conditional on waking/sleeping. Total movement was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.037, - 0.026)). Stratified analyses showed total physical activity was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.040, - 0.028)), whereas sleep disturbance was not related to glucose rate of change (p = 0.07, 95% CI (< - 0.001, 0.013)). The interaction term was positively related to glucose rate of change (p < 0.001, 95% CI (0.029, 0.047)). This study provides temporal evidence of a relationship between total movement and glycemic control in pregnancy, which is conditional on time of day. Movement is beneficially related with glycemic control while awake, but not during sleep.
Assuntos
Glicemia/metabolismo , Exercício Físico , Gravidez/fisiologia , Sono , Adulto , Feminino , Humanos , Fotoperíodo , Gravidez/metabolismo , VigíliaRESUMO
Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine ß-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B12, vitamin B6, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.
Assuntos
Carbono/metabolismo , Ciclo Menstrual/metabolismo , Gravidez/metabolismo , Estradiol/metabolismo , Feminino , Ácido Fólico/metabolismo , Homocisteína/metabolismo , Humanos , S-Adenosilmetionina/metabolismo , Vitamina B 12/metabolismoRESUMO
BACKGROUND: This study aimed to evaluate spexin as a novel blood marker and to describe the relationship of this peptide with selected biochemical metabolites measured during the transition period in dairy cows. Additionally, mRNA expression of the spexin gene as well as spexin receptors - galanin receptor type 2 and galanin receptor type 3, was investigated in several bovine tissues. Blood samples were collected at weekly intervals starting at 21 days before the estimated parturition day until 21 days in milk to determine concentrations of spexin, nonesterified fatty acids, ß-hydroxybutyrate acid, total and active ghrelin, progesterone, glucose, insulin, IGF-I, triglycerides, cholesterol, leptin, corticosterone and 17-ß-estradiol as well as the activity of aspartate transaminase, alkaline phosphatase and gamma-glutamyl transferase. RESULTS: Spexin concentration decreased from 21 d before parturition to calving day and next it rose during the first 14 d of lactation. The lowest concentration of spexin was recorded on the calving day and it differed from the mean level of this peptide before parturition as well as postpartum. Moreover, differences were observed between mean spexin concentrations before and after calving. Spexin levels were moderately negatively correlated with NEFA (r = - 0.39) and total ghrelin contents (r = - 0.41), weakly correlated with BHBA (r = - 0.35) while they showed a moderate positive relationship with progesterone concentrations (r = 0.42). Moreover, we detected that mRNA expression of GALR2, GALR3 and SPX is present in various bovine tissues (kidney, bowel, rumen, spinal cord, lung, skeletal muscle, liver, heart, fat and spleen). CONCLUSION: A negative correlation between spexin concentration and NEFA, BHBA and total ghrelin contents as well as a positive relationship with levels of progesterone, metabolites and hormones, which are key players in the dairy cow transition period, may confirm an important function of this peptide in metabolism regulation. Thus measurement of spexin concentration could provide useful supplementary information for dairy cow herd health monitoring.