| 11. |
- Altmäe, Signe, 1978-, et al.
(författare)
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MicroRNAs miR-30b, miR-30d, and miR-494 Regulate Human Endometrial Receptivity
- 2013
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Ingår i: Reproductive Sciences. - : Springer Science and Business Media LLC. - 1933-7191 .- 1933-7205. ; 20:3, s. 308-317
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) act as important epigenetic posttranscriptional regulators of gene expression. We aimed to gain more understanding of the complex gene expression regulation of endometrial receptivity by analyzing miRNA signatures of fertile human endometria. We set up to analyze miRNA signatures of receptive (LH + 7, n = 4) versus prereceptive (LH + 2, n = 5) endometrium from healthy fertile women. We found hsa-miR-30b and hsa-miR-30d to be significantly upregulated, and hsa-miR-494 and hsa-miR-923 to be downregulated in receptive endometrium. Three algorithms (miRanda, PicTar, and TargetScan) were used for target gene prediction. Functional analyses of the targets using Ingenuity Pathways Analysis and The Database for Annotation, Visualization and Integrated Discovery indicated roles in transcription, cell proliferation and apoptosis, and significant involvement in several relevant pathways, such as axon guidance, Wnt/β-catenin, ERK/MAPK, transforming growth factor β (TGF-β), p53 and leukocyte extravasation. Comparison of predicted miRNA target genes and our previous messenger RNA microarray data resulted in a list of 12 genes, including CAST, CFTR, FGFR2, and LIF that could serve as a panel of genes important for endometrial receptivity. In conclusion, we suggest that a subset of miRNAs and their target genes may play important roles in endometrial receptivity.
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| 12. |
- Altmäe, Signe, et al.
(författare)
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Tissue Factor and Tissue Factor Pathway Inhibitors TFPI and TFPI2 in Human Secretory Endometrium - Possible Link to Female Infertility
- 2011
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Ingår i: Reproductive Sciences. - : Springer Science and Business Media LLC. - 1933-7191 .- 1933-7205. ; 18:7, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate tissue factor (TF) and its inhibitors TFPI and TFPI2 in secretory endometrium of fertile women and in women with unexplained infertility in relation to endometrial receptivity. In addition, common variation in the regulatory area of TF and TFPI genes was studied. Immunostaining of TF and TFPI, together with the appearance of pinopodes, revealed similar expression pattern in fertile endometrium throughout the secretory phase, being highest at the time of implantation. When compared protein expression levels at the time of implantation, infertile women demonstrated significantly higher TFPI expression in luminal epithelium. Furthermore, polymorphism TF -603 A/G was associated with the endometrial protein level in infertile women, being highest in women with GG genotype, and variation TFPI -287 T/C was associated with unexplained infertility, where infertile women presented more frequently T allele than fertile women. Contrary to TF and TFPI, TFPI2 showed different mRNA and protein expression patterns in fertile endometrium, and no differences between fertile and infertile women were detected. We conclude that the TF pathway is involved in normal endometrial maturation, where TF and TFPI seem to have important roles at the time of embryo implantation. Higher TFPI expression level during the time of embryo implantation and TFPI -287 T allele could be risk factors for unexplained infertility. No distinct involvement of TFPI2 in the regulation of endometrial receptivity and unexplained infertility was found.
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| 13. |
- Bellavia, Andrea, et al.
(författare)
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Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia
- 2023
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 216:Part 1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per -and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics.Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in > 90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Ma-chine Regression.Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, beta =-0.21, 95% CI:-0.38,-0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, beta =-0.22, 95% CI:-0.44,-0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1,beta =-0.16, 95% CI-0.31,-0.02) and the Estonian population (Q2 vs. Q1,beta =-0.27, 95% CI-0.45,-0.08), and for PFOA in the Estonian population (Q4 vs. Q1, beta =-0.31, 95% CI-0.61,-0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals.Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP me-tabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.
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| 14. |
- Jaimes-Mogollon, Aylen Lisset, et al.
(författare)
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Review on Volatolomic Studies as a Frontier Approach in Animal Research
- 2021
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Ingår i: Advanced Biology. - : John Wiley & Sons. - 2701-0198. ; 5:6
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Forskningsöversikt (refereegranskat)abstract
- This paper presents a comprehensive review of the research studies in volatolomics performed on animals so far. At first, the procedures proposed for the collection, preconcentration, and storing of the volatile organic compounds emitted by various biological samples of different animals are presented and discussed. Next, the results obtained in the analysis of the collected volatile samples with analytical equipment are shown. The possible volatile biomarkers identified for various diseases are highlighted for different types of diseases, animal species, and biological samples analyzed. The chemical classes of these compounds, as well as the biomarkers found in a higher number of animal diseases, are indicated, and their possible origin is analyzed. The studies that dealt with the diagnosis of various diseases from sample measurement with electronic nose systems are also presented and discussed. The paper ends with a final remark regarding the necessity of optimization and standardization of sample collection and analysis procedures for obtaining meaningful results.
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| 15. |
- Kiisholts, Kristina, et al.
(författare)
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Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models
- 2021
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into diseased cells. To achieve that goal, we used highly potential delivery vectors, cell-penetrating peptides (CPPs), as oligonucleotide carriers for the development of a therapeutic approach for endometriosis and cancer. Despite marked differences, both of these conditions still exhibit similarities, like excessive, uncoordinated, and autonomous cellular proliferation and invasion, accompanied by overlapping gene expression patterns. Thus, in the current study, we investigated the therapeutic effects of CPP and siRNA nanoparticles using in vitro models of benign endometriosis and malignant glioblastoma. We demonstrated that CPPs PepFect6 and NickFect70 are highly effective in transfecting cell lines, primary cell cultures, and three-dimensional spheroids. CPP nanoparticles are capable of inducing siRNA-specific knockdown of therapeutic genes, ribonucleotide reductase subunit M2 (RRM2), and vascular endothelial growth factor (VEGF), which results in the reduction of in vitro cellular proliferation, invasion, and migration. In addition, we proved that it is possible to achieve synergistic suppression of endometriosis cellular proliferation and invasion by combining gene therapy and hormonal treatment approaches by co-administering CPP/siRNA nanoparticles together with the endometriosis-drug danazol. We suggest a novel target, RRM2, for endometriosis therapy and as a proof-of-concept, we propose a CPP-mediated gene therapy approach for endometriosis and cancer.
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| 16. |
- Koel, Mariann, et al.
(författare)
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Human endometrial cell-type-specific RNA sequencing provides new insights into the embryo-endometrium interplay
- 2022
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Ingår i: HUMAN REPRODUCTION OPEN. - : Oxford University Press (OUP). - 2399-3529. ; 2022:4
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Which genes regulate receptivity in the epithelial and stromal cellular compartments of the human endometrium, and which molecules are interacting in the implantation process between the blastocyst and the endometrial cells? SUMMARY ANSWER: A set of receptivity-specific genes in the endometrial epithelial and stromal cells was identified, and the role of galectins (LGALS1 and LGALS3), integrin beta 1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in embryo-endometrium dialogue among many other protein-protein interactions were highlighted. WHAT IS KNOWN ALREADY: The molecular dialogue taking place between the human embryo and the endometrium is poorly understood due to ethical and technical reasons, leaving human embryo implantation mostly uncharted. STUDY DESIGN, SIZE, DURATION: Paired pre-receptive and receptive phase endometrial tissue samples from 16 healthy women were used for RNA sequencing. Trophectoderm RNA sequences were from blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cell-type-specific RNA-seq analysis of freshly isolated endometrial epithelial and stromal cells using fluorescence-activated cell sorting (FACS) from 16 paired pre-receptive and receptive tissue samples was performed. Endometrial transcriptome data were further combined in silico with trophectodermal gene expression data from 466 single cells originating from 17 blastocysts to characterize the first steps of embryo implantation. We constructed a protein-protein interaction network between endometrial epithelial and embryonal trophectodermal cells, and between endometrial stromal and trophectodermal cells, thereby focusing on the very first phases of embryo implantation, and highlighting the molecules likely to be involved in the embryo apposition, attachment and invasion. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 499 epithelial and 581 stromal genes were up-regulated in the receptive phase endometria when compared to pre-receptive samples. The constructed protein-protein interactions identified a complex network of 558 prioritized protein-protein interactions between trophectodermal, epithelial and stromal cells, which were grouped into clusters based on the function of the involved molecules. The role of galectins (LGALS1 and LGALS3), integrin beta 1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in the embryo implantation process were highlighted. LARGE SCALE DATA: RNA-seq data are available at www.ncbi.nlm.nih.gov/geo under accession number GSE97929. LIMITATIONS, REASONS FOR CAUTION: Providing a static snap-shot of a dynamic process and the nature of prediction analysis is limited to the known interactions available in databases. Furthermore, the cell sorting technique used separated enriched epithelial cells and stromal cells but did not separate luminal from glandular epithelium. Also, the use of biopsies taken from non-pregnant women and using spare IVF embryos (due to ethical considerations) might miss some of the critical interactions characteristic of natural conception only. WIDER IMPLICATIONS OF THE FINDINGS: The findings of our study provide new insights into the molecular embryo-endometrium interplay in the first steps of implantation process in humans. Knowledge about the endometrial cell-type-specific molecules that co-ordinate successful implantation is vital for understanding human reproduction and the underlying causes of implantation failure and infertility. Our study results provide a useful resource for future reproductive research, allowing the exploration of unknown mechanisms of implantation. We envision that those studies will help to improve the understanding of the complex embryo implantation process, and hopefully generate new prognostic and diagnostic biomarkers and therapeutic approaches to target both infertility and fertility, in the form of new contraceptives.
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| 17. |
- Lavogina, Darja, et al.
(författare)
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Endocrine disrupting chemicals interfere with decidualization of human primary endometrial stromal cells in vitro
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Multiple studies have shown associations between exposure to endocrine disrupting chemicals (EDCs) and reduced fertility in women. However, little is known about the target organs of chemical disruption of female fertility. Here, we focus on the hormone-sensitive uterine lining, the endometrium, as a potential target. Decidualization is the morphological and functional change that endometrial stromal cells undergo to support endometrial receptivity, which is crucial for successful implantation, placentation, and pregnancy. We investigated the effect of nine selected EDCs on primary human endometrial stromal cell decidualization in vitro. The cells were exposed to a decidualization-inducing mixture in the presence or absence of 1 mu M of nine different EDCs for nine days. Extent of decidualization was assessed by measuring the activity of cAMP dependent protein kinase, Rho-associated coiled-coil containing protein kinase, and protein kinase B in lysates using photoluminescent probes, and secretion of prolactin into the media by using ELISA. Decidualization-inducing mixture upregulated activity of protein kinases and prolactin secretion in cells derived from all women. Of the tested chemicals, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB) and perfluorooctanesulfonic acid (PFOS) significantly reduced decidualization as judged by the kinase markers and prolactin secretion. In addition, bisphenol A (BPA) reduced prolactin secretion but did not significantly affect activity of the kinases. None of the EDCs was cytotoxic, based on the assessment of total protein content or activity of the viability marker casein kinase 2 in lysates. These results indicate that EDCs commonly present in the blood circulation of reproductive-aged women can reduce decidualization of human endometrial stromal cells in vitro. Future studies should focus on detailed hazard assessment to define possible risks of EDC exposure to endometrial dysfunction and implantation failure in women.
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| 18. |
- Lokk, Kaie, et al.
(författare)
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DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns
- 2014
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Ingår i: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 15:4, s. r54-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites. RESULTS: Only 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases. CONCLUSIONS: This genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.
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| 19. |
- Läänelaid, Siret, et al.
(författare)
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Physical and Sedentary Activities in Association with Reproductive Outcomes among Couples Seeking Infertility Treatment : A Prospective Cohort Study
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 18:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the association of physical activity (PA) with assisted reproductive technology (ART) treatment and pregnancy outcomes among couples seeking infertility treatment.Methods: This prospective cohort study was carried out among 128 infertile individuals (64 couples), entering the infertility clinic for ART procedures. Baseline PA (before entering any treatment) was assessed using accelerometry for both women and men. For every couple the infertility treatment outcomes were recordedResults: The couples that required invasive ART procedures such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) spent less time in vigorous PA (-73 min/week per couple, woman + man) than those couples who became spontaneously pregnant after entering the study (p = 0.001). We observed no significant associations between the time spent in physical activities and positive pregnancy test or live birth.Conclusions: Our results do not support a positive nor negative relation between the time the couples spent in physical activities and the chances of getting pregnant or having a baby among patients seeking infertility treatment. However, couples undergoing invasive ART procedures did less vigorous PA than couples that became spontaneously pregnant, suggesting that PA may interfere with their reproductive health.
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| 20. |
- Merisalu, Ave, et al.
(författare)
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The contribution of genetic variations of aryl hydrocarbon receptor pathway genes to male factor infertility
- 2007
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 1556-5653 .- 0015-0282. ; 88:4, s. 854-859
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether the polymorphisms in aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor repressor (AHRR), and aryl hydrocarbon receptor nuclear translocator (ARNT) genes are associated with male factor infertility. Design: An association study. Setting: University research laboratory and andrology clinic. Patient(s): The subjects were infertile Estonian men (n = 112) with azoospermia or oligozoospermia and controls (n = 212) with normal sperm parameters. Intervention(s): Blood samples were obtained for DNA extraction and genotyping. Main Outcome Measure(s): AHR (Arg554Lys), AHRR (Pro 185Ala), and ARNT (G/C allele) polymorphisms were genotyped using allele-specific polymerase chain reaction. Allele and genotype frequencies were compared between infertile men and controls and separately in the normozoospermia, oligozoospermia, and azoospermia groups. Result(s): The AHRR Ala185Ala genotype was implicated in susceptibility to male factor infertility. Ala/Ala genotype frequency increased in the following order: normozoospermia (18.0%), oligozoospermia (26.0%), azoospermia (42.1 %). Allele and genotype frequencies of AHR and ARNT polymorphisms were similar between cases and controls. Conclusion(s): We demonstrated that the AHRR Pro185Ala polymorphism contributed to a predisposition to male factor infertility in the Estonian population. A greater prevalence of the Ala/Ala genotype was found among infertile patients.
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