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Uterine Patterning, Endometrial Gland Development, and Implantation Failure in Mice Exposed Neonatally to Genistein.

ABSTRACT: BACKGROUND:Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects. OBJECTIVES:Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects. METHODS:Female mice were exposed to GEN on postnatal days (PND)1-5 and uterine tissues collected on PND5, PND22-26, and during pregnancy. Analysis of tissue weights, morphology, and gene expression was performed using standard histology, confocal imaging with three-dimensional analysis, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and microarrays. The response of ovariectomized adults to 17?-estradiol (E2) and artificial decidualization were measured. Leukemia inhibitory factor (LIF) injections were given intraperitoneally and implantation sites visualized. Gene expression patterns were compared with curated data sets to identify upstream regulators. RESULTS:GEN-exposed mice exhibited reduced uterine weight gain in response to E2 treatment or artificial decidualization compared with controls; however, expression of select hormone responsive genes remained similar between the two groups. Uteri from pregnant GEN-exposed mice were posteriorized and had reduced glandular epithelium. Implantation failure was not rescued by LIF administration. Microarray analysis of GEN-exposed uteri during early pregnancy revealed significant overlap with several conditional uterine knockout mouse models, including Foxa2, Wnt4, and Sox17. These models exhibit reduced endometrial glands, features of posteriorization and implantation failure. Expression of Foxa2, Wnt4, and Sox17, as well as genes important for neonatal uterine differentiation (Wnt7a, Hoxa10, and Msx2), were severely disrupted on PND5 in GEN-exposed mice. DISCUSSION:Our findings suggest that neonatal GEN exposure in mice disrupts expression of genes important for uterine development, causing posteriorization and diminished gland function during pregnancy that contribute to implantation failure. These findings could have implications for women who consumed soy-based formulas as infants. https://doi.org/10.1289/EHP6336.

SUBMITTER: Jefferson WN

PROVIDER: S-EPMC7138129 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Uterine Patterning, Endometrial Gland Development, and Implantation Failure in Mice Exposed Neonatally to Genistein.

Jefferson Wendy N WN Padilla-Banks Elizabeth E Suen Alisa A AA Royer Lindsey J LJ Zeldin Sharon M SM Arora Ripla R Williams Carmen J CJ

Environmental health perspectives 20200318 3

<h4>Background</h4>Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects.<h4>Objectives</h4>Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects.<h4>M ...[more]

PMID: 32186404

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Project description:IntroductionSuccessful embryo implantation, is the initiating step of pregnancy, relies on not only the high quality of the embryo but also the synergistic development of a healthy endometrium. Characterization and identification of biomarkers for the receptive endometrium is an effective method for increasing the probability of successful embryo implantation.MethodsEndometrial tissues from 22 women with a history of recurrent implantation failure (RIF) and 19 fertile controls were collected using biopsy catheters on 7-9 days after the peak of luteinizing hormone. Differentially expressed proteins (DEPs) were identified in six patients with RIF and six fertile controls using isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics analysis.ResultsTwo hundred and sixty-three DEPs, including proteins with multiple bioactivities, such as protein translation, mitochondrial function, oxidoreductase activity, fatty acid and amino acid metabolism, were identified from iTRAQ. Four potential biomarkers for receptive endometrium named tubulin polymerization-promoting protein family member 3 TPPP3, S100 Calcium Binding Protein A13 (S100A13), 17b-hydroxysteroid dehydrogenase 2 (HSD17B2), and alpha-2-glycoprotein 1, zinc binding (AZGP1) were further verified using ProteinSimple Wes and immunohistochemical staining in all included samples (n=22 for RIF and n=19 for controls). Of the four proteins, the protein levels of TPPP3 and HSD17B2 were significantly downregulated in the endometrium of patients with RIF.DiscussionPoor endometrial receptivity is considered the main reason for the decrease in pregnancy success rates in patients suffering from RIF. iTRAQ techniques based on isotope markers can identify and quantify low abundance proteomics, and may be suitable for identifying differentially expressed proteins in RIF. This study provides novel evidence that TPPP3 and HSD17B2 may be effective targets for the diagnosis and treatment of non-receptive endometrium and RIF.

Project description:Exosomes are nanoparticles (∼100 nm diameter) released from cells, which can transfer small RNAs and mRNA via the extracellular environment to cells at distant sites. We hypothesised that exosomes or the slightly larger microvesicles (100-300 nm) are released from the endometrial epithelium into the uterine cavity, and that these contain specific micro (mi)RNA that could be transferred to either the trophectodermal cells of the blastocyst or to endometrial epithelial cells, to promote implantation. The aim of this study was to specifically identify and characterise exosomes/microvesicles (mv) released from endometrial epithelial cells and to determine whether exosomes/mv are present in uterine fluid. Immunostaining demonstrated that the tetraspanins, CD9 and CD63 used as cell surface markers of exosomes are present on the apical surfaces of endometrial epithelial cells in tissue sections taken across the menstrual cycle: CD63 showed cyclical regulation. Exosome/mv pellets were prepared from culture medium of endometrial epithelial cell (ECC1 cells) and from uterine fluid and its associated mucus by sequential ultracentifugation. Exosomes/mv were positively identified in all preparations by FACS and immunofluorescence staining following exosome binding to beads. Size particle analysis confirmed the predominance of particles of 50-150 nm in each of these fluids. MiRNA analysis of the ECC1 cells and their exosomes/mv demonstrated sorting of miRNA into exosomes/mv: 13 of the 227 miRNA were specific to exosomes/mv, while a further 5 were not present in these. The most abundant miRNA in exosomes/mv were hsa-miR-200c, hsa-miR-17 and hsa-miR-106a. Bioinformatic analysis showed that the exosome/mv-specific miRNAs have potential targets in biological pathways highly relevant for embryo implantation. Thus exosomes/mv containing specific miRNA are present in the microenvironment in which embryo implantation occurs and may contribute to the endometrial-embryo cross talk essential for this process.

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Uterine Patterning, Endometrial Gland Development, and Implantation Failure in Mice Exposed Neonatally to Genistein.

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Uterine Patterning, Endometrial Gland Development, and Implantation Failure in Mice Exposed Neonatally to Genistein.

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