Reproductive Tract Function Research Articles

Omics-based cutting-edge technologies for identifying predictive biomarkers to measure the impact of air borne particulate matter exposure on male reproductive health

The reproductive lifespan of an individual is a critical determinant of their health, population dynamics, and aging. Research has established a clear association between environmental air pollution, particulate matter (PM), and reproductive health. Recent studies have focused on the impact of air pollution on male reproductive health. Chronic or acute exposure to airborne PM0.1, PM2.5, and PM10 has been found to trigger mitochondrial oxidative stress, double-strand DNA breaks, epigenetic modifications, and endocrine disruption in male reproductive tract functions. Consequently, identifying and validating PM-associated predictive biomarkers, including genes, transcripts, epimutations, proteins, and metabolites, hold promise for improving male reproductive efficiency. Omics-based techniques, such as next-generation sequencing, comparative genomic hybridization, genome-wide association studies, single-cell RNA sequencing, microarray analysis, mass spectroscopy, 2D gel electrophoresis, Raman spectroscopy, near-infrared spectroscopy, and nuclear magnetic resonance, have provided crucial insights into the pathological mechanisms underlying air pollution-related male reproductive health issues. This article presents a comprehensive assessment of existing evidence in this field, offering a methodical examination of findings that hold immense potential for addressing the adverse effects of air pollution on male reproductive health.

Uterine Uptake of Estrogen and Progestogen-Based Radiotracers in Rhesus Macaques with Endometriosis.

Endometriosis is an estrogen-dependent disorder of menstruating primates where tissues similar to the inner lining of the uterus exist "ectopically" outside of the uterus. The ectopic endometrium, like the endometrium within the uterus, expresses estrogen receptors (ER) and progesterone receptors (PR) and undergoes hormone-dependent cell proliferation and bleeding each menstrual cycle. The goal of this study was to conduct abdominopelvic positron emission tomography (PET) scans with computed tomography (CT) imaging of rhesus macaques (Macaca mulatta) using radiotracers that target ER and PR [16α-[18F]fluoroestradiol (FES) and 12-[18F]fluoro-furanyl-nor-progesterone (FFNP)] in individuals with and without endometriosis. We also aimed to determine if menstrual cycle phase and/or the presence of endometriosis affected the uptake of these radiotracers. Rhesus macaques with either clinically diagnosed endometriosis (n = 6) or no endometriosis (n = 4) underwent PET/CT scans with FES. A subset of the animals also underwent PET/CT scans with FFNP. Standard uptake values corrected for body weight (SUVs) were obtained for each radiotracer in target and background tissues (e.g., intestinal). We performed repeated measure analysis of variance tests to determine how uterine and background uptake differed with scan time, phase of the menstrual cycle, and disease state. Abdominopelvic PET/CT could not resolve small, individual endometriotic lesions. However, macaques with endometriosis displayed higher uterine uptake compared to those without the disorder. Radiotracer uptake differed by menstrual cycle phase with increased uterine uptake of both radiotracers in the proliferative phase of the menstrual cycle. Background intestinal uptake of FFNP increased over time after infusion, but only during the proliferative phase. PET/CT with FES and FFNP support the concept that ER and PR levels are altered in individuals with endometriosis. This highlights the impact of the disease on typical reproductive tract function and may provide a novel pathway for the identification of individuals with endometriosis.

Role for Nongenomic Estrogen Signaling in Male Fertility.

Estrogen actions are mediated by both nuclear (n) and membrane (m) localized estrogen receptor 1 (ESR1). Male Esr1 knockout (Esr1KO) mice lacking functional Esr1 are infertile, with reproductive tract abnormalities. Male mice expressing nESR1 but lacking mESR1 (nuclear-only estrogen receptor 1 mice) are progressively infertile due to testicular, rete testis, and efferent ductule abnormalities similar to Esr1KO males, indicating a role for mESR1 in male reproduction. The H2NES mouse expresses only mESR1 but lacks nESR1. The goal of this study was to identify the functions of mESR1 alone in mice where nESR1 was absent. Breeding trials showed that H2NES males are fertile, with decreased litter numbers but normal pup numbers/litter. In contrast to Esr1KO mice, H2NES testicular, and epididymal weights were not reduced, and seminiferous tubule abnormalities were less pronounced. However, Esr1KO and H2NES males both had decreased sperm motility and a high incidence of abnormal sperm morphology. Seminiferous tubule and rete testis dilation and decreased efferent ductule epithelial height characteristic of Esr1KO males were reduced in H2NES. Consistent with this, expression of genes involved in fluid transport and ion movement that were reduced in Esr1KO (Aqp1, Car2, Car14, Cftr) were partially or fully restored to wild-type levels in H2NES. In summary, in contrast to Esr1KO males, H2NES males are fertile and have reduced phenotypic and functional abnormalities in the testis and efferent ductules. Thus, mESR1 alone, in the absence of nESR1, can partially regulate male reproductive tract structure and function, emphasizing its importance for overall estrogen action.

New insights into lumicrine secreted signalling that regulates the function of the mammalian male reproductive tract

New insights into lumicrine secreted signalling that regulates the function of the mammalian male reproductive tract

Knowledge on the male reproductive tract and testicular cancer among adolescents in Austria.

Testicular cancer is the most frequent malignant tumour among young adults. Therefore, regular self-examination for early detection is recommended by all guidelines. The fact that the knowledge of young adults living in Austria on this important topic is unknown, prompted the current investigation. To evaluate the knowledge on anatomy and function of the male reproductive tract and of testicular cancer in particular a German questionnaire recently developed by Anheuser etal. (Urologe 2019;58:1331-1337) was applied. This 4-page questionnaire contains mainly multiple-choice questions. This questionnaire was distributed in three different schools to male and female students in the 11th and 12th school level. A total of 337 students (mean age: 17.3 years; male: n=183; female: n=154) completed the questionnaire. In a simple pictogramm, 63% were able to correctly identify the prostate, 87% the testis and 64% the epididymis. Half of the students (49.3%) could describe the function of the testis. The question regarding the age peak of testicular cancer was correctly answered by 81%, yet 18% believed that testicular cancer is caused by the sexual contact. The purpose of the testicular self-examination was correctly answered by only 54.9% with a higher rate for women (67.5%vs. 44.3%, p=0.001). With a theoretical maximal score of 15, the students reached a mean overall of 10.4 with no sex difference (p>0.05). Differences were noted for the school type: the highest score was present in the Gymnasium (11.2), followed by the Realgymnasium (10.8) and the HTL (9.8; p=0.001). This survey demonstrates relevant knowledge deficits of young adults regarding the male reproductive tract, testicular cancer and self-examination.

Sperm quality metrics were improved by a biomimetic microfluidic selection platform compared to swim-up methods

Sperm selection is an essential component of all assisted reproductive treatments (ARTs) and is by far the most neglected step in the ART workflow in regard to technological innovation. Conventional sperm selection methodologies typically produce a higher total number of sperm with variable motilities, morphologies, and levels of DNA integrity. Gold-standard techniques, including density gradient centrifugation (DGC) and swim-up (SU), have been shown to induce DNA fragmentation through introducing reactive oxygen species (ROS) during centrifugation. Here, we demonstrate a 3D printed, biologically inspired microfluidic sperm selection device (MSSP) that utilizes multiple methods to simulate a sperms journey toward selection. Sperm are first selected based on their motility and boundary-following behavior and then on their expression of apoptotic markers, yielding over 68% more motile sperm than that of previously reported methods with a lower incidence of DNA fragmentation and apoptosis. Sperm from the MSSP also demonstrated higher motile sperm recovery after cryopreservation than that of SU or neat semen. Experiments were conducted side-by-side against conventional SU methods using human semen (n = 33) and showed over an 85% improvement in DNA integrity with an average 90% reduction in sperm apoptosis. These results that the platform is easy-to-use for sperm selection and mimics the biological function of the female reproductive tract during conception.

Endometrial Inflammation and Impaired Spontaneous Decidualization: Insights into the Pathogenesis of Adenomyosis

Adenomyosis is an estrogen-dependent gynecologic disease characterized by the myometrial invasion of the endometrial tissue. This review summarized the current understanding and recent findings on the pathophysiology of adenomyosis, focusing on repeated menstruation, persistent inflammation, and impaired spontaneous decidualization. A literature search was performed in the PubMed and Google Scholar databases from inception to 30 April 2022. Thirty-one full-text articles met the eligibility criteria. Repeated episodes of physiological events (i.e., endometrial shedding, damage, proliferation, differentiation, repair, and regeneration) during the menstrual cycle are associated with inflammation, angiogenesis, and immune processes. The decidualization process in humans is driven by the rise in progesterone levels, independently of pregnancy (i.e., spontaneous decidualization). Adenomyotic cells produce angiogenic and fibrogenic factors with the downregulation of decidualization-associated molecules. This decidualization dysfunction and persistent inflammation are closely related to the pathogenesis of adenomyosis. Recently, it has been found that the reproductive tract microbiota composition and function in women with adenomyosis differ from those without. An increase in opportunistic pathogens and a decrease in beneficial commensals may promote impaired defense mechanisms against inflammation and predispose women to uncontrolled endometrial inflammation. However, currently, there is no direct evidence that adenomyosis is linked to pre-existing inflammation and impaired spontaneous decidualization. Overall, persistent inflammation, impaired spontaneous decidualization, and microbiota dysbiosis (i.e., an imbalance in the composition and function of endometrial microbiota) may be involved in the pathophysiology of adenomyosis.

Maternal obesity and ovarian failure: is leptin the culprit?

At the time of its discovery and characterization in 1994, leptin was mostly considered a metabolic hormone able to regulate body weight and energy homeostasis. However, in recent years, a great deal of literature has revealed leptin's pleiotropic nature, through its involvement in numerous physiological contexts including the regulation of the female reproductive tract and ovarian function. Obesity has been largely associated with infertility, and leptin signalling is known to be dysregulated in the ovaries of obese females. Hence, the disruption of ovarian leptin signalling was shown to contribute to the pathophysiology of ovarian failure in obese females, affecting transcriptional programmes in the gamete and somatic cells. This review attempts to uncover the underlying mechanisms contributing to female infertility associated with obesity, as well as to shed light on the role of leptin in the metabolic dysregulation within the follicle, the effects on the oocyte epigenome, and the potential long-term consequence to embryo programming.

Possible mechanisms in Ficus exasperata ethanol root fraction amelioration of lead-induced corpus cavernosal contractile impairments in male Wistar rats.

Background:Lead exposure is reported to cause impaired male reproductive tract functions often due to elevated oxidative species. F. exasperata leaf extract contains potent phyto-antioxidants with beneficial endothelial functions. Objectives: This study investigates the effect of ethanolic extract of F. exasperata (EEFE) treatment on the corpus cavernosal contractile activity in lead-exposed adult male Wistar rats. Materials & Methods: Corpus cavernosum strips (CS) were excised from control, EEFE only treated (400 mg/kg), lead + EEFE treated and lead only treated (100 mg/kg) male Wistar rats. Cumulative contractile responses of CS to acetylcholine, potassium chloride, and calcium influx were determined. Furthermore, cumulative dose responses to acetylcholine after incubation in LNAME, indomethacin, nifedipine, and acetovanillone were also determined by measuring isometric contractions using Ugo Basile data capsule acquisition system. Results: Relaxation(%) response to cumulative doses of acetylcholine (10-9–10-5 M) was enhanced in EEFE only treated (59%) compared to lead only (45%). Contractile response to KCl (10-60 M) was restrained in control and EEFE cotreated when compared to lead only treated. Preincubation of the CS with nifedipine (10-4 M) suppressed the relaxation(%) in the lead + EEFE co-treated. Preincubation of the CS in indomethacin improved the relaxant response(%) of the CS in EEFE only and lead + EEFE co-treated (53.53% ±2.80 & 54.65%± 2.95 respectively) compared with the lead only treated (45.40%±1.79). Preincubation with L-NAME significantly reduced relaxation response(%) in EEFE only treated group. Relaxation response(%) of the CS was enhanced in the lead + EEFE group after preincubation with acetovanillone. Conclusion: The study suggests that L-type and voltage-gated calcium channels, NO, and potent antioxidant activity, are important in EEFE amelioration of lead-induced contractile impairments.

Dietary tributyrin improves reproductive performance, antioxidant capacity, and ovary function of broiler breeders

The objective of this experiment was to investigate the influence of dietary tributyrin on reproduction performance and ovary function of broiler breeders with different egg laying rate. Two hundred fifty-six AA broiler breeders (48-wk-old) were allocated to 4 treatment in a 2 × 2 factorial arrangement with the main effects of tributyrin supplementation (0 and 1,000 mg/kg tributyrin [TRI]) and 2 egg laying rate levels (average [AR, 81.01 ± 0.79%] and low [LR, 70.98 ± 0.95%]). The results shown that the LR breeders presented higher egg weight, but lower egg laying rate, qualified egg rate and feed efficiency than the AR breeders (P(laying) < 0.05). Also, the superoxidase dismutase (SOD) activity in magnum was lower while malondialdehyde (MDA) was higher in ovary and magnum of LR breeders than that in the AR breeders (P(laying) < 0.05). Dietary supplementation with tributyrin significantly enhanced egg weight (P(TRI) < 0.05), increased albumen height as well as Haugh unit (HU) in AR breeders (P(interaction) < 0.05), and also had higher total antioxidant capacity (T-AOC) and lower MDA in ovary (P(TRI) < 0.05). The cell apoptosis rate and proapoptosis related gene expression (caspase 8, 9 and Bax) in the ovary of LR breeders was higher, while anti-apoptosis related gene (Bcl-2) expression were lower in LR breeders when compared with the AR breeders (P(laying) < 0.05). Dietary supplementation with tributyrin decreased the cell apoptosis rate and downregulated caspase 9 expression in LR breeders (P(Interaction) < 0.05), up-regulated the Bcl-2 expression in both 2 breeders (P(TRI) < 0.05). These findings suggest that the breeders with lower egg laying rate also characterized by deteriorate ovary function indicated by lower antioxidant capacity and higher cell apoptosis rate. Dietary supplementation with tributyrin increased egg albumen quality, decreased ovarian proapoptosis related gene expression to improve reproductive tract function; and the positive effect on egg albumen quality is more pronounced in average reproductive breeders.

Male fertility in mice requires classical and nonclassical androgen signaling.

Molecular mechanisms by which androgens signal through the androgen receptor (AR) to maintain male fertility are poorly understood. Transgenic mice were produced expressing mutant ARs that can only (1) alter gene transcription through the classical response pathway (AR-C) or (2) activate kinase signaling cascades via the nonclassical pathway (AR-NC). AR-C is sufficient to produce sperm and fertility. Haploid germ cell production, the blood-testis barrier, and spermatid migration are supported by AR-NC. Gene expression essential for chromosome synapsis during meiosis requires AR-C. We identify targets of androgen signaling required for male fertility and provide a mechanistic explanation for meiotic germ cell arrest in the absence of androgen signaling. Prostate differentiation occurs with AR-C alone, but full development requires synergistic nonclassical signaling. Both AR signaling pathways are necessary for normal male reproductive tract development and function, validating our mouse models for studies of AR functions in other target tissues.

YAP and TAZ are required for the postnatal development and the maintenance of the structural integrity of the oviduct.

The development of the Müllerian ducts into the female reproductive tract requires the coordination of multiple signaling pathways that regulate proliferation, apoptosis and differentiation. The Hippo pathway has been reported to interact with several pathways with established roles in Müllerian duct development; yet, its potential roles in reproductive tract development and function remain mostly uncharacterized. The objective of this study was therefore to characterize the roles of the Hippo transcriptional coactivators YAP and TAZ in the female reproductive tract using transgenic mouse models. This report shows that the concomitant conditional inactivation of Yap and Taz in the mouse Müllerian duct mesenchyme results in postnatal developmental defects of the oviduct. Most notably, discontinuities in the myosalpinx layer lead to the progressive formation of cystic dilations of the isthmus. These defects prevented embryo transport and subsequent implantation in older animals, causing infertility. The loss of YAP/TAZ did not appear to affect other biological processes known to be required for the maintenance of oviductal wall integrity, such as TGF-β/SMAD and Notch signaling and the biogenesis of miRNA, suggesting that the Hippo pathway acts independently of these processes to direct oviduct development. Taken together, these results suggest redundant and essential roles for YAP and TAZ in the postnatal development of the oviduct and the maintenance of its structural integrity.

A Study of Histochemical Characteristics of Mucosubstances in Normal Endocervical Glands

Background: The apical epithelial surfaces of mammalian respiratory, gastrointestinal, and reproductive tracts are coated by mucus, a mixture of water, ions, glycoproteins, proteins, and lipids. Mucins are mainly of two types- Neutral and Acidic. Mucus plays an important role in reproductive function and defence of the female reproductive tract. Objectives: To know the mucin distribution in normal endocervical glands. Methodology: This is a retrospective, observational , analytical, case control study aimed to evaluate mucin histochemical pattern in normal endocervical glands. Ten histologically proven blocks of normal endocervical glands were taken. Tissue sections were stained by, PAS, PAS-diastase, Phenylhydrazine-PAS, Alcian blue pH 2.5, Alcian Blue pH 1, combined Alcian blue-PAS, Aldehyde fuschin and combined Aldehyde fuchsin Alcian blue techniques. Results: Results were tabulated according to colour intensity into different grades ranging from + to ++++. Regarding mucin histochemistry of normal endocervical glands; the epithelium and glands show mixture of both neutral and acidic mucins. Acidic mucins are more in amount than neutral. In acidic mucins, sialomucins are predominantly seen. Conclusion: Mucin histochemical patterns serve as valuable, cost-effective tool for diagnosis in histopathology and for the researchers in histology, where a slight change in the mucin pattern may help in the early diagnosis of the disease process.

ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile.

Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor-α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to its rarity, mutations in ESR1 gene and the underlying molecular mechanisms of EIS have not been thoroughly studied. Here, we investigate known ESR1 mutants, Q375H and R394H, associated with EIS patients using in vitro and in vivo systems. Comparison of the transcriptome and deoxyribonucleic acid methylome from stable cell lines of both Q375H and R394H clinical mutants shows a differential profile compared with wild-type ERα, resulting in loss of estrogen responsiveness. Molecular dynamic simulation shows that both ESR1 mutations change the ERα conformation of the ligand-receptor complexes. Furthermore, we generated a mouse model Esr1-Q harboring the human mutation using CRISPR/Cas9 genome editing. Female and male Esr1-Q mice are infertile and have similar phenotypes to αERKO mice. Overall phenotypes of the Esr1-Q mice correspond to those observed in the patient with Q375H. Finally, we explore the effects of a synthetic progestogen and a gonadotropin-releasing hormone inhibitor in the Esr1-Q mice for potentially reversing the impaired female reproductive tract function. These findings provide an important basis for understanding the molecular mechanistic consequences associated with EIS.

Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis.

Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the β value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).

Evaluation of the association between exosomal levels and female reproductive system and fertility outcome during aging: a systematic review protocol

BackgroundExosomes may have critical roles in the maternal-embryo cross-talk for the recognition and maintenance of pregnancy during maternal aging. Exosomes have the capability to carry developmental signaling molecules with the ability to modulate gene expressions and affect growth and regulation of embryo during pregnancy. Systematic review aims to evaluate age-related alterations in the exosomal content and functions that can influence the reproductive performance in human and animal models as conveyors of senescence signals.MethodsA literature search of electronic databases including MEDLINE (PubMed), Embase, ProQuest, Scopus, Google Scholar, WHO, SID, MAGIRAN, and Barakat will be conducted. Following the online search, articles will be screened by two independent reviewers according to inclusion and exclusion criteria. Eligible studies will be critically appraised by reviewers at the study level for methodological quality using Joanna Briggs Institute’s standardized critical appraisal tools. The extracted data from selected studies will cover the study populations, methods, current evidence about the physiological role of extracellular vesicles and exosomes in reproductive system, relevant outcomes, and possible conclusions about the effectiveness of exposure.DiscussionRegarding the role of exosomes and their cargoes in the function of reproductive tract, the possible beneficial or adverse effects following exosomal administration from younger women to older women will be evaluated in the systematic review. As a result, exosome therapy could be suggested as a novel therapeutic agent if the favorable results are identified.

Attention Worthy: Prenatal Phthalate Exposure and Subsequent ADHD Diagnosis.

Open in a separate window Exposure to phthalates, a class of endocrine-disrupting chemicals (EDCs) used in plastics manufacture, is ubiquitous.1 Some research suggests that phthalates may adversely affect neurodevelopment,2,3,4 potentially increasing the risk of attention deficit/hyperactivity disorder (ADHD).5,6 A study published in Environmental Health Perspectives found that prenatal exposure to certain phthalate metabolites was associated with increased odds of clinically confirmed ADHD in a group of 3-year-old children.7 Originally, phthalate research focused on reproductive end points, owing to the similarity between these chemicals and the steroidal hormones that control reproductive tract development and function. However, epidemiological studies have also reported associations between phthalate exposure and behaviors linked to ADHD, although the findings have been inconsistent.6,8,9,10,11,12 Open in a separate window More than 5% of children in the United States have ADHD, a disorder characterized by impaired focus and working memory. Improved diagnosis may partly, but not entirely, explain recent increases in prevalence of the disorder, which appears to have both genetic and environmental underpinnings.14 Image: © gali estrange/Shutterstock.

Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme.

WNT signaling plays essential roles in the development and function of the female reproductive tract. Although crosstalk with the Hippo pathway is a key regulator of WNT signaling, whether Hippo itself plays a role in female reproductive biology remains largely unknown. Here, we show that conditional deletion of the key Hippo kinases Lats1 and Lats2 in mouse Müllerian duct mesenchyme cells caused them to adopt the myofibroblast cell fate, resulting in profound reproductive tract developmental defects and sterility. Myofibroblast differentiation was attributed to increased YAP and TAZ expression (but not to altered WNT signaling), leading to the direct transcriptional upregulation of Ctgf and the activation of the myofibroblast genetic program. Müllerian duct mesenchyme cells also became myofibroblasts in male mutant embryos, which impeded the development of the male reproductive tract and resulted in cryptorchidism. The inactivation of Lats1/2 in differentiated uterine stromal cells in vitro did not compromise their ability to decidualize, suggesting that Hippo is dispensable during implantation. We conclude that Hippo signaling is required to suppress the myofibroblast genetic program and maintain multipotency in Müllerian mesenchyme cells.

Type I IFNs in the female reproductive tract: The first line of defense in an ever-changing battleground.

The primary function of the female reproductive tract (FRT) is to enable successful reproduction, yet the biologic mechanisms required to accomplish this, which include fluctuating sex hormones and tolerance of semen and a semi-allogeneic fetus, can leave this unique mucosal environment susceptible to pathogenic challenge. Consequently, the FRT has evolved specialized innate and adaptive immune responses tailored to protecting itself from infection without compromising reproductive success. A family of innate immune cytokines that has emerged as important regulators of these immune responses is the type I IFNs. Type I IFNs are typically rapidly produced in response to pathogenic stimulation and are capable of sculpting pleotropic biologic effects, including immunomodulation, antiproliferative effects, and inducing antiviral and bactericidal molecules. Here, we review what is currently known about type I IFN-mediated immunity in the FRT in human, primate, and murine models and explore their importance with respect to three highly relevant FRT infections: HIV, Zika, and Chlamydia.

Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation.

To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.