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Molecular and Cellular Endocrinology Feb 2024The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and... (Review)
Review
The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and 12-weeks' gestation. One way to quantify potential harm to the fetus in the first trimester is to measure a corollary effect on the placenta. Placental biomarkers are widely present in maternal circulation, cord blood, and placental tissue biopsied at birth or at the time of pregnancy termination. Here we evaluate ten diverse pathways involving molecules expressed in the first trimester human placenta based on their relevance to normal fetal development and to the hypothesis of placental-fetal endocrine disruption (perturbation in development that results in abnormal endocrine function in the offspring), namely: human chorionic gonadotropin (hCG), thyroid hormone regulation, peroxisome proliferator activated receptor protein gamma (PPARγ), leptin, transforming growth factor beta, epiregulin, growth differentiation factor 15, small nucleolar RNAs, serotonin, and vitamin D. Some of these are well-established as biomarkers of placental-fetal endocrine disruption, while others are not well studied and were selected based on discovery analyses of the placental transcriptome. A literature search on these biomarkers summarizes evidence of placenta-specific production and regulation of each biomarker, and their role in fetal reproductive tract, brain, and other specific domains of fetal development. In this review, we extend the theory of fetal programming to placental-fetal programming.
Topics: Infant, Newborn; Pregnancy; Humans; Female; Placenta; Pregnancy Trimester, First; Fetus; Biomarkers; Gestational Age
PubMed: 37852527
DOI: 10.1016/j.mce.2023.112075 -
Acta Biomaterialia Jul 2023Pathologies associated with uteroplacental hypoxia, such as preeclampsia are among the leading causes of maternal and perinatal morbidity in the world. Its fundamental...
Pathologies associated with uteroplacental hypoxia, such as preeclampsia are among the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and endothelial cells against a collagen extracellular matrix in a microfluidic platform. The model yields a functional syncytium with barrier properties, polarization, secretion of relevant extracellular membrane components, thinning of the materno-fetal space, hormone secretion, and transporter function. The model is exposed to low oxygen conditions and perfusion flow is modulated to induce a pathological environment. This results in reduced barrier function, hormone secretion, and microvilli as well as an increased nuclei count, characteristics of preeclamptic placentas. The model is implemented in a titer plate-based microfluidic platform fully amenable to high-throughput screening. We thus believe this model could aid mechanistic understanding of preeclampsia and other placental pathologies associated with hypoxia/ischemia, as well as support future development of effective therapies through target and compound screening campaigns. STATEMENT OF SIGNIFICANCE: The human placenta is a unique organ sustaining fetal growth but is also the source of severe pathologies, such as preeclampsia. Though leading cause of perinatal mortality in the world, preeclampsia remains untreatable due to a lack of relevant in vitro placenta models. To better understand the pathology, we have developed 3D placental barrier models in a microfluidic device. The platform allows parallel culture of 40 perfused physiological miniaturized placental barriers, comprising a differentiated syncytium and endothelium that have been validated for transporter functions. Exposure to a hypoxic and ischemic environment enabled the mimicking of preeclamptic characteristics in high-throughput, which we believe could lead to a better understanding of the pathology as well as support future effective therapies development.
Topics: Pregnancy; Female; Humans; Placenta; Pre-Eclampsia; Endothelial Cells; Hypoxia; Ischemia; Lab-On-A-Chip Devices; Hormones
PubMed: 37116636
DOI: 10.1016/j.actbio.2023.04.033 -
International Journal of Molecular... Dec 2023Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the... (Review)
Review
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring.
Topics: Child; Female; Pregnancy; Humans; Diabetes, Gestational; Cardiovascular Diseases; Placenta; Metabolic Syndrome; Fibroblast Growth Factors; Hormones
PubMed: 38139126
DOI: 10.3390/ijms242417298 -
American Family Physician Aug 2023Acute pelvic pain is defined as noncyclic, intense pain localized to the lower abdomen and/or pelvis, with a duration of less than three months. Signs and symptoms are...
Acute pelvic pain is defined as noncyclic, intense pain localized to the lower abdomen and/or pelvis, with a duration of less than three months. Signs and symptoms are often nonspecific. The differential diagnosis is broad, based on the patient's age and pregnancy status and gynecologic vs. nongynecologic etiology. Nongynecologic etiologies include gastrointestinal, urinary, and musculoskeletal conditions. Urgent gynecologic conditions include ectopic pregnancy, ruptured ovarian cyst, adnexal torsion, and pelvic inflammatory disease. Approximately 40% of ectopic pregnancies are misdiagnosed at the presenting visit. Urgent nongynecologic conditions include appendicitis and pyelonephritis. Less urgent etiologies include sexually transmitted infections, pelvic floor myofascial pain, dysmenorrhea, and muscle strain. Approximately 15% of untreated chlamydia infections lead to pelvic inflammatory disease. History and physical examination findings guide laboratory testing. Questions should focus on the type, onset, location, and radiation of pain; timing and duration of symptoms; aggravating and relieving factors; and associated symptoms. Performing a urine pregnancy test or beta human chorionic gonadotropin test is an important first step for sexually active, premenopausal patients. Imaging options should be considered, with transvaginal ultrasonography first, followed by computed tomography. Magnetic resonance imaging can be useful if ultrasonography and computed tomography are nondiagnostic.
Topics: Female; Humans; Pregnancy; Pelvic Inflammatory Disease; Pelvic Pain; Acute Pain; Chorionic Gonadotropin, beta Subunit, Human; Dysmenorrhea; Pregnancy, Ectopic
PubMed: 37590858
DOI: No ID Found -
The American Journal of Pathology Dec 2023Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still...
Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.
Topics: Humans; Rats; Pregnancy; Female; Animals; Placenta; Polycystic Ovary Syndrome; Hyperandrogenism; Uterus; Arteries; Dihydrotestosterone; Insulin; Uterine Artery
PubMed: 37689383
DOI: 10.1016/j.ajpath.2023.08.008 -
Steroids Aug 2023Cytochrome P450 aromatase (AROM) and steroid sulfatase (STS) are the two key enzymes for the biosynthesis of estrogens in human, and maintenance of the critical balance... (Review)
Review
Cytochrome P450 aromatase (AROM) and steroid sulfatase (STS) are the two key enzymes for the biosynthesis of estrogens in human, and maintenance of the critical balance between androgens and estrogens. Human AROM, an integral membrane protein of the endoplasmic reticulum, is a member of the cytochrome P450 superfamily. It is the only enzyme to catalyze the conversion of androgens with non-aromatic A-rings to estrogens characterized by the aromatic A-ring. Human STS, also an integral membrane protein of the endoplasmic reticulum, is a Ca-dependent enzyme that catalyzes the hydrolysis of sulfate esters of estrone and dehydroepiandrosterone to the unconjugated steroids, the precursors of the most potent forms of estrogens and androgens, namely, 17β-estradiol, 16α,17β-estriol, testosterone and dihydrotestosterone. Expression of these steroidogenic enzymes locally within organs and tissues of the endocrine, reproductive, and central nervous systems is the key for maintaining high levels of the reproductive steroids. The enzymes have been drug targets for the prevention and treatment of diseases associated with steroid hormone excesses, especially in breast, endometrial and prostate malignancies. Both enzymes have been the subjects of vigorous research for the past six decades. In this article, we review the important findings on their structure-function relationships, specifically, the work that began with unravelling of the closely guarded secrets, namely, the 3-D structures, active sites, mechanisms of action, origins of substrate specificity and the basis of membrane integration. Remarkably, these studies were conducted on the enzymes purified in their pristine forms from human placenta, the discarded and their most abundant source. The purification, assay, crystallization, and structure determination methodologies are described. Also reviewed are their functional quaternary organizations, post-translational modifications and the advancements made in the structure-guided inhibitor design efforts. Outstanding questions that still remain open are summarized in closing.
Topics: Humans; Female; Pregnancy; Steryl-Sulfatase; Placenta; Androgens; Aromatase; Estrogens; Estrone; Membrane Proteins
PubMed: 37207843
DOI: 10.1016/j.steroids.2023.109249 -
The FEBS Journal Nov 2023Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small...
Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone-related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone-related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid-disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors.
Topics: Animals; Humans; Female; Pregnancy; Prealbumin; Rafoxanide; Placenta; Thyroid Hormones; Amyloidosis; Anthelmintics; Anti-Infective Agents
PubMed: 37522420
DOI: 10.1111/febs.16915 -
Clinica Chimica Acta; International... Jan 2024Reproductive biomarkers are important regulators in women, especially during pregnancy and childbirth. Because of their essential role in women's health, the discovery... (Review)
Review
Reproductive biomarkers are important regulators in women, especially during pregnancy and childbirth. Because of their essential role in women's health, the discovery and quantification of reproductive biomarkers is of great clinical importance. Nowadays, there are many detection strategies to detect these biomarkers, including VEGF, human chorionic gonadotropin (hCG), etc. Consider the limitations and problems of conventional diagnostic methods, new methods are being developed, one of the most important being methods based on nanotechnology. This review includes a review of methods for diagnosing reproductive biomarkers, ranging from mainstream to nanotechnology-based methods. The bulk of this article is an in-depth introduction to the latest advances in biosensor and nanosensor research for the detection and quantitative identification of reproductive biomarkers.
Topics: Pregnancy; Humans; Female; Reproduction; Chorionic Gonadotropin; Biomarkers; Parturition
PubMed: 37992849
DOI: 10.1016/j.cca.2023.117668 -
Reproduction in Domestic Animals =... Sep 2023Methods to diagnose and monitor equine pregnancy continue to advance with improved instrumentation enabling the development of novel, non-invasive approaches to assess... (Review)
Review
Methods to diagnose and monitor equine pregnancy continue to advance with improved instrumentation enabling the development of novel, non-invasive approaches to assess fetal well-being and viability using ultrasound and endocrine testing. From early embryonic loss to placentitis, that is typically encountered later in gestation, fetal viability and development as well as placental function can be evaluated using two fundamentally different, structural and functional, approaches. Ultrasound provides structural information on embryonic and fetal growth using such parameters as combined thickness of the uterus and placenta (CTUP), visual assessment of fetal fluids, activity, heart rate and multiple biometrics involving the fetal head and eyes, limbs and joints among many others, depending on the stage of gestation. Endocrine profiles that include progesterone and 5α-dihydroprogesterone, other metabolites, androgens and estrogens can be evaluated simultaneously using liquid chromatography-tandem mass spectrometry (LC-MS/MS) providing more functional information on fetal and placental competence and development. Endocrine information can be used in making clinical decisions including the need for progestin supplementation or when it can cease, and even estimating gestational stage in mares that cannot be easily palpated or scanned, as with mini-breeds or rancorous animals most notably. When used together, monitoring gestation by ultrasound and hormonal analysis provides unusual insight into feto-placental well-being and the progress of pregnancy, helping to identify problems needing therapeutic intervention.
Topics: Pregnancy; Horses; Animals; Female; Placenta; Chromatography, Liquid; Tandem Mass Spectrometry; Progesterone; Fetal Development
PubMed: 37191550
DOI: 10.1111/rda.14392