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1.
J Clin Pharmacol ; 62 Suppl 1: S94-S114, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106781

RESUMO

Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal-fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady-state unbound plasma concentration in the fetal plasma (or area under the plasma concentration-time curve) to the corresponding maternal plasma concentration (ie, Kp,uu ). Second, the maximum unbound peak (Cu,max,ss,f ) and trough (Cu,min,ss,f ) fetal steady-state plasma concentrations. We (and others) have developed a maternal-fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug-specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal-fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.


Assuntos
Troca Materno-Fetal , Placenta , Animais , Simulação por Computador , Feminino , Feto/metabolismo , Humanos , Troca Materno-Fetal/fisiologia , Modelos Biológicos , Placenta/metabolismo , Gravidez
2.
J Clin Pharmacol ; 62 Suppl 1: 140-146, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106779

RESUMO

Morphine may be administered in pregnant women as an analgesic agent. The transplacental pharmacokinetics (PK) of morphine varies during pregnancy because of physiological and metabolic changes. In this work, we use a multi-compartment model to simulate ex vivo human placental transfer studies of morphine. The computational model is based on a recently published model for metformin with both passive and active transport kinetics. Modifications were made to incorporate morphine-specific transfer parameters. Parameters for the PK models were determined via the nonlinear regression method. In addition, the Latin hypercube sampling (LHS) method was used for the global parameter analysis of the model. Simulation results show good agreement between the model and observed fetal and maternal morphine concentrations. In addition, the lower efflux of morphine from fetal to maternal plasma reflects reduced P-glycoprotein (P-gp) transport as pregnancy progresses, which leads to slower clearance of morphine in the maternal plasma. The LHS analysis also indicates the more significant roles played by the passive diffusion parameters than the active transport parameter on the fetal/maternal morphine concentrations. In conclusion, we used an in silico model to investigate the transplacental properties of morphine and to predict the in vivo transplacental properties of morphine when PK parameters change.


Assuntos
Troca Materno-Fetal , Morfina , Simulação por Computador , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Modelos Biológicos , Placenta/metabolismo , Gravidez
3.
J Clin Pharmacol ; 62 Suppl 1: S115-S128, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106784

RESUMO

There is limited information about the transfer of antidepressants and antipsychotics across the human placenta. The objective of the current review was to systematically screen the scientific literature using relevant keywords to collect quantitative data on placental transfer of these drugs in humans and to give an overview of current modeling approaches used in this context. The collected data encompassed clinically measured fetal:maternal (F:M) concentration ratios (ie, the ratio between drug concentrations measured in the umbilical cord and drug concentrations measured in the mother) and transfer data obtained from ex vivo cotyledon perfusion experiments. These data were found for 18 antidepressants and some of their pharmacologically active metabolites, and for 10 antipsychotics and the metabolites thereof. Based on the collected data, similar maternal and fetal exposure could be observed for only a few compounds (eg, norfluoxetine and desvenlafaxine), whereas for most drugs (eg, paroxetine, sertraline, and quetiapine), fetal exposure appeared to be on average lower than maternal exposure. Venlafaxine appeared to be an exception in that the data indicated equivalent or higher concentrations in the umbilical cord than in the mother. Physiologically based pharmacokinetic (PBPK) models were sporadically used to investigate maternal pharmacokinetics of antidepressants or antipsychotics (eg, for sertraline, aripiprazole, and olanzapine), although without explicitly addressing fetal drug exposure. It is recommended that PBPK modeling is applied more frequently to these drugs. Although no substitute for clinical studies, these tools can help to better understand pregnancy-induced pharmacokinetic changes and ultimately contribute to a more evidence-based pharmacotherapy of depression and psychosis in pregnant subjects.


Assuntos
Antipsicóticos , Placenta , Antidepressivos , Antipsicóticos/uso terapêutico , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Placenta/metabolismo , Gravidez , Sertralina/metabolismo
4.
Biomed Pharmacother ; 154: 113613, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058146

RESUMO

Acetaminophen is among the most widely used analgesics; however, the proportion and mechanism of transplacental transfer of unbound acetaminophen with actual pharmacological activity remain unknown. Our hypothesis is that acetaminophen gradually penetrates the blood-placenta barrier to reach the fetus. A multiple microdialysis coupled to liquid chromatography with photodiode array detection method was developed to monitor acetaminophen levels in the maternal blood, placenta, fetus, and amniotic fluid of a pregnant rat and investigate this hypothesis. The pharmacokinetic data indicates that acetaminophen exhibits a nonlinear behavior in the maternal blood within the dosage regimen of 100 and 300 mg/kg. In addition, acetaminophen penetrates the placenta, fetus, and amniotic fluid during treatment. The transplacental transfer ratio represented by the area under the concentration curve (AUC) ratio for the conceptus (the collective term for the fetus, placenta, and amniotic fluid) and maternal blood (AUCtissue/AUCblood) was approximately 11-23 % after acetaminophen (100 and 300 mg/kg) administration. However, the transporter of multidrug resistance-associated protein (MRP) inhibitor MK-571 did not significantly change the transplacental transfer ratio. This basic study provides constructive information for the clinical application of acetaminophen in pregnant women.


Assuntos
Acetaminofen , Troca Materno-Fetal , Acetaminofen/metabolismo , Líquido Amniótico/metabolismo , Animais , Cromatografia Líquida , Feminino , Feto/metabolismo , Humanos , Placenta/metabolismo , Gravidez , Ratos
5.
Nat Commun ; 13(1): 4571, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931682

RESUMO

Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring's developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.


Assuntos
Quimerismo , Troca Materno-Fetal , Animais , Feminino , Feto , Mamíferos , Camundongos , Parto , Placenta , Gravidez
6.
Placenta ; 127: 77-87, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35981406

RESUMO

INTRODUCTION: The acquisition of humoral immunity in utero is essential for the fetus. The crucial protein, which is responsible for this part of immunity, is immunoglobulin-G (IgG). Immune functions of IgGs are mediated via the interaction of the crystallizable fragment (Fc) region of IgG with specific Fc γ receptors (FcγRs). However, an atypical FcγR, the neonatal Fc receptor (FcRn), is a key regulator of IgG transfer across the human placenta. During the last four decades ex vivo placental perfusion studies have contributed significantly to the study of mechanisms of IgG transfer across the multicellular placental barrier. METHOD: A PubMed search was conducted by using specific keywords: placenta, perfusion and IgG to review manuscripts using human placental perfusion to study the transplacental transfer of IgG. Relevant studies found in reference lists of these manuscripts were also added to the review, and references were included that supported or gave nuance to the discussion of the mechanisms of IgG kinetics in the placenta. RESULTS AND DISCUSSION: We found twenty publications on the study of transplacental transfer of IgG using human ex vivo placental perfusion, by research groups with partly different settings. This review summarizes knowledge about placental IgG transfer, with a strong focus on the contributions from ex vivo placental perfusion studies.


Assuntos
Imunoglobulina G , Placenta , Feminino , Feto/metabolismo , Humanos , Recém-Nascido , Troca Materno-Fetal , Perfusão , Placenta/metabolismo , Gravidez
7.
Metallomics ; 14(9)2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36002020

RESUMO

Selenium deficiency has been considered to increase the risk of gestational complications. Our previous work showed that maternal selenium deficiency suppressed proliferation, induced autophagy dysfunction, and apoptosis in the placenta of mice. However, other effects of maternal selenium deficiency on the placenta and the underlying mechanisms remain unclear. In the present study, dietary selenium deficiency in dams significantly suppressed glutathione peroxidase (GSH-Px) activity, total antioxidant capacity (T-AOC), and increased malondialdehyde (MDA) content in the placentae, confirming the oxidative stress in the placenta. By transcriptome sequencing analysis, the DEGs were involved in many biological processes, including ion transport, lipid metabolic process, immune response, transmembrane transport, and others. According to the KEGG analysis, the DEGs were primarily enriched in metabolic pathways, PI3K-Akt signaling pathway, and others. Among these, the steroid hormone biosynthesis pathway enriched the most DEGs. Hsd3b1, an ER enzyme involved in progesterone synthesis, was validated downregulated. Consistently, the progesterone content in the serum of the selenium-deficient group was decreased. Ion transporters and transmembrane transporters, such as Heph, Trf, Slc39a8, Slc23a1, Atp7b, and Kcnc1, were reduced in the selenium-deficient placentae. Immune response-related genes, including Ccl3, Ccl8, Cxcl10, and Cxcl14, were increased in the selenium-deficient placentae, along with an increase in macrophage number. These results suggested that maternal selenium deficiency may impair progesterone biosynthesis, reduce nutrient transporters expression, and promote immune response by increasing the oxidative stress of the placentae. This present study provides a novel insight into the possible cause of placenta disorder during pregnancy.


Assuntos
Proteínas de Transporte de Cátions , Selênio , Animais , Antioxidantes/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Imunidade , Troca Materno-Fetal , Camundongos , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Placenta/metabolismo , Gravidez , Progesterona/metabolismo , Progesterona/farmacologia , Selênio/metabolismo , Transcriptoma
8.
Front Immunol ; 13: 837281, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844513

RESUMO

The concept of biological identity has been traditionally a central issue in immunology. The assumption that entities foreign to a specific organism should be rejected by its immune system, while self-entities do not trigger an immune response is challenged by the expanded immunotolerance observed in pregnancy. To explain this "immunological paradox", as it was first called by Sir Peter Medawar, several mechanisms have been described in the last decades. Among them, the intentional transfer and retention of small amounts of cells between a mother and her child have gained back attention. These microchimeric cells contribute to expanding allotolerance in both organisms and enhancing genetic fitness, but they could also provoke aberrant alloimmune activation. Understanding the mechanisms used by microchimeric cells to exert their function in pregnancy has proven to be challenging as per definition they are extremely rare. Profiting from studies in the field of transplantation and cancer research, a synergistic effect of microchimerism and cellular communication based on the secretion of extracellular vesicles (EVs) has begun to be unveiled. EVs are already known to play a pivotal role in feto-maternal tolerance by transferring cargo from fetal to maternal immune cells to reshape their function. A further aspect of EVs is their function in antigen presentation either directly or on the surface of recipient cells. Here, we review the current understanding of microchimerism in the feto-maternal tolerance during human pregnancy and the potential role of EVs in mediating the allorecognition and tropism of microchimeric cells.


Assuntos
Quimerismo , Vesículas Extracelulares , Feminino , Feto , Humanos , Tolerância Imunológica , Troca Materno-Fetal , Gravidez
9.
Placenta ; 126: 83-89, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35785693

RESUMO

Since the full development of the ex vivo dual perfusion model of the human placenta cotyledon, the technique has provided essential insight into how nutrients, lipids, gases, immunoglobulins, endocrine agents, pharmaceuticals, chemicals, nanoparticles, micro-organisms and parasites might traverse the maternofetal barrier. Additionally, the model has been instrumental in gaining a better understanding of the regulation of vascular tone, endocrinology and metabolism within this organ. The human placenta is unique amongst species in its anatomy and transfer modalities. This orthologous diversity therefore requires an appropriate consideration of placental transfer rates of compounds, particles and micro-organisms specific to humans. Different research centres have adapted this model with a wide variation in perfusion parameters, including in the establishment of perfusion, perfusate composition, gassing regime, cannulation method, flow rates, perfused tissue mass, and also in the application of quality control measures. The requirement to harmonise and standardise perfusion practice between centres is largely driven by the need to obtain consistency in our understanding of placental function, but also in the qualification of the model for acceptance by regulatory agencies in drug and toxicology testing. A pilot study is proposed, aiming to describe how existing inter-centre variation in perfusion methodology affects placental metabolism, protein synthesis, oxygen consumption, the materno-fetal transfer of key molecular markers, and placental structure.


Assuntos
Cotilédone , Placenta , Feminino , Humanos , Troca Materno-Fetal , Perfusão , Projetos Piloto , Placenta/metabolismo , Gravidez , Padrões de Referência
10.
Dev Cell ; 57(12): 1442-1452, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35700729

RESUMO

In various placental mammals, the bidirectional exchange of cells during pregnancy can lead to the acquisition of genetically unique cells that can persist in both mother and child for decades. Over the years, it has become increasingly clear that this phenomenon, termed fetomaternal microchimerism may play key roles in a number of biological processes. In this perspective, we explore the concept of fetomaternal microchimerism and outline how fetal microchimeric cells are detected and immunologically tolerated within the maternal setting. Moreover, we discuss undertakings in the field that hint at the significant plasticity of fetal microchimeric cells and their potential roles in promoting maternal wound healing. Finally, we explore the multifaceted roles of fetal microchimeric cells in cancer development and progression. A deeper understanding of fetomaternal chimerism in healthy and diseased states will be key toward developing more efficient anti-cancer treatments and regenerative therapies.


Assuntos
Quimerismo , Neoplasias , Animais , Criança , Feminino , Feto , Humanos , Mamíferos , Troca Materno-Fetal , Neoplasias/genética , Placenta , Gravidez , Cicatrização
11.
Reprod Toxicol ; 111: 194-203, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35714934

RESUMO

Although the use of medication during pregnancy is common, information on exposure to the developing fetus and potential teratogenic effects is often lacking. This study used a rat model to examine the placental transfer of three small-molecule drugs with molecular weights ranging from approximately 300 to 800 Da with different physicochemical properties. Time-mated Sprague Dawley (Hsd:SD) rats aged 11-13 weeks were administered either glyburide, rifaximin, or fentanyl at gestational day 15. Maternal blood, placentae, and fetuses were collected at 5 min, 30 min, 1 h, 4 h, 8 h, 24 h, 48 h, and 96 h post-dose. To characterize the rate and extent of placental drug transfer, we calculated several pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL), and volume of distribution (Vd) for plasma, placenta, and fetus tissues. The results indicated showed that fetal exposure was lowest for glyburide, accounting for only 2.2 % of maternal plasma exposure as measured by their corresponding AUC ratio, followed by rifaximin (37.9 %) and fentanyl (172.4 %). The fetus/placenta AUC ratios were found to be 10.7 % for glyburide, 11.8 % for rifaximin, and 39.1 % for fentanyl. These findings suggest that although the placenta acts as a protective shield for the fetus, the extent of protection varies for different drugs and depends on factors such as molecular weight, lipid solubility, transporter-mediated efflux, and binding to maternal and fetal plasma proteins.


Assuntos
Troca Materno-Fetal , Placenta , Animais , Feminino , Fentanila/metabolismo , Fentanila/farmacologia , Feto , Glibureto/metabolismo , Glibureto/farmacologia , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Rifaximina/farmacologia
12.
Rev. Ciênc. Méd. Biol. (Impr.) ; 21(1): 130-133, maio 05,2022.
Artigo em Português | LILACS | ID: biblio-1370806

RESUMO

Introdução: a síndrome antifosfolípide (SAF) é caracterizada por eventos trombóticos e perdas gestacionais de repetição sendo considerada a trombofilia adquirida mais comum. Objetivo: realizar uma revisão narrativa da passagem transplacentária de anticorpos em pacientes com SAF. Metodologia: revisão narrativa da literatura. Resultados: quando não está associada a alguma doença do tecido conectivo é dita primária e quando em associação com lúpus eritematosos sistêmico é dita secundária. A morbidade gestacional é frequente e torna-se de importância avaliar a passagem desses anticorpos transplacentariamente, desde que existem modelos animais da síndrome com transferência passiva desses anticorpos. A passagem transplacentária de anticorpos específicos já foi determinada em estudos, os quais demonstraram baixos níveis destes anticorpos no soro materno, porém uma eficiente passagem transplacentária para o neonato. Conclusão: existem poucos estudos sobre essa passagem materno-infantil em pacientes com SAF, que são aqui revisados.


Introduction: a antiphospholipid syndrome (APS) is characterized by thrombotic events and recurrent pregnancy losses and is considered the most common acquired thrombophilia. Objective: to carry out a narrative review of the transplacental passage and antibodies in patients with APS. Methodology: narrative literature review Results: when it is not associated with any connective tissue disease, it is said to be primary and when in association with systemic lupus erythematosus it is said to be secondary. Gestational morbidity is frequent and it is important to evaluate the passage of these antibodies transplacentally, since there are animal models of the syndrome with passive transfer of these antibodies. The transplacental passage of specific antibodies has already been determined in studies, which demonstrated low levels of these antibodies in the maternal serum, but an efficient transplacental passage for the newborn. Conclusion: there are few studies on this maternal-infant passage in patients with APS, which are reviewed here.


Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Adulto , Complicações na Gravidez , Síndrome Antifosfolipídica , Anticorpos Antifosfolipídeos , Troca Materno-Fetal , Aleitamento Materno
13.
J Reprod Immunol ; 151: 103632, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35504113

RESUMO

The immune cells, especially innate immune cells (Natural Killer cells and Macrophages) residing at the maternal-fetal interface are playing critical roles during pregnancy. Here we discuss the immunological characteristic at the maternal-fetal interface during normal pregnancy. These key decidual immune cells are reshaped of their uterus-specific homeostatic functions within this uterus microenvironment. Through emphasizing the similarities and differences between decidua immune microenvironments with tumor or transplantation immune microenvironments, distinctive immune cell niche with activated, tolerant, proangiogenic and nurturing characteristic at the maternal interface is exhibited. Deeper understanding of the immunological microenvironment during pregnancy yield important insight not only into the pathogenesis of various human pregnancy complications, but also suggest ways to better manipulate these immune cells in cancer and transplant organs.


Assuntos
Decídua , Complicações na Gravidez , Feminino , Humanos , Células Matadoras Naturais , Macrófagos , Troca Materno-Fetal , Gravidez , Útero
15.
Biol Reprod ; 107(1): 301-316, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35552600

RESUMO

The placenta is the interface between the fetal and maternal environments during mammalian gestation, critically safeguarding the health of the developing fetus and the mother. Placental trophoblasts origin from embryonic trophectoderm that differentiates into various trophoblastic subtypes through villous and extravillous pathways. The trophoblasts actively interact with multiple decidual cells and immune cells at the maternal-fetal interface and thus construct fundamental functional units, which are responsible for blood perfusion, maternal-fetal material exchange, placental endocrine, immune tolerance, and adequate defense barrier against pathogen infection. Various pregnant complications are tightly associated with the defects in placental development and function maintenance. In this review, we summarize the current views and our recent progress on the mechanisms underlying the formation of placental functional units, the interactions among trophoblasts and various uterine cells, as well as the placental barrier against pathogen infections during pregnancy. The involvement of placental dysregulation in adverse pregnancy outcomes is discussed.


Assuntos
Placenta , Animais , Feminino , Feto , Mamíferos , Troca Materno-Fetal , Placenta/metabolismo , Gravidez , Trofoblastos/fisiologia
16.
J Anim Sci ; 100(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35580043

RESUMO

Experimental and epidemiological studies suggest that maternal nutritional status during early pregnancy, including the period around the time of conception, may induce long-lasting epigenetic changes in the offspring. However, this remains largely unexplored in livestock. Therefore, the objective of this study was to evaluate if modification of the maternal diet of sheep (CTR: control; UND: 50% undernutrition) during the periconceptional period (42 d in total: -14/+28 from mating), would impact CpG methylation in muscle tissue (Longissimus dorsi) of adult offspring (11.5 mo old). Reduced representation bisulfite sequencing identified 262 (Edge-R, FDR < 0.05) and 686 (logistic regression, FDR < 0.001) differentially methylated regions (DMRs) between the UND and CTR groups. Gene ontology analysis identified genes related to development, functions of the muscular system, and steroid hormone receptor activity within the DMRs. The data reported here show that nutritional stress during early pregnancy leads to epigenetic modifications in the muscle of the resulting offspring, with possible implications for cardiac dysfunction, muscle physiology, and meat production.


The formation of the epigenetic pattern of an organism is highly sensitive to environmental factors, especially during early mammalian development, when epigenetic reprogramming of the whole genome takes place. In utero adverse conditions experienced during early pregnancy, such as maternal undernutrition, may induce long-lasting epigenetic changes in the resulting offspring. This study investigated the CpG methylation variations in muscle tissue of adult offspring induced by differences in the diet of their mothers during pregnancy. Our data show that undernutrition during pregnancy leads to epigenetic alterations in the muscle of the offspring, with a potential impact on animal health and productivity.


Assuntos
Desnutrição , Doenças dos Ovinos , Animais , Metilação de DNA , Epigênese Genética , Feminino , Desnutrição/veterinária , Fenômenos Fisiológicos da Nutrição Materna , Troca Materno-Fetal , Músculos , Gravidez , Ovinos
17.
Placenta ; 122: 29-45, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35397340

RESUMO

At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription. Here we provide a narrative review of studies that used the ex vivo placenta perfusion model to study placental drug transport and vascular effects of pharmaceuticals. For studies on placental transfer, we found that the methodology used varied substantially between studies as well as the way in which data was reported. Across the different therapeutic groups, ex vivo measurements of transfer generally corresponded well to in vivo findings. Still, further standardization of the perfusion technique would facilitate a broader use of perfusion data, e.g. in the context of quantitative systems pharmacology models as has been explored in recent years. Only few studies investigated the effects of drugs on the vascular tone using the ex vivo dual-side perfusion model. The model was particularly applied to study vasodilatory effects of pharmaceuticals in the fetoplacental circulation. In conclusion, the ex vivo dually perfused human cotyledon provides a relevant system to gain insights in placental drug disposition and study effects on the fetoplacental vasculature.


Assuntos
Troca Materno-Fetal , Placenta , Transporte Biológico , Feminino , Humanos , Perfusão , Preparações Farmacêuticas/metabolismo , Placenta/metabolismo , Gravidez
18.
Proc Natl Acad Sci U S A ; 119(15): e2113310119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35377817

RESUMO

Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic­polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood­brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte­endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.


Assuntos
Barreira Hematoencefálica , Ciclo-Oxigenase 2 , Encefalite , Troca Materno-Fetal , Microglia , Efeitos Tardios da Exposição Pré-Natal , Animais , Barreira Hematoencefálica/anormalidades , Barreira Hematoencefálica/fisiopatologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Encefalite/imunologia , Feminino , Deleção de Genes , Troca Materno-Fetal/imunologia , Camundongos , Microglia/enzimologia , Poli I-C/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
19.
Life Sci ; 298: 120521, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367241

RESUMO

BACKGROUND: Maternal undernutrition during pregnancy disrupts both fetal growth and development with perturbations to certain physiological processes within the maternal-fetal-placental unit, including metabolic function. However, it is unknown if hypoglycemia during pregnancy alters maternal-fetal-placental drug metabolism as mediated by cytochrome P450 (CYP) enzymes. Despite this, hypoglycemia reduces CYP enzyme activity in non-pregnant animals. We therefore hypothesised that in a sheep model of hypoglycemia induced by late gestation undernutrition (LGUN), maternal-fetal-placental CYP activity would be reduced, and that fetal glucose infusion (LGUN+G) would rescue reduced CYP activity. METHODS: At 115d gestation (term, 150d), ewes were allocated to control (100% metabolic energy requirement (MER); n = 11), LGUN (50% MER; n = 7) or LGUN+G (50% MER + fetal glucose infusion; n = 6) and maintained on their diets until post-mortem. Maternal-fetal-placental CYP activity assays were performed at 131-133d gestation. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation and incubated with CYP-specific probe drugs. Metabolite concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). RESULTS: CYP2C19 and CYP3A were undetectable in placenta or fetal liver, and CYP1A2 was undetectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were unaffected by LGUN. Maternal-fetal-placental CYP1A2 activity was reduced in response to LGUN in the maternal compartment only. CONCLUSIONS: Reduced maternal-fetal-placental CYP1A2 activity, but not placental-specific CYP1A2 activity, may lead to the developing fetus being exposed to increased concentrations of CYP1A2-specific substrates and suggests further consideration of drug dosing is required in instances of late gestation maternal undernutrition.


Assuntos
Hipoglicemia , Desnutrição , Animais , Cromatografia Líquida , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Feto/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Desnutrição/metabolismo , Troca Materno-Fetal , Placenta/metabolismo , Gravidez , Ovinos , Espectrometria de Massas em Tandem
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