Uterine Fluid in Pregnancy: A Biological and Clinical Outlook

In mammals, the uterine fluid volume is dynamically regulated during early pregnancy, the disruption of which, by hormonal or nonhormonal factors, can compromise embryonic development, intrauterine embryonic location, and embryo implantation. The uterine glands have a pivotal role in regulating the molecular contents of uterine fluid, such as maintaining normal ion strength and secreting essential proteins, such as leukemia inhibitory factor (LIF), required for embryonic development and successful implantation. Extracellular vesicles (EVs) that carry a variety of macromolecules (e.g., proteins or RNAs) have been detected in the uterine fluid of mammalian species, including humans, and have the potential to mediate embryo–uterine interactions. Functional noncoding (nc)RNAs encapsulated within and floating outside EVs can be transferred into floating blastocysts, suggesting a putative function in the genetic and/or epigenetic regulation of embryonic features, which might modulate embryonic and placental development. Maternal exposures or eating habits have been reported to change the intrauterine (uterine fluid) environment, which might influence embryo quality and epigenetic regulation of gene expression. This mechanism might help explain the observed epigenetic inheritance of maternally acquired traits, as in the case of metabolic disorders. Once considered a simple medium for sperm and embryo transport, the functional spectrum of uterine fluid is now expanding. Novel molecular players, such as extracellular vesicles and mobile RNAs, have been detected in the uterine fluid of livestock, rodents, and humans. These novel molecules, together with previously known ions and proteins, ensure uterine fluid homeostasis and facilitate embryo–maternal interactions. Here, we propose that these molecules may also carry information that mirrors maternal environmental exposure and possibly relay such information to the embryo via uterine fluid, generating long-term epigenetic effects on the offspring via embryonic and placental programming. Moreover, the development of systematic profiling of uterine fluid molecular signatures may now hold promise, relying on high-throughput methods and non-invasive biomarkers for clinical use. Once considered a simple medium for sperm and embryo transport, the functional spectrum of uterine fluid is now expanding. Novel molecular players, such as extracellular vesicles and mobile RNAs, have been detected in the uterine fluid of livestock, rodents, and humans. These novel molecules, together with previously known ions and proteins, ensure uterine fluid homeostasis and facilitate embryo–maternal interactions. Here, we propose that these molecules may also carry information that mirrors maternal environmental exposure and possibly relay such information to the embryo via uterine fluid, generating long-term epigenetic effects on the offspring via embryonic and placental programming. Moreover, the development of systematic profiling of uterine fluid molecular signatures may now hold promise, relying on high-throughput methods and non-invasive biomarkers for clinical use. a gynecological condition characterized by the abnormal presence of endometrial tissue in the myometrium of the uterus. medical procedure where a small amount of amniotic fluid containing fetal cells from the amniotic sac is collected and used for fetal genetic examination. abnormal number of chromosomes in a cell, originating during cell division and associated with human birth defects and cancers. a specific stage of an early embryonic development comprising an inner cell mass and trophoblast. concept where initial small changes can make large differences in a later state via a deterministic nonlinear system. villi sprouted from the chorion providing a contact area with maternal blood and responsible for efficient exchange of gases and nutrients for fetal development. forms a closed continuous loop. in humans, embryo implantation usually occurs in the fundus; in rodents, embryo implantation occurs at the antimesometrial pole along the uterine horn. a type of chemokines whose two N-terminal cysteines are separated by ‘X’ amino acids. a chloride channel in the cell membrane. aka, ‘fetal programming’ or ‘Barker’s hypothesis’; developed by Barker and colleagues from epidemiological studies to describe the permanent effects of undernutrition in utero on infant health, and the correlation of infant birth weight with subsequent risks for heart disease and metabolic disorders. process that occurs during the early stage of pregnancy when a floating blastocyst adheres to the endometrium and implants within the uterus. This process is critical to pregnancy establishment. parental experience that can be passed down to future generations in a non-DNA sequence-based manner. the process whereby epididymal-derived vesicles fuse with sperm and transfer information into maturing sperm in the epididymis. a membrane-bound Na+ channel. include exosomes and ectosomes: phospholipid bilayer-enclosed particles released from cells into the extracellular environment, mediating long-term communication. belongs to HLA nonclassical class 1 heavy chain paralogs and has a role in immune tolerance in pregnancy. gynecological condition where a distally blocked fallopian tube fills with fluid. the mass of cells in a blastocyst that will give rise to the entire fetal structure. cytokine produced by activated macrophages to mediate inflammatory responses. an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. nonprotein-coding transcripts >200 nucleotides long. uterine epithelium closing over and making contact with blastocysts, thereby facilitating embryo implantation. abnormal metabolic processes in the body; examples include obesity and diabetes. cell-free RNAs, such as those in EVs, and in bodily fluids outside EVs. stem from a single defective gene on autosomes that are inherited according to Mendel’s laws. glycoprotein that protects from infection by preventing the pathogen from reaching the cell surface. diagnosis focus on anatomic and physiological problems before (preimplantation) or during early gestation. genetic detection of preimplantation embryos or oocytes before fertilization. genetic detection of preimplantation embryos or oocytes before fertilization that does not screen for a specific disease. small haploid cell that forms during oogenesis but lacks the ability to be fertilized. the only proprotein convertase associated with uterine remodeling and embryo implantation. the second most important human blood group system; usually used to determine the risk of hemolytic diseases in the newborn. belongs to a serine/threonine kinase subfamily that increases the protein abundance and/or ion channel activity. a member of the voltage-gated ion channel superfamily that regulates calcium homeostasis. derived from mature tRNAs. cells forming the outer layer of a blastocyst that develop into a large part of the placenta. a method used to characterize genetic diversity and detect minor variants in a complex genetic population. a total of all secreted molecules and elements in the uterine fluid. term proposed by Von Hoffman in 1884, referring to cells surrounded by fetal villi in the placental secretion; used to describe all uterine secretions nurturing an embryo in utero; also known as the ‘histotroph.’ extracellular membrane vesicles released into the uterine luminal fluid. protein that stimulates vasculogenesis and angiogenesis. a group of voltage-gated Ca2+-permeable ion channels. also called aquaporins; integral membrane proteins facilitating water transport to and from cells.