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1.
Rev Med Suisse ; 15(668): 1914-1919, 2019 Oct 23.
Artigo em Francês | MEDLINE | ID: mdl-31643151

RESUMO

Following the introduction of non-invasive tests, antenatal screening for trisomy 21 underwent important changes. Clinicians had to rapidly adapt their practice, especially in the field of antenatal counseling. On a population wide scale, new strategies and guidelines have been implemented. This article reviews the basic concepts of antenatal screening, including the use of non-invasive cell-free fetal DNA testing.


Assuntos
Diagnóstico Pré-Natal/métodos , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Feto/citologia , Feto/metabolismo , Humanos , Gravidez
2.
Medicine (Baltimore) ; 98(29): e16458, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335703

RESUMO

We evaluated the clinical value of the cerebroplacental ratio (CPR) in predicting neonatal acidosis according to the gestational weeks in late pregnancy.From July 2016 to June 2017, 1018 neonates without acidosis and 218 neonates with acidosis (confirmed postpartum) underwent a prenatal examination and hospital delivery at 28 to 41 weeks in our hospital. The CPR was calculated as the ratio of the prenatal middle cerebral artery-pulsation index (MCA-PI) to the umbilical artery-pulsation index (UA-PI).In neonates without acidosis, the fetal UA-PI decreased with increased gestational age during late pregnancy. Similarly, the MCA-PI decreased with increased gestational age, and decreased significantly during the full pregnancy term. Additionally, the CPR peaked in the middle of the late pregnancy period and then decreased. In contrast, in neonates with acidosis, the prenatal UA-PI increased significantly, MCA-PI declined significantly, and CPR declined significantly in relation to normal values (P < .05). For the prediction of neonatal acidosis, the UA-PI was suitable after 32 weeks and the MCA-PI was suitable before 37 weeks. The cutoff values of the CPR for the prediction of neonatal acidosis at 28 to 31 weeks, 32 to 36 weeks, and 37 to 41 weeks were 1.29, 1.36, and 1.22, respectively. Unlike the UA-PI and MCA-PI, the CPR was suitable as an independent predictor of neonatal acidosis at all late pregnancy weeks. In neonates with acidosis, the z score of the UA-PI increased significantly, whereas the z scores of the MCA-PI and CPR decreased significantly, in relation to normal values (P < .05).The CPR can be used to evaluate the adverse status of fetuses during late pregnancy, providing an early prediction of neonatal acidosis.


Assuntos
Acidose/diagnóstico , Doenças do Recém-Nascido/diagnóstico , Artéria Cerebral Média/diagnóstico por imagem , Fluxo Pulsátil , Artérias Umbilicais/diagnóstico por imagem , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Feto/metabolismo , Feto/fisiopatologia , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/metabolismo , Doenças do Recém-Nascido/fisiopatologia , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal/métodos , Prognóstico , Ultrassonografia Doppler em Cores/métodos , Ultrassonografia Pré-Natal/métodos
3.
Medicine (Baltimore) ; 98(30): e16556, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348278

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) may be 1 of etiologic factors responsible for congenital heart diseases (CHDs). Variations of the microsomal epoxide hydrolase (EPHX1) gene, as well as their possible interactions with PAHs exposure, may increase susceptibility to CHDs.This case-control study investigated the risk of CHDs in relation to the EPHX1 polymorphisms and assessed the interactions between these polymorphisms and PAHs exposure in 357 mothers of CHDs fetuses and 270 control mothers. Logistic regression models for the risk of CHDs were applied to determine the effect of genetic polymorphisms using additive, recessive, and dominant genetic models, as well as gene-exposure interactions. Multiple testing was adjusted by applying the false discovery rate (FDR).None of the maternal genetic polymorphisms of EPHX1 was associated with CHDs occurrence. Only the single nucleotide polymorphism rs1051740 was associated with an increased risk of right-sided obstructive malformations under the recessive model (adjusted odds ratio [aOR] = 1.852, 95% confidence interval [CI]: 1.065, 3.22) before FDR correction. A possible modifying effect of PAHs exposure on genetic polymorphisms of EPHX1 was found in susceptibility to CHDs, though no multiplicative-scale interactions between maternal exposure to PAHs and polymorphisms of EPHX1 gene were seento affect the risk of CHDs.The role of EPHX1 gene polymorphisms for CHDs need to be further evaluated, in particularly by interacting with PAHs exposure.


Assuntos
Poluentes Atmosféricos/toxicidade , Epóxido Hidrolases/genética , Cardiopatias Congênitas/genética , Exposição Materna/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adulto , Estudos de Casos e Controles , China , Feminino , Feto/metabolismo , Predisposição Genética para Doença/embriologia , Predisposição Genética para Doença/genética , Cardiopatias Congênitas/embriologia , Humanos , Modelos Logísticos , Mães , Razão de Chances , Polimorfismo de Nucleotídeo Único , Gravidez
4.
Cytogenet Genome Res ; 158(4): 199-204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315112

RESUMO

Here, we report a molecular characterization of a small supernumerary marker chromosome (sSMC) derived from the most proximal region of 13q present in a fetus with coarctation of the aorta at ultrasound examination during prenatal diagnosis. Cultured umbilical cord blood cells showed a de novo extra ring-shaped sSMC in 76% of the cells using a standard banding technique. SNP array revealed a tetrasomy of about 28.4 Mb in the long arm of chromosome 13 from band 13q11 to 13q14.11 in the fetus's cells. Metaphase/interphase FISH using specific probes located at 13q11, 13q12.11, and 13q14.11, respectively, demonstrated that the supernumerary ring chromosome was derived from an inverted duplication of the region 13q11q14.11 with a conventional centromere. To the best of our knowledge, this is the first time that an inverted duplication of the most proximal region 13q11q14.11 in a ring chromosome is characterized. The findings we presented here deepen our understanding of the clinical consequences of tetrasomy in this region and may be of help for further studies of critical regions in chromosome 13.


Assuntos
Coartação Aórtica/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 13/genética , Doenças Fetais/genética , Diagnóstico Pré-Natal , Cromossomos em Anel , Tetrassomia/genética , Adulto , Centrômero/genética , Bandeamento Cromossômico , Feminino , Doenças Fetais/diagnóstico , Feto/metabolismo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
5.
Orv Hetil ; 160(26): 1007-1014, 2019 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-31230467

RESUMO

The extensive metabolism of estrogen hormones, where oxidized forms, structural isomers and conjugated products appear in many tissues locally as well as in systemic circulation, is believed to be associated with a number of diseases. Targeted estrogen metabolomic studies have been largely associated with postmenopausal, malignant advert immune conditions. Although the role of estriol in maintaining pregnancy and the biological activity of estrogen metabolites is known, a relatively small number of publications have addressed the formation and transformation of these compounds during pregnancy. The aim of this study is to present in detail the formation and progression of estrogen metabolites during pregnancy and to summarize the knowledge of their role in undesirable processes occurring during gestation. Orv Hetil. 2019; 160(26): 1007-1014.


Assuntos
Estriol/metabolismo , Estrogênios/metabolismo , Feto/metabolismo , Placenta/metabolismo , Placentação/fisiologia , Pré-Eclâmpsia/metabolismo , Feminino , Humanos , Gravidez
6.
Biochimie ; 163: 142-151, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201844

RESUMO

Widely dispersed throughout the entire body tissues, gangliosides (GGs) are essential components of neuronal cell membranes, where exhibit a vital role in neuronal function and brain development, directly influencing the neural tube formation, neurogenesis, neurotransmission, etc. Due to several factors, partial or complete closing faults of the fetal neural tube may occur in the first trimester of pregnancy, generating a series of neural tube defects (NTD), among which anencephaly. The absence in anencephaly of the forebrain and skull bones determines the exposure to the amniotic fluid of the remaining brain tissue and the spinal cord, causing the degeneration of the nervous system tissue. Based on the previously achieved information related to the direct alteration of neural development with deficient concentration of several GGs, a systematic and comparative mass spectrometry (MS) mapping assay on GGs originating from fetuses in different intrauterine developmental stages, i.e. the 29th (denoted An29), 35th (An35) and the 37th (An37) gestational weeks was here conducted. Our approach, based on Orbitrap MS under high sensitivity, resolution and mass accuracy conditions, enabled for the first time the nanoelectrospray ionization, detection and identification of over 150 glycoforms, mainly novel, polysialylated species. Such a pattern, specific for incipient developmental stages reliably documents the brain development stagnation, characteristic for anencephaly. Further, the fragmentation MS2-MS3 experiments by collision induced dissociation (CID) confirmed the incidence in all three samples of GT2(d18:1/16:2) as a potential biomarker. Therefore, this fingerprinting of the anencephalic gangliosidome may serve in development of approaches for routine screening and early diagnosis.


Assuntos
Anencefalia/metabolismo , Encéfalo/metabolismo , Desenvolvimento Fetal , Gangliosídeos/análise , Espectrometria de Massas por Ionização por Electrospray , Anencefalia/diagnóstico , Anencefalia/fisiopatologia , Biomarcadores/análise , Encéfalo/fisiopatologia , Confiabilidade dos Dados , Feto/metabolismo , Feto/fisiopatologia , Humanos , Masculino , Metabolômica , Sensibilidade e Especificidade
7.
Environ Toxicol ; 34(7): 878-885, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31037826

RESUMO

Perfluorooctanoic acid (PFOA) is an octanoic acid and is found in wildlife and humans. We have investigated mitochondrial toxicity in isolated mitochondria from, placenta, brain, liver, and heart after oral exposure with PFOA in mice during gestational days (7-15). Histopathological examination and mitochondrial toxicity parameters were assayed. Results indicated that PFOA decreased the weight of the fetus and placenta, the length of the fetus and the diameter of the placenta, dead fetuses and dead macerated fetuses in treated mice with 25 mg/kg. Histopathological examination showed that PFOA induced pathological abnormalities in liver, brain, heart, and placenta. Also, PFOA induced mitochondria toxicity in brain, liver, heart of mouse fetus. Our results indicate that PFOA up to 20 mg/kg exposure adversely affect embryofetal/developmental because for mitochondria dysfunction. These results suggested that mitochondrial dysfunction induced by PFOA in liver, heart, and brain lead to developmental toxicity and abnormality in tissues.


Assuntos
Aborto Espontâneo/induzido quimicamente , Caprilatos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Feto/efeitos dos fármacos , Fluorcarbonetos/toxicidade , Exposição Materna/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/ultraestrutura , Feminino , Feto/metabolismo , Feto/patologia , Coração/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/ultraestrutura , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/fisiologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/fisiologia , Miocárdio/ultraestrutura , Gravidez
8.
Med Sci Monit ; 25: 3170-3180, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31036798

RESUMO

The umbilical cord is the only connection between the mother and the fetus, through which it is possible to transport respiratory gases, nutrients, and metabolites. Thanks to the umbilical cord, the fetus has also the ability to move, which is necessary for its proper psychomotor development. The correct structure and function of umbilical vessels and the entire umbilical cord determine the possibility of proper development and survival of the fetus. Umbilical cord anatomy should be assessed in the ultrasound examination in the first trimester. It is of vital importance to confirm the correct number of umbilical vessels and their intra-abdominal course, as well as carefully assessing the abdominal and placental insertion sites. In the latter half of pregnancy, the use of the Doppler imaging enables assessment of the function of the fetal-placental vessels, thus providing valuable information about the condition of the fetus.


Assuntos
Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal/métodos , Cordão Umbilical/anormalidades , Cordão Umbilical/diagnóstico por imagem , Feminino , Sofrimento Fetal/diagnóstico por imagem , Feto/diagnóstico por imagem , Feto/metabolismo , Humanos , Gravidez
9.
Med Sci Monit ; 25: 3354-3365, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061382

RESUMO

BACKGROUND Maternal folate deficiency-mediated metabolic disruption is considered to be associated with the risk of intrauterine growth retardation (IUGR), but the exact mechanism remains unclear. The retrotransposon long interspersed nucleotide element-1 (LINE-1), which can induce birth defects via RNA intermediates, plays crucial roles during embryonic development. We investigated potential relationships between maternal folate and DNA methylation, and possible roles of LINE-1 in IUGR. MATERIAL AND METHODS The IUGR model was established by feeding female mice 1 of 3 diets - control diet (CD), folate-deficient diet for 2 weeks (FD2w), and folate-deficient diet for 4 weeks (FD4w) - prior to mating. Maternal serum folate, 5-methyltetrahydrofolate (5-MeTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) concentrations and global DNA methylation were assessed by LC/MS/MS method. LINE-1 methylation levels in fetuses were examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LINE-1 expression levels were validated by real-time PCR. RESULTS Maternal folate deficiency caused plasma folate and 5-MeTHF levels to decrease and SAH level to increase in the FD4w group. Compared with the CD group, methylation levels of genomic DNA and LINE-1 decreased significantly in placenta and fetal tissues from the FD4w group. Expression of LINE-1 open reading frame 1 (ORF1) protein was elevated in fetal liver tissues. Furthermore, a strong correlation was found between methylation and disrupted one-carbon metabolism, implying that dietary folate plays important roles during embryogenesis. CONCLUSIONS Maternal dietary folate deficiency impaired one-carbon metabolism, leading to global DNA and LINE-1 hypomethylation, and then increased retrotransposition in fetuses, which can lead to IUGR.


Assuntos
Retardo do Crescimento Fetal/genética , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Animais , Metilação de DNA/genética , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Elementos Nucleotídeos Longos e Dispersos/genética , Elementos Nucleotídeos Longos e Dispersos/fisiologia , Masculino , Troca Materno-Fetal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Gravidez , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Tetra-Hidrofolatos/metabolismo
10.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945692

RESUMO

A parental diagnosis was performed for an unborn foetus of a healthy couple, who was due for ultrasound detection of multiple malformations and abnormal amniotic fluid karyotypes. For an accurate diagnosis, routine G-banding analysis and next generation sequencing (NGS) were carried out. Finally, conventional cytogenetic analysis suggested that the foetus had a karyotype of47,XX,+mar[52]/46,XN, meanwhile NGS also revealed a partial tetrasomy of 27.84Mb from 4q26-q31.21 (117,385,735-145,225,759), and G-banding analysis excluded the couple to have carried the 4q26-q31.21 duplication. We have identified a de novo mosaic small supernumerary marker chromosomes (sSMC) derived from 4q26-q31.21 in a foetus with hemivertebra, polydactyly, abnormal ears, and heart and ventricular septal defect.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Cromossomos Humanos Par 4/genética , Feto/patologia , Marcadores Genéticos , Diagnóstico Pré-Natal , Tetrassomia , Adulto , Análise Citogenética , Feminino , Feto/metabolismo , Humanos , Masculino , Mosaicismo , Gravidez
11.
J Pediatr Surg ; 54(6): 1198-1205, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30894247

RESUMO

BACKGROUND/PURPOSE: Wilms tumor (WT) is the most common childhood kidney cancer globally. Our prior unbiased proteomic screen of WT disparities revealed increased expression of Fragile X-Related 1 (FXR1) in Kenyan specimens where survival is dismal. FXR1 is an RNA-binding protein that associates with poor outcomes in multiple adult cancers. The aim of this study therefore was to validate and characterize the FXR1 expression domain in WT. METHODS: Quantitative FXR1 gene expression was compared between WT, adjacent, adult, and fetal kidney specimens. The cellular and subcellular expression domain of FXR1 was characterized across these tissues using immunoperoxidase staining. RNA-sequencing of FXR1 was performed from WT and other pediatric malignancies to examine its broader target potential. RESULTS: FXR1 was detected in all clinical WT specimens evaluated (n = 82), and as a result appeared independent of demographic, histology, or adverse event. Specific cytosolic staining was strongest in blastema, intermediate and variable in epithelia, and weakest in stroma. When present, areas of skeletal muscle differentiation stained strongly for FXR1. qPCR revealed increased FXR1 expression in WT compared to adult and adjacent kidney (p < 0.0002) but was similar to fetal kidney (p = 0.648). RNA-sequencing revealed expression of FXR1 in multiple pediatric tumors, greatest in rhabdomyosarcoma and WT. CONCLUSIONS: FXR1 was expressed consistently across this broad sampling of WT and most robustly in the primitive blastema. Notably, FXR1 labeled a specific self-renewing progenitor population of the fetal kidney.


Assuntos
Neoplasias Renais/genética , Proteínas de Ligação a RNA/genética , Tumor de Wilms/genética , Adulto , Estudos de Casos e Controles , Feto/química , Feto/metabolismo , Feto/patologia , Humanos , Quênia , Rim/química , Rim/metabolismo , Rim/patologia , Neoplasias Renais/metabolismo , Proteínas de Ligação a RNA/metabolismo , Tumor de Wilms/metabolismo
12.
Gene Expr Patterns ; 32: 1-11, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30822518

RESUMO

The main purpose of this in situ hybridization study was to investigate MMPs and TIMPs mRNA expression in developing mandibular condylar cartilage and limb bud cartilage. At E14.0, MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the periosteum of mandibular bone, and in the condylar anlage. At E15.0 MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the perichondrium of newly formed condylar cartilage and the periosteum of developing bone collar, whereas, expression of MMP-14 and TIMP-1 mRNAs were restricted to the inner layer of the periosteum/perichondrium. This expression patterns continued until E18.0. Further, from E13.0 to 14.0, in the developing tibial cartilage, MMP-2, -14, and TIMP-2 mRNAs were expressed in the periosteum/perichondrium, but weak MMP-14 and no TIMP-1 mRNA expression was recognized in the perichondrium. These results confirmed that the perichondrium of condylar cartilage has characteristics of periosteum, and suggested that MMPs and/or TIMPs are more actively involved in the development of condylar (secondary) cartilage than tibial (primary) cartilage. MMP-9-positive cells were observed in the bone collar of both types of cartilage, and they were consistent with osteoclasts/chondroclasts. MMP-13 mRNA expression was restricted to the chondrocytes of the lower hypertrophic cell zone in tibial cartilage at E14.0, indicating MMP-13 can be used as a marker for lower hypertrophic cell zone. It was also expressed in chondrocytes of newly formed condylar cartilage at E15.0, and continuously expressed in the lower hypertrophic cell zone until E18.0. These results confirmed that progenitor cells of condylar cartilage are rapidly differentiated into hypertrophic chondrocytes, which is a unique structural feature of secondary cartilage different from that of primary cartilage.


Assuntos
Cartilagem/metabolismo , Botões de Extremidades/metabolismo , Côndilo Mandibular/metabolismo , Animais , Cartilagem/fisiologia , Cartilagem Articular/embriologia , Condrócitos/metabolismo , Condrogênese/genética , Feto/metabolismo , Hibridização In Situ , Botões de Extremidades/fisiologia , Côndilo Mandibular/fisiologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Transcriptoma/genética
13.
Int J Mol Sci ; 20(5)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857182

RESUMO

The use of polyphenols is a promising strategy for preventing or alleviating intrauterine growth restriction (IUGR) because polyphenol supplementation increases plasma antioxidant capacity and improves oxidative stress at the feto-placental unit; which are recognized as main issues in IUGR. However, there is a scarcity of experimental data on both realistic benefits and potential hazards of polyphenol supplementation during gestation. Hence, we aimed to use a swine model of IUGR pregnancy to determine possible effects of maternal supplementation with polyphenols (hydroxytyrosol) on placental expression of genes involved in antioxidant homeostasis, vascularization and fetal growth and thus on antioxidant status, DNA-methylation and phenotypic traits (morphology and homeostasis) of the fetus. Hydroxytyrosol improves placental gene expression and fetal antioxidant status and glucose metabolism in a sex-dependent manner, in which males were favored in spite of developmental failures. Concomitantly, hydroxytyrosol prevented hypomethylation of DNA associated with oxidative stress. Finally, no major deleterious effects of hydroxytyrosol supplementation on constriction of the ductus arteriosus, a possible secondary effect of polyphenols during pregnancy, were found.


Assuntos
Antioxidantes/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Retardo do Crescimento Fetal/tratamento farmacológico , Expressão Gênica/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Placenta/efeitos dos fármacos , Polifenóis/uso terapêutico , Animais , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Feto/efeitos dos fármacos , Feto/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Álcool Feniletílico/uso terapêutico , Placenta/metabolismo , Gravidez , Suínos
14.
J Perinat Med ; 47(3): 311-318, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30759069

RESUMO

Background In prenatal diagnosis, a thickened nuchal translucency (NT) is one of the most sensitive and specific markers for several defects but it may also be found in 5% of healthy fetuses. The pathophysiological causes that lead to an increase in NT are not yet fully understood. Metabolomics represents a new promising approach, useful for studying different metabolites in biological organisms in response to environmental stressors. The aim of our study was to investigate the metabolomic profile of the amniotic fluid samples (AFS) of euploid fetuses with enlarged nuchal translucency (ENT) compared to a control group (C group). Methods This study was carried out on a group of women who underwent second-trimester amniocentesis for advanced maternal age (C group) or for NT ≥95th percentile (ENT group) found during first-trimester aneuploidy screening. AFS were analyzed with proton nuclear magnetic resonance (1H-NMR) and high-performance liquid chromatography (HPLC), and subsequent multivariate and univariate statistical analyses were conducted, followed by pathway analysis. Results In total, 67 AFS from the C group and 23 from the ENT group were analyzed. Partial least square discriminate analysis was carried out (R2X=0.784, R2Y=0.658, Q2=0.622, P<0.0001). A different metabolic profile was observed in the ENT group compared with the C group, suggesting an energetic shift to a glycolytic phenotype in an oxidative environment in the ENT group compared to the C group. Conclusion Metabolomic studies enable the identification of metabolic alterations occurring in fetuses with ENT. These findings may provide a new basis for better understanding the pathophysiological mechanisms in this prenatal phenomenon.


Assuntos
Líquido Amniótico/metabolismo , Metaboloma , Medição da Translucência Nucal , Adulto , Estudos de Casos e Controles , Feminino , Feto/metabolismo , Humanos , Gravidez
15.
Immunity ; 50(2): 462-476.e8, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770246

RESUMO

Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Feto/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Células Epiteliais/citologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Feto/metabolismo , Humanos , Recém-Nascido , Mucosa Intestinal/embriologia , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/imunologia , Intestinos/embriologia , Intestinos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Gravidez , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Toxicol Appl Pharmacol ; 365: 112-123, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639414

RESUMO

We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110 mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5 mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and 62.5 mg/kg/d from GD 8-18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5 mg SMV/kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5 mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.


Assuntos
Feto/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Sinvastatina/toxicidade , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Feto/metabolismo , Idade Gestacional , Masculino , Técnicas de Cultura de Órgãos , Organogênese/efeitos dos fármacos , Gravidez , Ratos Sprague-Dawley , Medição de Risco , Diferenciação Sexual/efeitos dos fármacos , Desenvolvimento Sexual/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
17.
Biochemistry ; 58(8): 1155-1166, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30698412

RESUMO

Zika virus (ZIKV) is an enveloped RNA virus from the flavivirus family that can cause fetal neural abnormalities in pregnant women. Previously, we established that ZIKV-EP (envelope protein) binds to human placental chondroitin sulfate (CS), suggesting that CS may be a potential host cell surface receptor in ZIKV pathogenesis. In this study, we further characterized the GAG disaccharide composition of other biological tissues (i.e., mosquitoes, fetal brain cells, and eye tissues) in ZIKV pathogenesis to investigate the role of tissue specific GAGs. Heparan sulfate (HS) was the major GAG, and levels of HS-6-sulfo, HS 0S (unsulfated HS), and CS 4S disaccharides were the main differences in the GAG composition of Aedes aegypti and Aedes albopictus mosquitoes. In human fetal neural progenitor and differentiated cells, HS 0S and CS 4S were the main disaccharides. A change in disaccharide composition levels was observed between undifferentiated and differentiated cells. In different regions of the bovine eyes, CS was the major GAG, and the amounts of hyaluronic acid or keratan sulfate varied depending on the region of the eye. Next, we examined heparin (HP) of various structures to investigate their potential in vitro antiviral activity against ZIKV and Dengue virus (DENV) infection in Vero cells. All compounds effectively inhibited DENV replication; however, they surprisingly promoted ZIKV replication. HP of longer chain lengths more strongly promoted activity in ZIKV replication. This study further expands our understanding of role of GAGs in ZIKV pathogenesis and carbohydrate-based antivirals against flaviviral infection.


Assuntos
Aedes/metabolismo , Dengue/tratamento farmacológico , Olho/metabolismo , Feto/metabolismo , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/farmacologia , Infecção por Zika virus/tratamento farmacológico , Aedes/virologia , Animais , Antivirais/farmacologia , Bovinos , Cercopithecus aethiops , Dengue/metabolismo , Dengue/patologia , Dengue/virologia , Vírus da Dengue/patogenicidade , Olho/efeitos dos fármacos , Feto/efeitos dos fármacos , Glicosaminoglicanos/química , Heparitina Sulfato/química , Humanos , Técnicas In Vitro , Mosquitos Vetores/virologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células Vero , Internalização do Vírus , Replicação Viral , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
18.
Nat Immunol ; 20(3): 301-312, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664737

RESUMO

The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Feto/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD5/genética , Antígenos CD5/imunologia , Antígenos CD5/metabolismo , Células Cultivadas , Feto/citologia , Feto/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Memória Imunológica/genética , Imunofenotipagem , Intestinos/citologia , Intestinos/embriologia , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo
19.
Clin Sci (Lond) ; 133(1): 55-74, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30622158

RESUMO

Hypertension is the primary risk factor for cardiovascular disease that constitutes a serious worldwide health concern and a significant healthcare burden. As the majority of hypertension has an unknown etiology, considerable research efforts in both experimental models and human cohorts has focused on the premise that alterations in the fetal and perinatal environment are key factors in the development of hypertension in children and adults. The exact mechanisms of how fetal programming events increase the risk of hypertension and cardiovascular disease are not fully elaborated; however, the focus on alterations in the biochemical components and functional aspects of the renin-angiotensin (Ang) system (RAS) has predominated, particularly activation of the Ang-converting enzyme (ACE)-Ang II-Ang type 1 receptor (AT1R) axis. The emerging view of alternative pathways within the RAS that may functionally antagonize the Ang II axis raise the possibility that programming events also target the non-classical components of the RAS as an additional mechanism contributing to the development and progression of hypertension. In the current review, we evaluate the potential role of the ACE2-Ang-(1-7)-Mas receptor (MasR) axis of the RAS in fetal programming events and cardiovascular and renal dysfunction. Specifically, the review examines the impact of fetal programming on the Ang-(1-7) axis within the circulation, kidney, and brain such that the loss of Ang-(1-7) expression or tone, contributes to the chronic dysregulation of blood pressure (BP) and cardiometabolic disease in the offspring, as well as the influence of sex on potential programming of this pathway.


Assuntos
Angiotensina I/metabolismo , Pressão Sanguínea , Feto/metabolismo , Hipertensão/etiologia , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Feminino , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Placenta/metabolismo , Placenta/fisiopatologia , Gravidez , Nascimento Prematuro/metabolismo , Nascimento Prematuro/fisiopatologia , Fatores de Risco , Fatores Sexuais , Transdução de Sinais
20.
Development ; 146(2)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696714

RESUMO

The scarcity of embryonic/foetal material as a resource for direct study means that there is still limited understanding of human retina development. Here, we present an integrated transcriptome analysis combined with immunohistochemistry in human eye and retinal samples from 4 to 19 post-conception weeks. This analysis reveals three developmental windows with specific gene expression patterns that informed the sequential emergence of retinal cell types and enabled identification of stage-specific cellular and biological processes, and transcriptional regulators. Each stage is characterised by a specific set of alternatively spliced transcripts that code for proteins involved in the formation of the photoreceptor connecting cilium, pre-mRNA splicing and epigenetic modifiers. Importantly, our data show that the transition from foetal to adult retina is characterised by a large increase in the percentage of mutually exclusive exons that code for proteins involved in photoreceptor maintenance. The circular RNA population is also defined and shown to increase during retinal development. Collectively, these data increase our understanding of human retinal development and the pre-mRNA splicing process, and help to identify new candidate disease genes.


Assuntos
Perfilação da Expressão Gênica , Retina/embriologia , Retina/metabolismo , Processamento Alternativo/genética , Animais , Biomarcadores/metabolismo , Cílios/metabolismo , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Células Fotorreceptoras de Vertebrados/citologia , Células Fotorreceptoras de Vertebrados/metabolismo , Análise de Componente Principal , RNA/genética , RNA/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Retina/citologia , Retina/ultraestrutura , Transcriptoma/genética
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