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Trends in Endocrinology and Metabolism:... Mar 2020Epidemiological studies have revealed that caffeine consumption during pregnancy is associated with adverse gestational outcomes, yet the underlying mechanisms remain... (Review)
Review
Epidemiological studies have revealed that caffeine consumption during pregnancy is associated with adverse gestational outcomes, yet the underlying mechanisms remain obscure. Recent animal studies with physiologically relevant dosages have begun to dissect adverse effects of caffeine during pregnancy with respect to oviduct contractility, embryo development, uterine receptivity, and placentation that jointly contribute to pregnancy complications. Interestingly, caffeine's effects are highly variable between individual animals under well-controlled experimental settings, suggesting the possibility of epigenetic regulation of these phenotypes, in addition to genetic variants. Moreover, caffeine exposure during sensitive windows of pregnancy may induce epigenetic changes in the developing fetus or even the germ cells to cause adult-onset diseases in subsequent generations. We discuss these research frontiers in light of emerging data.
Topics: Animals; Caffeine; Epigenesis, Genetic; Female; Humans; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 31818639
DOI: 10.1016/j.tem.2019.11.004 -
Journal of Molecular Medicine (Berlin,... Apr 2021Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth.... (Review)
Review
Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT-ovaries, fallopian tubes, uterus, cervix and vagina-facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.
Topics: Animals; CRISPR-Cas Systems; Drug Discovery; Estrous Cycle; Extracellular Matrix; Female; Fertility; Gene Editing; Genital Diseases, Female; Genitalia, Female; Gestational Age; Gonadal Steroid Hormones; Humans; Maternal-Fetal Exchange; Mice; Organoids; Pituitary Hormones, Anterior; Placenta; Precision Medicine; Pregnancy; Stem Cells; Tissue Engineering
PubMed: 33580825
DOI: 10.1007/s00109-020-02028-0 -
Reproductive Biology and Endocrinology... Mar 2020Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking,... (Review)
Review
BACKGROUND
Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases.
OBJECTIVE
The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included.
METHODS
A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts.
RESULTS AND CONCLUSIONS
Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption.
Topics: Alcohol Drinking; Animals; Endometriosis; Female; Humans; Infertility, Female; Polycystic Ovary Syndrome; Pregnancy; Smoking; Substance-Related Disorders
PubMed: 32164734
DOI: 10.1186/s12958-020-0567-7 -
Human Reproduction Update Nov 2022To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones...
BACKGROUND
To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may be fertilized in the fallopian tubes, and the resulting zygote is transported toward the uterus, where it can implant and continue developing. The cervix acts as a physical barrier to protect the fetus throughout pregnancy, and the vagina acts as a birth canal (involving uterine and cervix mechanisms) and facilitates copulation. Fertility can be compromised by pathologies that affect any of these organs or processes, and therefore, being able to accurately model them or restore their function is of paramount importance in applied and translational research. However, innate differences in human and animal model reproductive tracts, and the static nature of 2D cell/tissue culture techniques, necessitate continued research and development of dynamic and more complex in vitro platforms, ex vivo approaches and in vivo therapies to study and support reproductive biology. To meet this need, bioengineering is propelling the research on female reproduction into a new dimension through a wide range of potential applications and preclinical models, and the burgeoning number and variety of studies makes for a rapidly changing state of the field.
OBJECTIVE AND RATIONALE
This review aims to summarize the mounting evidence on bioengineering strategies, platforms and therapies currently available and under development in the context of female reproductive medicine, in order to further understand female reproductive biology and provide new options for fertility restoration. Specifically, techniques used in, or for, the uterus (endometrium and myometrium), ovary, fallopian tubes, cervix and vagina will be discussed.
SEARCH METHODS
A systematic search of full-text articles available in PubMed and Embase databases was conducted to identify relevant studies published between January 2000 and September 2021. The search terms included: bioengineering, reproduction, artificial, biomaterial, microfluidic, bioprinting, organoid, hydrogel, scaffold, uterus, endometrium, ovary, fallopian tubes, oviduct, cervix, vagina, endometriosis, adenomyosis, uterine fibroids, chlamydia, Asherman's syndrome, intrauterine adhesions, uterine polyps, polycystic ovary syndrome and primary ovarian insufficiency. Additional studies were identified by manually searching the references of the selected articles and of complementary reviews. Eligibility criteria included original, rigorous and accessible peer-reviewed work, published in English, on female reproductive bioengineering techniques in preclinical (in vitro/in vivo/ex vivo) and/or clinical testing phases.
OUTCOMES
Out of the 10 390 records identified, 312 studies were included for systematic review. Owing to inconsistencies in the study measurements and designs, the findings were assessed qualitatively rather than by meta-analysis. Hydrogels and scaffolds were commonly applied in various bioengineering-related studies of the female reproductive tract. Emerging technologies, such as organoids and bioprinting, offered personalized diagnoses and alternative treatment options, respectively. Promising microfluidic systems combining various bioengineering approaches have also shown translational value.
WIDER IMPLICATIONS
The complexity of the molecular, endocrine and tissue-level interactions regulating female reproduction present challenges for bioengineering approaches to replace female reproductive organs. However, interdisciplinary work is providing valuable insight into the physicochemical properties necessary for reproductive biological processes to occur. Defining the landscape of reproductive bioengineering technologies currently available and under development for women can provide alternative models for toxicology/drug testing, ex vivo fertility options, clinical therapies and a basis for future organ regeneration studies.
Topics: Animals; Female; Humans; Pregnancy; Bioengineering; Embryo Implantation; Genitalia, Female; Reproduction; Uterus
PubMed: 35652272
DOI: 10.1093/humupd/dmac025 -
The American Journal of Pathology Jan 2021Unlike other human cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube... (Review)
Review
Unlike other human cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube epithelium. The prevailing paradigm in the genesis of high-grade serous carcinoma (HGSC), the most common ovarian cancer, posits to its development in fallopian tubes through stepwise tumor progression. Recent progress has been made not only in gathering terabytes of omics data but also in detailing the histologic-molecular correlations required for looking into, and making sense of, the tissue origin of HGSC. This emerging paradigm is changing many facets of ovarian cancer research and routine gynecology practice. The precancerous landscape in fallopian tubes contains multiple concurrent precursor lesions, including serous tubal intraepithelial carcinoma (STIC), with genetic heterogeneity providing a platform for HGSC evolution. Mathematical models imply that a prolonged time (decades) elapses from the development of a TP53 mutation, the earliest known molecular alteration, to an STIC, followed by a shorter span (6 years) for progression to an HGSC. Genetic predisposition accelerates the trajectory. This timeline may allow for the early diagnosis of HGSC and STIC, followed by intent-to-cure surgery. This review discusses the recent advances in this tubal paradigm and its biological and clinical implications, alongside the promise and challenge of studying STIC and other precancerous lesions of HGSC.
Topics: Animals; Carcinogenesis; Carcinoma in Situ; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Disease Progression; Fallopian Tubes; Female; Humans; Precancerous Conditions
PubMed: 33011111
DOI: 10.1016/j.ajpath.2020.09.006 -
Cell Aug 2021Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD synthesis plays an...
Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.
Topics: 3' Untranslated Regions; ADP-Ribosylation; Animals; Base Sequence; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum Stress; Fallopian Tubes; Female; Humans; Mice, Inbred NOD; Mice, SCID; NAD; Nicotinamide-Nucleotide Adenylyltransferase; Nucleic Acid Conformation; Ovarian Neoplasms; Poly(ADP-ribose) Polymerases; Polyribosomes; Protein Biosynthesis; Proteostasis; RNA, Messenger; RNA, Small Interfering; Ribosomal Proteins; Ribosomes; Mice
PubMed: 34314702
DOI: 10.1016/j.cell.2021.07.005 -
Cancer Research Nov 2021The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this...
The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein TGF beta induced (TGFBI, also known as βig-h3). STIC lesions in the fimbria expressed high levels of TGFBI, which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. stimulation of macrophages with TGFβ and IL4 induced secretion of TGFBI, whereas IFNγ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvβ3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production . Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated β3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumor-promoting actions of TGFβ and a potential therapeutic target. SIGNIFICANCE: Analysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.
Topics: Animals; Apoptosis; Cell Proliferation; Cystadenocarcinoma, Serous; Extracellular Matrix; Female; Humans; Immunosuppressive Agents; Macrophages; Mice; Mice, Inbred C57BL; Ovarian Neoplasms; Peritoneal Neoplasms; Prognosis; Transforming Growth Factor beta1; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 34561272
DOI: 10.1158/0008-5472.CAN-21-0536 -
Journal of Animal Science Jan 2023In vitro-cultured oocytes are separated from the follicular micro-environment in vivo and are more vulnerable than in vivo oocytes to changes in the external...
In vitro-cultured oocytes are separated from the follicular micro-environment in vivo and are more vulnerable than in vivo oocytes to changes in the external environment. This vulnerability disrupts the homeostasis of the intracellular environment, affecting oocyte meiotic completion, and subsequent embryonic developmental competence in vitro. Glycine, one of the main components of glutathione (GSH), plays an important role in the protection of porcine oocytes in vitro. However, the protective mechanism of glycine needs to be further clarified. Our results showed that glycine supplementation promoted cumulus cell expansion and oocyte maturation. Detection of oocyte development ability showed that glycine significantly increased the cleavage rate and blastocyst rate during in vitro fertilization (IVF). SMART-seq revealed that this effect was related to glycine-mediated regulation of cell membrane structure and function. Exogenous addition of glycine significantly increased the levels of the anti-oxidant GSH and the expression of anti-oxidant-related genes (glutathione peroxidase 4 [GPX4], catalase [CAT], superoxide dismutase 1 [SOD1], superoxide dismutase 2 [SOD2], and mitochondrial solute carrier family 25, member 39 [SLC25A39]), decreased the lipid peroxidation caused by reactive oxygen species (ROS) and reduced the level of malondialdehyde (MDA) by enhancing the functions of mitochondria, peroxisomes and lipid droplets (LDs) and the levels of lipid metabolism-related factors (peroxisome proliferator activated receptor coactivator 1 alpha [PGC-1α], peroxisome proliferator-activated receptor γ [PPARγ], sterol regulatory element binding factor 1 [SREBF1], autocrine motility factor receptor [AMFR], and ATP). These effects further reduced ferroptosis and maintained the normal structure and function of the cell membrane. Our results suggest that glycine plays an important role in oocyte maturation and later development by regulating ROS-induced lipid metabolism, thereby protecting against biomembrane damage.
Topics: Pregnancy; Female; Swine; Animals; Reactive Oxygen Species; In Vitro Oocyte Maturation Techniques; Antioxidants; Lipid Peroxidation; Glycine; Embryonic Development; Oocytes; Blastocyst; Glutathione
PubMed: 36573588
DOI: 10.1093/jas/skac425 -
Cell Feb 2024The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains...
The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.
Topics: Animals; Female; Mice; Pregnancy; Aging; Genitalia, Female; Inflammation; Uterus; Vagina; Single-Cell Analysis
PubMed: 38325365
DOI: 10.1016/j.cell.2024.01.021 -
International Journal of Molecular... Feb 2020Embryo-maternal crosstalk is an important event that involves many biological processes, which must occur perfectly for pregnancy success. This complex communication... (Review)
Review
Embryo-maternal crosstalk is an important event that involves many biological processes, which must occur perfectly for pregnancy success. This complex communication starts from the zygote stage within the oviduct and continues in the uterus up to the end of pregnancy. Small extracellular vesicles (EVs) are part of this communication and carry bioactive molecules such as proteins, lipids, mRNA, and miRNA. Small EVs are present in the oviductal and uterine fluid and have important functions during fertilization and early embryonic development. Embryonic cells are able to uptake oviductal and endometrium-derived small EVs. Conversely, embryo-derived EVs might modulate oviductal and uterine function. In this review, our aim is to demonstrate the role of extracellular vesicles modulating embryo-maternal interactions during early pregnancy.
Topics: Animals; Blastocyst; Cell Communication; Endometrium; Extracellular Vesicles; Female; Humans; Oviducts; Zygote
PubMed: 32050564
DOI: 10.3390/ijms21031163