Ultrasound-driven facile fabrication of Pd doped SnO2 hierarchical superstructures: Structural, growth mechanism, dermatoglyphics, and anti-cancer activity.

This research introduces a novel method that leverages Spirulina extract (S.E) as a bio-surfactant in the ultrasound-assisted synthesis (UAS) of Pd3+ (0.25-10 mol%) doped tin oxide (SnO2) self-assembled superstructures. Nanotechnology has witnessed significant advancements in recent years, driven by the exploration of novel synthesis methods and the development of advanced nanomaterials tailored for specific applications. Metal oxide nanoparticles, particularly SnO2, have garnered considerable attention due to their versatile properties and potential applications in various fields, including gas sensing, catalysis, and biomedical engineering. The study explores how varying influential parameters like S.E concentration, sonication time, pH, and sonication power can influence the resulting superstructures' morphology, size, and shape. A theoretical model for forming different hierarchical superstructures (HS) is proposed. X-ray diffraction (XRD) analysis confirms the crystalline tetragonal rutile phase of the SnO2:Pd HS. Raman spectroscopy reveals a red shift in the A1g mode, indicating phonon confinement due to various defects in the SnO2 structure. Further characterization using transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) provides insights into particle size, surface morphology, elemental composition, and binding energy. The study also demonstrates the application of optimized SnO2:3Pd HS in developing latent fingerprints (LFPs) on different surfaces using a simple powder dusting (PD) method, with the fingerprints (FPs) visualized under normal light. A mathematical model developed in Python-based software is used to analyze various features of the developed FPs, including pore properties such as number, position, inter-spacing, area, and shape. Additionally, an in vitro MTT assay shows concentration-dependent anticancer activity of SnO2:3Pd nanoparticles (NPs) on MCF7 cell lines, highlighting their potential as a promising cancer treatment option. Overall, the study suggests that the optimized HS can serve as multifunctional platforms for biomedical and dermatoglyphics applications, demonstrating the versatility and potential of the synthesized materials.

Tetrahydrobenzothiophene derivatives ameliorate Mia PaCa-2 cell progression and induces apoptosis via inhibiting EGFR2 tyrosine kinase signal.

A series of new thiophene analogues with acarbonitrile-basedmoiety were designed and synthesized via structural optimization. The conjugates were assessed for their in-vitro cytotoxic activity against a human pancreatic cancer cell line (Mia PaCa-2) and among them compound 5b showed IC50 value of 13.37 ± 2.37 µM. The compounds 5b (20 µM & 25 µM) and 7c (30 & 35 µM) also showed reduced clonogenicity, enhanced ROS and decreased mitochondrial membrane potential in Mia PaCa-2 cells. Treatment with these compounds also increased apoptotic population as evident with the double staining assay. Among the evaluated series, compounds 5b, 5g, 7c, and 9a attained a greater inhibitory potency than first generation's reversible EGFR inhibitor, Gefitinib. EGFR2 enzyme inhibitory studies revealed that 5b efficiently and arbitrarily suppressed the development of EGFR2 dependent cells and inhibited the enzymatic activity with an IC50 value of 0.68 µM; interestingly, the most effective molecule 5b with N-methyl piperazine substitution, has 1.29-fold greater potency than well-known EGFR inhibitor Gefitinib and increased Gefitinib's anti-growth impact with 2.04 folds greater against Mia PaCa-2. The in-vitro studies were validated with in-silico docking studies wherein compounds 5b and 7c exhibited binding energies of -8.2 and -7.4 Kcal/mol respectively. The present study reveals that tetrahydrobenzothiophene based analogues could be a promising lead for the evolution of potent chemo preventives over pancreatic cancer.

Potential applications of Fe3+-activated Sr9Al6O18 nanophosphors for fingerprint detection, oxidative stress, and thrombosis treatment.

This study reports on the synthesis of Fe3+-activated Sr9Al6O18 nanophosphors (SAO:Fe NPs) using a simple solution combustion process, which emits a pale green light and possesses excellent fluorescence properties. An in-situ powder dusting method was utilized to extract unique ridge features of latent fingerprints (LFPs) on various surfaces using ultra-violet 254 nm excitation. The results showed that SAO:Fe NPs possess high contrast, high sensitivity, and no background interference, enabling the observation of LFPs for longer periods. Poroscopy, which is the examination of sweat pores on the skin's papillary ridges, is important in the identification process, and the YOLOv8x program based on deep convolutional neural networks was used to study the features visible in FPs. The potential of SAO:Fe NPs to ameliorate oxidative stress and thrombosis was analyzed. The results showed that SAO:Fe NPs have antioxidant properties by scavenging 2,2-diphenylpicrylhydrazyl (DPPH) and normalized the stress markers in NaNO2-induced oxidative stress in Red Blood Cells (RBC). In addition, SAO:Fe inhibited platelet aggregation induced by adenosine diphosphate (ADP). Therefore, SAO:Fe NPs may have potential applications in advanced cardiology and forensic sciences. Overall, this study highlights the synthesis and potential applications of SAO:Fe NPs, which can enhance the sensitivity and specificity of fingerprint detection and provide insights into developing novel treatments for oxidative stress and thrombosis.

Exploration of NMI-MsCl mediated amide bond formation for the synthesis of novel 3,5-substituted-1,2,4-oxadiazole derivatives: synthesis, evaluation of anti-inflammatory activity and molecular docking studies.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives 9a-e and 10a-e in good to excellent yields by employing NMI-MsCl mediated amide bond formation reaction. The anti-inflammatory potential of the newly synthesized compounds were evaluated by anti-denaturation assay using diclofenac sodium as the reference drug. The compounds 9a and 9d demonstrated promising activity profile when compared to the reference standard. The SAR and molecular docking studies were also carried out for obtaining more details about the profound activity profile of the synthesized molecules. The synthesized compounds were docked against two target proteins TGF-ß and IL-1 by AutoDock vina and Auto Dock 4.2.

Precise Sn-Doping Modulation for Optimizing CdWO4 Nanorod Photoluminescence.

The cadmium tungstate rods have been given much attention due to their potential for usage in numerous luminescent applications. We have prepared single crystalline Sn-doped Cd1-xSnxWO4 (where x = 0, 1, 3, and 5%) nanorods (NRDs) and characterized them using refined X-ray diffraction and TEM analysis, revealing a monoclinic phase and a crystallite size that decreased from 62 to 38 nm as Sn concentration increased. Precise Sn doping modulation in CdWO4 NRDs causes surface recombination of electrons and holes, which causes the PL intensity to decrease as the Sn content rises. The chromaticity diagram shows that an increase in the Sn content caused a change in the emission color from sky blue to light green, which was attributed to the increased defect density. The photoluminescence time decay curve of all samples fit well with double-order exponential decay, and the average decay lifetime was found to be 1.11, 0.93, and 1.16 ns for Cd1-xSnxWO4, x = 0, 1, and 5%, respectively. This work provides an understanding of the behavior of Sn-doped CdWO4 NRDs during electron transitions and the physical nature of emission that could be used in bio-imaging, light sources, displays, and other applications.

Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss.

Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.

Exploring the Impact of Climatic Variables on Arecanut Fruit Rot Epidemic by Understanding the Disease Dynamics in Relation to Space and Time.

To understand the spatio-temporal dynamics and the effect of climate on fruit rot occurrence in arecanut plantations, we evaluated the intensity of fruit rot in three major growing regions of Karnataka, India for two consecutive years (2018 and 2019). A total of 27 sampling sites from the selected regions were monitored and the percentage disease intensity (PDI) was assessed on 50 randomly selected palms. Spatial interpolation technique, ordinary kriging (OK) was employed to predict the disease occurrence at unsampled locations. OK resulted in aggregated spatial maps, where the disease intensity was substantial (40.25-72.45%) at sampling sites of the Malnad and coastal regions. Further, Moran's I spatial autocorrelation test confirmed the presence of significant spatial clusters (p ≤ 0.01) across the regions studied. Temporal analysis indicated the initiation of disease on different weeks dependent on the sampling sites and evaluated years with significant variation in PDI, which ranged from 9.25% to 72.45%. The occurrence of disease over time revealed that the epidemic was initiated early in the season (July) at the Malnad and coastal regions in contrary to the Maidan region where the occurrence was delayed up to the end of the season (September). Correlations between environmental variables and PDI revealed that, the estimated temperature (T), relative humidity (RH) and total rainfall (TRF) significantly positively associated (p = 0.01) with disease occurrence. Regression model analysis revealed that the association between Tmax, RH1 and TRF with PDI statistically significant and the coefficients for the predictors Tmax, RH1 and TRF are 1.731, 1.330 and 0.541, respectively. The information generated in the present study will provide a scientific decision support system, to generate forecasting models and a better surveillance system to develop adequate strategies to curtail the fruit rot of arecanut.

Design, synthesis and molecular docking studies of some 1-(5-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)piperazine derivatives as potential anti-inflammatory agents.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives in good to excellent yields. The anti-inflammatory potential of the newly synthesized compounds was evaluated by anti-denaturation assay using diclofenac sodium as the reference standard. Some of the compounds exhibited profound activity profile when compared to the standard drug. The molecular docking and SAR studies were carried out at the later stage for gaining more insights about the promising activity profile of the synthesized molecules.

Assessment of the Spatial Distribution and Risk Associated with Fruit Rot Disease in Areca catechu L.

Phytophthora meadii (McRae) is a hemibiotrophic oomycete fungus that infects tender nuts, growing buds, and crown regions, resulting in fruit, bud, and crown rot diseases in arecanut (Areca catechu L.), respectively. Among them, fruit rot disease (FRD) causes serious economic losses that are borne by the growers, making it the greatest yield-limiting factor in arecanut crops. FRD has been known to occur in traditional growing areas since 1910, particularly in Malnad and coastal tracts of Karnataka. Systemic surveys were conducted on the disease several decades ago. The design of appropriate management approaches to curtail the impacts of the disease requires information on the spatial distribution of the risks posed by the disease. In this study, we used exploratory survey data to determine areas that are most at risk. Point pattern (spatial autocorrelation and Ripley's K function) analyses confirmed the existence of moderate clustering across sampling points and optimized hotspots of FRD were determined. Geospatial techniques such as inverse distance weighting (IDW), ordinary kriging (OK), and indicator kriging (IK) were performed to predict the percent severity rates at unsampled sites. IDW and OK generated identical maps, whereby the FRD severity rates were higher in areas adjacent to the Western Ghats and the seashore. Additionally, IK was used to identify both disease-prone and disease-free areas in Karnataka. After fitting the semivariograms with different models, the exponential model showed the best fit with the semivariogram. Using this model information, OK and IK maps were generated. The identified FRD risk areas in our study, which showed higher disease probability rates (>20%) exceeding the threshold level, need to be monitored with the utmost care to contain and reduce the further spread of the disease in Karnataka.

Multiple Lesions Contribute to Infertility in Males Lacking Autoimmune Regulator.

Male factors, including those of autoimmune origin, contribute to approximately 50% of infertility cases in humans. However, the mechanisms underlying autoimmune male infertility are poorly understood. Deficiency in autoimmune regulator (AIRE) impairs central immune tolerance because of diminished expression of self-antigens in the thymus. Humans with AIRE mutations and mice with engineered ablation of Aire develop multiorgan autoimmunity and infertility. To determine the immune targets contributing to infertility in male Aire-deficient (-/-) mice, Aire-/- or wild-type (WT) males were paired with WT females. Aire-/- males exhibited dramatically reduced mating frequency and fertility, hypogonadism, and reduced serum testosterone. Approximately 15% of mice exhibited lymphocytic infiltration into the testis, accompanied by atrophy, azoospermia, and reduced numbers of mitotically active germ cells; the remaining mice showed normal testicular morphology, sperm counts, and motility. However, spermatozoa from all Aire-/- mice were defective in their ability to fertilize WT oocytes in vitro. Lymphocytic infiltration into the epididymis, seminal vesicle, and prostate gland was evident. Aire-/- male mice generated autoreactive antibodies in an age-dependent manner against sperm, testis, epididymis, prostate gland, and seminal vesicle. Finally, expression of Aire was evident in the seminiferous epithelium in an age-dependent manner, as well as in the prostate gland. These findings suggest that Aire-dependent central tolerance plays a critical role in maintaining male fertility by stemming autoimmunity against multiple reproductive targets.

Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that suppresses gene expression. Previously, we developed a conditional null model where EZH2 is knocked out in uterus. Deletion of uterine EZH2 increased proliferation of luminal and glandular epithelial cells. Herein, we used RNA-Seq in wild-type (WT) and EZH2 conditional knockout (Ezh2cKO) uteri to obtain mechanistic insights into the gene expression changes that underpin the pathogenesis observed in these mice. Ovariectomized adult Ezh2cKO mice were treated with vehicle (V) or 17ß-estradiol (E2; 1 ng/g). Uteri were collected at postnatal day (PND) 75 for RNA-Seq or immunostaining for epithelial proliferation. Weighted gene coexpression network analysis was used to link uterine gene expression patterns and epithelial proliferation. In V-treated mice, 88 transcripts were differentially expressed (DEG) in Ezh2cKO mice, and Bmp5, Crabp2, Lgr5, and Sprr2f were upregulated. E2 treatment resulted in 40 DEG with Krt5, Krt15, Olig3, Crabp1, and Serpinb7 upregulated in Ezh2cKO compared with control mice. Transcript analysis relative to proliferation rates revealed two module eigengenes correlated with epithelial proliferation in WT V vs. Ezh2cKO V and WT E2 vs. Ezh2cKO E2 mice, with a positive relationship in the former and inverse in the latter. Notably, the ESR1, Wnt, and Hippo signaling pathways were among those functionally enriched in Ezh2cKO females. Current results reveal unique gene expression patterns in Ezh2cKO uterus and provide insight into how loss of this critical epigenetic regulator assumingly contributes to uterine abnormalities.

Comparative study of the efficacy of gentamicin-coated intramedullary interlocking nail versus regular intramedullary interlocking nail in Gustilo type I and II open tibia fractures.

PURPOSE: Open tibia fracture is prone to infection, consequently causing significant morbidity and increasing the hospital stay, occupational loss and onset of chronic osteomyelitis. Intramedullary nailing is one choice for treating tibia shaft fractures. To improve the delivery of antibiotics at the tissue-implant interface, many methods have been proposed as a part of prophylaxis against infection. This study was conducted to study the role of gentamicin-impregnated intramedullary interlocking (IMIL) nail in the prevention of infection in Gustilo type I and II open tibia fractures and to compare the results with regular intramedullary nail. METHODS: The study included 28 patients with open tibia fractures (Gustilo type 1 or type 2); of them 14 underwent regular IMIL nailing and the other 14 were treated with gentamicin-coated nailing. Randomization was done by alternate allocation of the patients. Follow-up was done postoperatively (day 1), 1 week, 6 weeks, and 6 months for bone union, erythrocyte sedimentation rate (ESR), hemoglobin and C-reactive protein (CRP). Statistical significance was tested using unpaired t-test. A p value less than 0.05 was considered significant. RESULTS: There were 4 cases of infection in controls (regular IMIL nail) and no infection among patients treated with gentamicin-coated nail during the follow up (X2 = 4.66, p = 0.031). At 6 months postoperatively, CRP (p = 0.031), ESR (p = 0.046) and hemoglobin level (p = 0.016) showed significant difference between two groups. The bone healing rate was better with gentamicin-coated nail in comparison to regular IMIL nail at 6 months follow-up (p = 0.016). CONCLUSION: Gentamicin-coated IMIL nail has a positive role in preventing infection in Gustilo type I and II open tibia fractures.

The histone methyltransferase EZH2 is required for normal uterine development and function in mice†.

Enhancer of zeste homolog 2 (EZH2) is a rate-limiting catalytic subunit of a histone methyltransferase, polycomb repressive complex, which silences gene activity through the repressive histone mark H3K27me3. EZH2 is critical for epigenetic effects of early estrogen treatment, and may be involved in uterine development and pathologies. We investigated EZH2 expression, regulation, and its role in uterine development/function. Uterine epithelial EZH2 expression was associated with proliferation and was high neonatally then declined by weaning. Pre-weaning uterine EZH2 expression was comparable in wild-type and estrogen receptor 1 knockout mice, showing neonatal EZH2 expression is ESR1 independent. Epithelial EZH2 was upregulated by 17ß-estradiol (E2) and inhibited by progesterone in adult uteri from ovariectomized mice. To investigate the uterine role of EZH2, we developed a EZH2 conditional knockout (Ezh2cKO) mouse using a cre recombinase driven by the progesterone receptor (Pgr) promoter that produced Ezh2cKO mice lacking EZH2 in Pgr-expressing tissues (e.g. uterus, mammary glands). In Ezh2cKO uteri, EZH2 was deleted neonatally. These uteri had reduced H3K27me3, were larger than WT, and showed adult cystic endometrial hyperplasia. Ovary-independent uterine epithelial proliferation and increased numbers of highly proliferative uterine glands were seen in adult Ezh2cKO mice. Female Ezh2cKO mice were initially subfertile, and then became infertile by 9 months. Mammary gland development in Ezh2cKO mice was inhibited. In summary, uterine EZH2 expression is developmentally and hormonally regulated, and its loss causes aberrant uterine epithelial proliferation, uterine hypertrophy, and cystic endometrial hyperplasia, indicating a critical role in uterine development and function.

Mice lacking membrane estrogen receptor 1 are protected from reproductive pathologies resulting from developmental estrogen exposure†.

Both membrane and nuclear fractions of estrogen receptor 1 (ESR1) mediate 17ß-estradiol (E2) actions. Mice expressing nuclear (n)ESR1 but lacking membrane (m)ESR1 (nuclear-only estrogen receptor 1 [NOER] mice) show reduced E2 responsivity and reproductive abnormalities culminating in adult male and female infertility. Using this model, we investigated whether reproductive pathologies caused by the synthetic estrogen diethylstilbestrol (DES) are mitigated by mESR1 ablation. Homozygous and heterozygous wild-type (WT and HET, respectively) and NOER male and female mice were subcutaneously injected with DES (1 mg/kg body weight [BW]) or vehicle daily from postnatal day (PND) 1-5. Uterine histology was assessed in select DES-treated females at PND 5, whereas others were ovariectomized at PND 60 and treated with E2 (10 µg/kg BW) or vehicle 2 weeks later. Neonatal DES exposure resulted in ovary-independent epithelial proliferation in the vagina and uterus of WT but not NOER females. Neonatal DES treatment also induced ovary-independent adult expression of classical E2-induced transcripts (e.g., lactoferrin [Ltf] and enhancer of zeste homolog 2 [Ezh2]) in WT but not NOER mice. At PND 90, DES-treated WT and HET males showed smaller testes and a high incidence of bacterial pyogranulomatous inflammation encompassing the testes, epididymis and occasionally the ductus deferens with spread to lumbar lymph nodes; such changes were largely absent in NOER males. Results indicate that male and female NOER mice are protected from deleterious effects of neonatal DES, and thus mESR1 signaling is required for adult manifestation of DES-induced reproductive pathologies in both sexes.

Binder-free Sn-Si heterostructure films for high capacity Li-ion batteries.

This study fabricated and demonstrated a functional, stable electrode structure for a high capacity Li-ion battery (LIB) anode. Effective performance is assessed in terms of reversible lithiation for a significant number of charge-discharge cycles to 80% of initial capacity. The materials selected for this study are silicon and tin and are co-deposited using an advanced manufacturing technique (plasma-enhanced chemical vapour deposition), shown to be a scalable process that can facilitate film growth on 3D substrates. Uniform and hybrid crystalline-amorphous Si nanowire (SiNW) growth is achieved via a vapour-liquid-solid mechanism using a Sn metal catalyst. SiNWs of less than 300 nm diameter are known to be less susceptible to fracture and when grown this way have direct electrical conductivity to the current collector, with sufficient room for expansion. Electrochemical characterisation shows stable cycling at capacities of 1400 mA h g-1 (>4 × the capacity limit of graphite). This hybrid system demonstrates promising electrochemical performance, can be grown at large scale and has also been successfully grown on flexible carbon paper current collectors. These findings will have impact on the development of flexible batteries and wearable energy storage.

Highly sensitive ethylene glycol-doped PEDOT-PSS organic thin films for LPG sensing.

In this study, for the first time we report the fabrication of low-cost ethylene glycol (EG)-doped PEDOT-PSS (poly 3,4-ethylenedioxythiophene:polystyrene sulfonate) organic thin film sensors for the detection of LPG at room temperature. The prepared thin films were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible (UV-Vis) spectroscopy and thermogravimetric analysis (TGA) techniques for the analysis of their structural and morphological features. The doping of EG strongly improved the conductivity of pure PEDOT-PSS films by three orders of magnitude. The gas sensing responses of pristine and doped PEDOT-PSS thin films were investigated at room temperature by fabricating a sensor device on an ITO-coated glass substrate. The gas sensing characteristics of the prepared thin films were investigated for liquified petroleum gas (LPG), dimethyl propane, methane and butane test gases. The EG-doped PEDOT-PSS thin films exhibited excellent sensitivity for all the test gases, especially towards LPG, at room temperature. The sensitivity of the doped PEDOT-PSS films was recorded to be >90% for LPG with improved response and recovery time. The stability study indicated that the sensing response of doped PEDOT-PSS thin films was highly stable over a period of 30 days. Due to enhanced sensitivity, stability and fast response and recovery times, these EG-doped PEDOT-PSS thin films can be used in gas sensor technology, especially towards the detection of LPG at room temperature.

Estrogens in Male Physiology.

Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17ß-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.

Membrane estrogen receptor 1 is required for normal reproduction in male and female mice.

Steroid hormones, acting through their cognate nuclear receptors, are critical for many reproductive and non-reproductive functions. Over the past two decades, it has become increasingly clear that in addition to cytoplasmic/nuclear steroid receptors that alter gene transcription when liganded, a small fraction of cellular steroid receptors are localized to the cell membranes, where they mediate rapid steroid hormone effects. 17ß-Estradiol (E2), a key steroid hormone for both male and female reproduction, acts predominately through its main receptor, estrogen receptor 1 (ESR1). Most ESR1 is nuclear; however, 5-10% of ESR1 is localized to the cell membrane after being palmitoylated at cysteine 451 in mice. This review discusses reproductive phenotypes of a newly-developed mouse model with a C451A point mutation that precludes membrane targeting of ESR1. This transgenic mouse, termed the nuclear-only ESR1 (NOER) mouse, shows extensive male and female reproductive abnormalities and infertility despite normally functional nuclear ESR1 (nESR1). These results provide the first in vivo evidence that membrane-initiated E2/ESR1 signaling is required for normal male and female reproductive functions and fertility. Signaling mechanisms for membrane ESR1 (mESR1), as well as how mESR1 works with nESR1 to mediate estrogen effects, are still being established. We discuss some possible mechanisms by which mESR1 might facilitate nESR1 signaling, as well as the emerging evidence that mESR1 might be a major mediator of epigenetic effects of estrogens, which are potentially linked to various adult-onset pathologies.

Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice.

Estrogen receptor 1 (ESR1) mediates major reproductive functions of 17ß-estradiol (E2). Male Esr1 knockout (Esr1KO) mice are infertile due to efferent ductule and epididymal abnormalities. The majority of ESR1 is nuclear/cytoplasmic; however, a small fraction is palmitoylated at cysteine 451 in mice and localized to cell membranes, in which it mediates rapid E2 actions. This study used an Esr1 knock-in mouse containing an altered palmitoylation site (C451A) in ESR1 that prevented cell membrane localization, although nuclear ESR1 was expressed. These nuclear-only estrogen receptor 1 (NOER) mice were used to determine the roles of membrane ESR1 in males. Epididymal sperm motility was reduced 85% in 8-month-old NOER mice compared with wild-type controls. The NOER mice had decreased epididymal sperm viability and greater than 95% of sperm had abnormalities, including coiled midpieces and tails, absent heads, and folded tails; this was comparable to 4-month Esr1KO males. At 8 months, daily sperm production in NOER males was reduced 62% compared with controls. The NOER mice had histological changes in the rete testes, efferent ductules, and seminiferous tubules that were comparable with those previously observed in Esr1KO males. Serum T was increased in NOER males, but FSH, LH, and E2 were unchanged. Critically, NOER males were initially subfertile, becoming infertile with advancing age. These findings identify a previously unknown role for membrane ESR1 in the development of normal sperm and providing an adequate environment for spermatogenesis.