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      Morphological Alterations in Mouse Placenta Induced by Diazepam Translated title: Alteraciones Morfológicas Inducidas en la Placenta de Ratón por Diazepam

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          Abstract

          Diazepam (DZ) is a benzodiazepine that belongs to the group of minor tranquilizers with myo-relaxing and anticonvulsant properties. DZ and its metabolites cross the placental barrier in human, monkey, hamster, and mouse, and accumulate in the placenta. Our aim was to investigate, through histological techniques, and semifine sections if DZ induces morphological changes in the placenta. Twenty female mice of the ICR strain were distributed randomly in two groups. One group (DZ) was treated from days 6 to 17 of gestation with a single daily subcutaneous (sc) dose of DZ of 2.7 mg/kg/ (bw); the second, control group (C) was treated with saline solution. All females (10 DZ and 10 C) were killed by decapitation. Placentas were extracted and fixed in phosphates-buffered 10% formaldehyde, pH 7.3, dehydrated, and embedded in paraffin to obtain 3 µm thick sections or fixed in 2.5% glutaraldehyde, post-fixed in 1% OsO4, embedded in epoxy resin. Histological sections were stained with hematoxylin-eosin or Weigert´s iron hematoxylin. Semifine sections were stained with toluidine blue. All sections were observed under comparative light microscopy. The DZ-group showed thinned placental barrier with multiple vacuoles. Nuclei of trophoblast cells (TCs) and trophoblast giant cells (TGCs) presented heterochromatin in coarse granules, atypically distributed in the karyolymph and conspicuous nucleoli. The cytoplasm of the TGCs was vacuolated and chromatin had a similar appearance to that observed in TCs. The total area of the placental barrier was measured in µm2/µm2; the area in the DZ group was reduced as compared with the C group (P<0.001). Alterations of TGCs could be due to an interaction of DZ with peripheral type benzodiazepine receptors involved in progesterone biosynthesis. Administration of DZ in mice alters the placental barrier and TGCs which could affect their physiology and causes teratogenic effects on the ovary and testis involved in steroid hormones biosynthesis.

          Translated abstract

          El diazepam (DZ) es una benzodiazepina que forma parte de los tranquilizantes menores con propiedades miorrelajantes y anticonvulsivantes. El DZ y sus metabolitos atraviesan la barrera placentaria en el humano, mono, hámster y ratón, y se acumula en ésta. Nuestro propósito fue investigar a través de técnicas histológicas y en cortes semifinos si el DZ induce cambios morfológicos en la placenta de ratón. Hembras de ratón de la cepa ICR se distribuyeron al azar en dos grupos. Un grupo (DZ) fue tratado del día 6 al 17 de la gestación con dosis únicas diarias subcutáneas (sc) de DZ de 2.7 mg/kg (pc); el segundo grupo control (C) se trató con solución salina. Todas las hembras (10 DZ y 10 C), se sacrificaron por decapitación. Se extrajeron las placentas y se fijaron en formaldehido al 10% amortiguado con fosfatos pH 7.3, se deshidrataron y se incluyeron en parafina para obtener cortes de 3 µm, o se fijaron en glutaraldehido al 2.5%, se posfijaron en OsO4 al 1% y se embebieron en resina epóxica. Los cortes histológicos se tiñeron con hematoxilina-eosina o con hematoxilina férrica de Weigert. Los cortes semifinos se tiñeron con azul de toluidina. Todos los cortes se observaron en un microscopio óptico de comparación. El grupo DZ presentó en la barrera placentaria múltiples vacuolas. Los núcleos de las células del trofoblasto y las células trofoblásticas gigantes (TGCs) presentaron heterocromatina en grumos gruesos, distribuidos atípicamente en la cariolinfa y nucléolos conspicuos. El citoplasma de las TGCs estaba vacuolizado y la cromatina tenía una apariencia similar a la observada en las células trofoblásticas. El área total de la barrera placentaria se midió en µm2/mm2; el área en el grupo DZ era reducida en comparación del grupo C (P<0.001). Las alteraciones de las células trofoblásticas y de las TGCs podrían deberse a la interacción del DZ con los receptores benzodiazepínicos de tipo periférico involucrados en la biosíntesis de progesterona. La administración de DZ en el ratón altera la barrera placentaria y las TGCs que podrían afectar su fisiología y causar efectos teratogénicos en el ovario y el testículo involucrados en la biosíntesis de las hormonas esteroides.

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          Most cited references23

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          Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta.

          Trophoblast giant cells (TGCs) are the first terminally differentiated subtype to form in the trophoblast cell lineage in rodents. In addition to mediating implantation, they are the main endocrine cells of the placenta, producing several hormones which regulate the maternal endocrine and immune systems and promote maternal blood flow to the implantation site. Generally considered a homogeneous population, TGCs have been identified by their expression of genes encoding placental lactogen 1 or proliferin. In the present study, we have identified a number of TGC subtypes, based on morphology and molecular criteria and demonstrated a previously underappreciated diversity of TGCs. In addition to TGCs that surround the implantation site and form the interface with the maternal deciduas, we demonstrate at least three other unique TGC subtypes: spiral artery-associated TGCs, maternal blood canal-associated TGCs and a TGC within the sinusoidal spaces of the labyrinth layer of the placenta. All four TGC subtypes could be identified based on the expression patterns of four genes: Pl1, Pl2, Plf (encoded by genes of the prolactin/prolactin-like protein/placental lactogen gene locus), and Ctsq (from a placental-specific cathepsin gene locus). Each of these subtypes was detected in differentiated trophoblast stem cell cultures and can be differentially regulated; treatment with retinoic acid induces Pl1/Plf+ TGCs preferentially. Furthermore, cell lineage tracing studies indicated unique origins for different TGC subtypes, in contrast with previous suggestions that secondary TGCs all arise from Tpbpa+ ectoplacental cone precursors.
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            Trophoblast giant-cell differentiation involves changes in cytoskeleton and cell motility.

            Trophoblast giant-cell differentiation is well-characterized at the molecular level, yet very little is known about how molecular changes affect the cellular functions of trophoblast in embryo implantation. We have found, using both explanted E7.5 mouse embryo ectoplacental cone and the rat choriocarcinoma (Rcho-1) cell line, that trophoblast differentiation is distinguished by dramatic changes in cytoarchitecture and cell behavior. Undifferentiated trophoblast cells contain little organized actin and few small, peripheral focal complexes and exhibit high membrane protrusive activity, while differentiated trophoblast giant cells contain prominent stress fibers, large internal as well as peripheral focal adhesions, and become immotile. The dramatic changes in cell behavior and cytoskeletal organization of giant cells correlate with changes in the activities of the Rho family of small GTPases and a decrease in tyrosine phosphorylation of focal adhesion kinase. Together, these data provide detailed insight into the cellular properties of trophoblast giant cells and suggest that giant-cell differentiation is characterized by a transition from a motile to a specialized epithelial phenotype. Furthermore, our data support a phagocytic erosion, rather than a migratory infiltration, mechanism for trophoblast giant-cell invasion of the uterine stroma. Copyright 2001 Academic Press.
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              Placental transfer to diazepam and its disposition in the newborn.

              Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.
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                Author and article information

                Journal
                ijmorphol
                International Journal of Morphology
                Int. J. Morphol.
                Sociedad Chilena de Anatomía (Temuco, , Chile )
                0717-9502
                June 2014
                : 32
                : 2
                : 426-431
                Affiliations
                [01] Mexico D.F. orgnameUniversidad Nacional Autónoma de México orgdiv1Facultad de Medicina orgdiv2Departamento de Embriología Mexico
                Article
                S0717-95022014000200007 S0717-9502(14)03200200007
                10.4067/S0717-95022014000200007
                1dbb86cc-c952-4dc2-9a06-514a2041d395

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 20 October 2013
                : 17 February 2014
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 23, Pages: 6
                Product

                SciELO Chile


                Benzodiazepine,Diazepam,Mouse,Placenta,Histology,Benzodiazepinas,Ratón,Histología

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