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1.
Proc Natl Acad Sci U S A ; 121(8): e2310502121, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38346193

RESUMO

The placenta establishes a maternal-fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors, and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of transcription factors GATA2 and GATA3 in labyrinth trophoblast progenitors (LaTPs) have underdeveloped placenta and die by ~embryonic day 9.5. Single-cell RNA sequencing analysis revealed excessive accumulation of multipotent LaTPs upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate into matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promotes trophoblast progenitor-to-SynT commitment, ensuring establishment of the maternal-fetal exchange interface.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Troca Materno-Fetal , Gravidez , Feminino , Humanos , Animais , Camundongos , Placenta , Trofoblastos , Diferenciação Celular/fisiologia , Desenvolvimento Fetal , Fatores de Transcrição GATA
2.
Toxicol Lett ; 394: 66-75, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38423482

RESUMO

The placenta is a membrane that separates the fetus from the maternal circulation, and in addition to protecting the fetus, plays a key role in fetal growth and development. With increasing drug use in pregnancy, it is imperative that reliable models of estimating placental permeability and safety be established. In vitro methods and animal models such as rodent placenta are limited in application since the species-specific nature of the placenta prevents meaningful extrapolations to humans. In this regard, in silico approaches such as quantitative structure-property relationships (QSPRs) are useful alternatives. However, despite evidence that drug transport across the placenta is stereoselective (i.e., governed by the spatial arrangement of the atoms in a molecule), many QSPR models for placental transfer have been built using 2D descriptors that do not account for chirality and stereochemistry. In this study, we apply a chirality-sensitive and proven QSPR methodology titled "EigenValue ANalySis" (EVANS) to build QSPR models for placental transfer. We deploy EVANS along with robust machine learning algorithms to build (i) regression models on a dataset of environmental chemicals (dataset PD I) followed by (ii) classification models on a set of drug-like compounds (dataset PD II). The best models were found to achieve state-of-the-art performance, with the support vector machine algorithm returning rtrain2=0.85,rtest2=0.75 for PD I, and the logistic regression algorithm giving accuracy 0.88 and F1 score 0.93 for PD II. The best models were interpreted with the Shapley Additive Explanations paradigm, and it was found that autocorrelation descriptors are crucial for modelling placental permeability. In conclusion, we demonstrate the need of a chirality-sensitive approach for modelling placental transfer of chemicals, and present two predictive QSPR models that may reliably be used for prediction of placental transfer.


Assuntos
Troca Materno-Fetal , Placenta , Animais , Gravidez , Humanos , Feminino , Placenta/metabolismo , Feto , Transporte Biológico , Relação Quantitativa Estrutura-Atividade
3.
BMC Prim Care ; 25(1): 66, 2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388880

RESUMO

BACKGROUND: Foetal alcohol spectrum disorder (FASD) is the leading preventable cause of nongenetic mental disability. Given the patient care pathway, the General Practitioner (GP) is in the front line of prevention and identification of FASD. Acknowledging the importance of the prevalence of FASD, general practitioners are in the front line both for the detection and diagnosis of FASD and for the message of prevention to women of childbearing age as well as for the follow-up. OBJECTIVES: The main objective of the scoping review was to propose a reference for interventions that can be implemented by a GP with women of childbearing age, their partners and patients with FASD. The final aim of this review is to contribute to the improvement of knowledge and quality of care of patients with FASD. METHODS: A scoping review was performed using databases of peer-reviewed articles following PRISMA guidelines. The search strategy was based on the selection and consultation of articles on five digital resources. The advanced search of these publications was established using the keywords for different variations of FASD: "fetal alcohol syndrome," "fetal alcohol spectrum disorder," "general medicine," "primary care," "primary care"; searched in French and English. RESULTS: Twenty-three articles meeting the search criteria were selected. The interventions of GPs in the management of patients with FASD are multiple: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. FASD seems still underdiagnosed. CONCLUSION: The interventions of GPs in the management of patients with FASD are comprehensive: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. Prevention interventions would decrease the incidence of FASD, thereby reducing the incidence of mental retardation, developmental delays, and social, educational and legal issues. A further study with a cluster randomized trial with a group of primary care practitioners trained in screening for alcohol use during pregnancy would be useful to measure the impact of training on the alcohol use of women of childbearing age and on the clinical status of their children.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Clínicos Gerais , Criança , Humanos , Feminino , Gravidez , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Troca Materno-Fetal , Escolaridade , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Placenta ; 146: 42-49, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38169218

RESUMO

INTRODUCTION: The transplacental passage of cells between a mother and her fetus, known as microchimerism, is a less studied process during pregnancy. The frequency of maternal microchimeric cells in fetal tissues in physiological pregnancies and mechanisms responsible for transplacental cell trafficking are poorly understood. This study aimed to evaluate the placental trafficking of maternal peripheral blood mononuclear cells (PBMC) using human ex vivo placenta perfusion. METHODS: Ten placentas and maternal PBMC were obtained after healthy pregnancies. Flow cytometry was used to characterize PBMC subtypes. They showed a higher percentage of CD3+ T cells compared to CD56+ NK cells. The isolated PBMC were stained with a fluorescent dye and perfused through the maternal circuit of the placenta in an ex vivo perfusion system. Subsequent immunofluorescence staining for CD3+ T cells and CD56+ NK cells was performed on placental tissue sections, and the number of detectable PBMC in different tissue areas was counted using fluorescence microscopy. RESULTS: The applied method allowed discrimination of perfused autologous maternal cells from cells resident in the placenta before perfusion. Further, it allows additional immunohistochemical labelling and distinction of immune cell subsets. Perfused PBMC were detected in all analyzed placentas, mostly in contact to the syncytiotrophoblast. CD3+ T cells were identified more frequently than CD56+ NK cells and some CD3+ T cells were found inside fetoplacental tissues and vasculature. The results indicate that also other PBMCs than T or NK cells adhere to or enter villous tissue, but they have not been specified in this analysis. DISCUSSION: Previous studies have detected maternal cells in the fetal circulation which we could mimick in our ex vivo placenta perfusion experiments with fluorescence labelled autologous maternal PBMC. The applied experimental settings did not allow comparison of transmigration abilities of PBMC subsets, but slight modifications of the model will permit further studies of cell transfer processes and microchimerism in pregnancy.


Assuntos
Leucócitos Mononucleares , Placenta , Humanos , Gravidez , Feminino , Linfócitos T , Perfusão , Células Matadoras Naturais , Troca Materno-Fetal
5.
Arch Gynecol Obstet ; 309(1): 63-77, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37069381

RESUMO

PURPOSE: Adequate iron transportation from the mother across the placenta is crucial for fetal growth and establishing sufficient iron stores in neonates at birth. The past decade has marked significant discoveries in iron metabolism with the identification of new players and mechanisms. Immunohistochemical studies rendered valuable data on the localization of substantial iron transporters on placental syncytiotrophoblasts. However, the function and regulation of maternal-placentofetal iron transporters and iron handling is still elusive and requires more attention. METHODS: A thorough literature review was conducted to gather information about placental iron transfer, the role of regulators and maintenance of iron homeostasis. RESULTS: The role of classical and new players in maternal-fetal iron transport and the regulation in the placenta has been addressed in this review. Animal and human studies have been discussed. The role of placental iron regulation in thalassemia and hemochromatosis pregnancies has been reviewed. CONCLUSIONS: The current advances that highlight the mechanisms of placental iron regulation and transport in response to maternal and fetal signals have been presented.


Assuntos
Ferro , Placenta , Animais , Recém-Nascido , Gravidez , Feminino , Humanos , Ferro/metabolismo , Placenta/metabolismo , Troca Materno-Fetal , Feto , Trofoblastos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo
6.
J Pharm Sci ; 113(2): 486-492, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37981232

RESUMO

Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, the first PDE5 inhibitor to be approved. We also examined the contributions of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice by continuous infusion from gestational day (GD) 14.5 to 17.5, and the fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and Bcrp-knockout mice, respectively, while the corresponding values for sildenafil were equal to or less than that in wild-type mice, respectively. A transcellular transport study revealed that basal-to-apical transport of both tadalafil and sildenafil was significantly higher than transport in the opposite direction in MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified substrate of human and mouse BCRP, and it appears that the fetal transfer of tadalafil is, at least in part, attributed to the involvement of BCRP within the placental processes in mice. The transfer of sildenafil to the fetus was not significantly constrained by BCRP, even though sildenafil was indeed a substantial substrate for BCRP.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Troca Materno-Fetal , Inibidores da Fosfodiesterase 5 , Placenta , Citrato de Sildenafila , Tadalafila , Animais , Feminino , Humanos , Camundongos , Gravidez , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Camundongos Knockout , Inibidores da Fosfodiesterase 5/farmacocinética , Placenta/metabolismo , Citrato de Sildenafila/farmacocinética , Tadalafila/farmacocinética
7.
Nucleic Acids Res ; 52(D1): D738-D746, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37819042

RESUMO

Extensive evidence has demonstrated that the human microbiome and probiotics confer great impacts on human health, particularly during critical developmental stages such as pregnancy and infancy when microbial communities undergo remarkable changes and maturation. However, a major challenge in understanding the microbial community structure and interactions between mothers and infants lies in the current lack of comprehensive microbiome databases specifically focused on maternal and infant health. To address this gap, we have developed an extensive database called MAMI (Microbiome Atlas of Mothers and Infants) that archives data on the maternal and neonatal microbiome, as well as abundant resources on edible probiotic strains. By leveraging this resource, we can gain profound insights into the dynamics of microbial communities, contributing to lifelong wellness for both mothers and infants through precise modulation of the developing microbiota. The functionalities incorporated into MAMI provide a unique perspective on the study of the mother-infant microbiome, which not only advance microbiome-based scientific research but also enhance clinical practice. MAMI is publicly available at https://bioinfo.biols.ac.cn/mami/.


Assuntos
Microbiota , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Probióticos , Troca Materno-Fetal
9.
Part Fibre Toxicol ; 20(1): 48, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38072983

RESUMO

BACKGROUND: Extensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal-fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5-16.5. RESULTS: TiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-ß (TGF-ß) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes. CONCLUSION: Our study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.


Assuntos
Exposição Materna , Placenta , Gravidez , Camundongos , Feminino , Humanos , Animais , Placenta/metabolismo , Exposição Materna/efeitos adversos , Células Endoteliais , Camundongos Endogâmicos C57BL , Desenvolvimento Fetal , Troca Materno-Fetal , Titânio/toxicidade , Titânio/metabolismo
11.
Int J Mol Sci ; 24(23)2023 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-38069094

RESUMO

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.


Assuntos
Imunoglobulina G , Placenta , Gravidez , Feminino , Humanos , Placenta/metabolismo , Glicosilação , Trofoblastos/metabolismo , Imunomodulação , Troca Materno-Fetal
12.
Cell Death Dis ; 14(11): 780, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38012139

RESUMO

The maternal-fetal interface shares similarities with tumor tissues in terms of the immune microenvironment. Normal pregnancy is maintained due to the immunosuppressed state, but pyroptosis induced by MITA can trigger the body's immune response and disrupt the immunosuppressed state of the maternal-fetal interface, leading to abortion. In this study, we explored the role of MITA and TRIM38 in regulating pyroptosis and maintaining the immune tolerance of the maternal-fetal interface during pregnancy. Our findings show that the interaction between MITA and TRIM38 plays a crucial role in maintaining the immunosuppressed state of the maternal-fetal interface. Specifically, we observed that TRIM38-mediated K48 ubiquitination of MITA was higher in M2 macrophages, leading to low expression levels of MITA and thus inhibiting pyroptosis. Conversely, in M1 macrophages, the ubiquitination of K48 was lower, resulting in higher expression levels of MITA and promoting pyroptosis. Our results also indicated that pyroptosis played an important role in hindering the transformation of M1 to M2 and maintaining the immunosuppressed state of the maternal-fetal interface. These discoveries help elucidate the mechanisms that support the preservation of the immune tolerance microenvironment at the maternal-fetal interface, playing a vital role in ensuring successful pregnancy.


Assuntos
Proteínas de Membrana , Piroptose , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Feminino , Humanos , Gravidez , Aborto Espontâneo , Tolerância Imunológica , Macrófagos , Troca Materno-Fetal , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas de Membrana/metabolismo
13.
Epilepsia ; 64(12): 3354-3364, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37777821

RESUMO

OBJECTIVE: In the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small-molecule, highly lipid-soluble drug, CBD is likely to be distributed into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short-term placental effects, we conducted an ex vivo perfusion study in human placentas. METHODS: Placentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD-containing medium (250 ng/mL, .796 µmol·L-1 ; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography-tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 µmol·L-1 ; high therapeutic concentration; n = 8) and in those exposed to the vehicle. RESULTS: CBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066-9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48-72 ng/mL vs. 280 = ng/mL, range = 159-388 ng/mL, respectively; p < .01). Placental gene expression was not significantly altered by CBD. SIGNIFICANCE: The placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.


Assuntos
Canabidiol , Placenta , Gravidez , Feminino , Humanos , Troca Materno-Fetal , Canabidiol/farmacologia , Perfusão , Feto/metabolismo
15.
Artigo em Espanhol | IBECS | ID: ibc-226406

RESUMO

Introducción La infección por SARS-CoV-2 durante la gestación y su repercusión en el recién nacido eran, en los primeros meses de la pandemia, desconocidas. Recientes estudios han aportado información sobre la afectación clínica en el recién nacido y su evolución. En este trabajo se muestra cómo varía la inmunidad pasiva en el recién nacido con relación al momento de infección SARS-CoV-2 materno. Población y método Estudio observacional, prospectivo y longitudinal en un hospital de tercer nivel. Se recogieron datos epidemiológicos y clínicos de las madres y sus recién nacidos desde mayo del 2020 hasta junio del 2021. Resultados Se ha incluido a un total de 109 madres y 109 neonatos. El 28,4% de las infecciones maternas fueron en el primer trimestre, el 24,8% en el segundo y el 58,8% en el tercero. El 56% de las infecciones maternas fueron sintomáticas, solo una gestante con infección respiratoria grave ingresó en Cuidados Intensivos. La edad gestacional media de los recién nacidos fue de 39 semanas, con un peso medio de 3.232g y un perímetro craneal de 35cm. Ocho recién nacidos hijos de madre con SARS-CoV-2 requirieron ingreso en la UCI neonatal: 2 por ictericia, 2 por distrés respiratorio, uno por prematuridad moderada y 3 por otras causas no relacionadas con infección atribuible a SARS-CoV-2. Los anticuerpos tipo IgG fueron positivas en el 56,9% de los recién nacidos. De las madres infectadas durante el primer trimestre, las IgG fueron positivas en el 32,2% de los recién nacidos, en el segundo trimestre resultaron positivos el 81,5% y en el tercero, el 58,8%. Ningún neonato presentó IgM positivas. Conclusiones La infección por SARS-CoV-2 durante la gestación proporciona anticuerpos IgG a la mitad de los recién nacidos. La presencia de anticuerpos en el recién nacido es más probable cuando la infección se ha producido en el segundo trimestre de gestación (AU)


Introduction SARS-CoV-2 infection during pregnancy and its impact on the newborn were, in the first months of the pandemic, unknown. Recent studies have provided information on the clinical involvement in the newborn and its evolution. This work shows how passive immunity varies in the newborn in relation to the moment of maternal SARS-CoV-2 infection during pregnancy. Population and method Observational, prospective and longitudinal study in a third level hospital. Epidemiological and clinical data from mothers and their newborns were collected from May 2020 to June 2021. Results A total of 109 mothers and 109 neonates have been included. 28.4% of maternal infections were in the first trimester, 24.8% during the second and 58.8% in the third. 56% of maternal infections were symptomatic and only one pregnant woman with severe respiratory infection was admitted to intensive care. The mean gestational age of the newborns was 39 weeks, with a mean weight of 3232g and a head circumference of 35cm. Eight newborns born from mothers with SARS-CoV-2 required admission to the neonatal ICU: 2 due to jaundice, 2 due to respiratory distress, 1 due to moderate prematurity, and 3 due to other causes unrelated to infection attributable to SARS-CoV-2. IgG-type antibodies were positive in 56.9% of newborns. Of the mothers infected during the 1st trimester, IgG were positive in 32.2% of the newborns, in the second trimester 81.5% were positive and in the third 58.8%. No neonate had positive IgM. Conclusions SARS-CoV-2 infection during pregnancy provides IgG antibodies to half of newborns. The presence of antibodies in the newborn is more likely when the infection has occurred in the second trimester of pregnancy (AU)


Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Imunidade Materno-Adquirida , Troca Materno-Fetal , Imunoglobulinas/imunologia , Estudos Prospectivos , Estudos Longitudinais
16.
Science ; 381(6664): 1286, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37733842

RESUMO

Shifting pools of antigen can influence pregnancy-induced immune tolerance.


Assuntos
Quimerismo , Feto , Tolerância Imunológica , Troca Materno-Fetal , Criança , Feminino , Humanos , Gravidez , Troca Materno-Fetal/imunologia , Antígenos/imunologia , Feto/citologia , Feto/imunologia
17.
Science ; 381(6664): 1324-1330, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37733857

RESUMO

Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.


Assuntos
Quimerismo , Feto , Tolerância Imunológica , Memória Imunológica , Troca Materno-Fetal , Gravidez , Animais , Feminino , Camundongos , Gravidez/imunologia , Antígenos/imunologia , Plasticidade Celular , Feto/citologia , Feto/imunologia , Fatores de Transcrição Forkhead/imunologia , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia
18.
Toxicol Appl Pharmacol ; 476: 116651, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37549741

RESUMO

Epidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6 and 283 L.day-1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment.


Assuntos
Chumbo , Efeitos Tardios da Exposição Pré-Natal , Criança , Humanos , Gravidez , Feminino , Pré-Escolar , Chumbo/toxicidade , Gestantes , Placenta/metabolismo , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Toxicocinética , Teorema de Bayes , Osso e Ossos/metabolismo , Troca Materno-Fetal , Modelos Biológicos
19.
EBioMedicine ; 95: 104762, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37586112

RESUMO

BACKGROUND: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. METHODS: C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. FINDINGS: 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. INTERPRETATION: Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. FUNDING: This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.


Assuntos
Deficiência de Ácido Fólico , Infecções por HIV , Defeitos do Tubo Neural , Feminino , Gravidez , Humanos , Camundongos , Animais , Incidência , Placenta , Camundongos Endogâmicos C57BL , Ácido Fólico , Deficiência de Ácido Fólico/complicações , Defeitos do Tubo Neural/etiologia , Modelos Animais de Doenças , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Troca Materno-Fetal , Feto , Ontário
20.
J Reprod Immunol ; 159: 104124, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37541161

RESUMO

Fetal cells cross the placenta during pregnancy and some have the ability to persist in maternal organs and circulation long-term, a phenomenon termed fetal microchimerism. These cells often belong to stem cell or immune cell lineages. The long-term effects of fetal microchimerism are likely mixed, potentially depending on the amount of fetal cells transferred, fetal-maternal histocompatibility and fetal cell-specific properties. Both human and animal data indicate that fetal-origin cells partake in tissue repair and may benefit maternal health overall. On the other hand, these cells have been implicated in inflammatory diseases by studies showing increased fetal microchimerism in women with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. During pregnancy, preeclampsia is associated with increased cell-transfer between the mother and fetus, and an increase in immune cell subsets. In the current review, we discuss potential mechanisms of transplacental transfer, including passive leakage across the compromised diffusion barrier and active recruitment of cells residing in the placenta or fetal circulation. Within the conceptual framework of the two-stage model of preeclampsia, where syncytiotrophoblast stress is a common pathophysiological pathway to maternal and fetal clinical features of preeclampsia, we argue that microchimerism may represent a mechanistic link between stage 1 placental dysfunction and stage 2 maternal cardiovascular inflammation and endothelial dysfunction. Finally, we postulate that fetal microchimerism may contribute to the known association between placental syndromes and increased long-term maternal cardiovascular disease risk. Fetal microchimerism research represents an exciting opportunity for developing new disease biomarkers and targeted prophylaxis against maternal diseases.


Assuntos
Troca Materno-Fetal , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Placenta , Quimerismo , Feto
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