ABSTRACT
Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the ejaculation experience selectively activated estrogen receptor 2 (Esr2)-expressing neurons in the bed nucleus of the stria terminalis (BNST)-BNSTEsr2-and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNSTEsr2 elicited fast mating recovery in satiated mice of both sexes. In males, such hyperexcitability reduced mating motivation and was partially mediated by larger HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Thus, BNSTEsr2 not only encode a specific mating action but also represent a persistent state of sexual satiety, and alterations in a neuronal ion channel contribute to sexual experience-dependent long-term changes to mating drive.
Subject(s)
Estrogen Receptor beta , Motivation , Neurons , Satiation , Septal Nuclei , Sexual Behavior, Animal , Animals , Female , Male , Mice , Neurons/physiology , Satiation/physiology , Septal Nuclei/physiology , Sexual Behavior, Animal/physiology , Ejaculation/physiology , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/physiologyABSTRACT
Steviol glycosides, the active sweet components of stevia plant, have been recently found to possess a number of therapeutic properties, including some recorded anticancer ones against various cancer cell types (breast, ovarian, cervical, pancreatic, and colon cancer). Our aim was to investigate this anticancer potential on the two most commonly used breast cancer cell lines which differ in the phenotype and estrogen receptor (ER) status: the low metastatic, ERα+ MCF-7 and the highly metastatic, ERα-/ERß+ MDA-MB-231. Specifically, glycosides' effect was studied on cancer cells': (a) viability, (b) functionality (proliferation, migration, and adhesion), and (c) gene expression (mRNA level) of crucial molecules implicated in cancer's pathophysiology. Results showed that steviol glycosides induced cell death in both cell lines, in the first 24 hr, which was in line with the antiapoptotic BCL2 decrease. However, cells that managed to survive showcased diametrically opposite behavior. The low metastatic ERα+ MCF-7 cells acquired an aggressive phenotype, depicted by the upregulation of all receptors and co-receptors (ESR, PGR, AR, GPER1, EGFR, IGF1R, CD44, SDC2, and SDC4), as well as VIM and MMP14. On the contrary, the highly metastatic ERα-/ERß+ MDA-MB-231 cells became less aggressive as pointed out by the respective downregulation of EGFR, IGF1R, CD44, and SDC2. Changes observed in gene expression were compatible with altered cell functions. Glycosides increased MCF-7 cells migration and adhesion, but reduced MDA-MB-231 cells migratory and metastatic potential. In conclusion, the above data clearly demonstrate that steviol glycosides have different effects on breast cancer cells according to their ER status, suggesting that steviol glycosides might be examined for their potential anticancer activity against breast cancer, especially triple negative breast cancer (TNBC).
Subject(s)
Estrogen Receptor alpha , Neoplasms , Diterpenes, Kaurane , ErbB Receptors , Estrogen Receptor beta/physiology , Glucosides , Glycosides/pharmacology , Matrix Metalloproteinase 14 , Proto-Oncogene Proteins c-bcl-2 , RNA, Messenger , Receptors, EstrogenABSTRACT
BACKGROUND: CD4+ T cells temporally transition from protective to pathological during ischemic heart failure (HF; 8 weeks postmyocardial infarction). Cellular mechanisms mediating this shift are unknown. METHODS: RNA-sequencing of cardiac CD4+ T cells and flow cytometric analysis of immune cells was conducted. RESULTS: RNA-sequencing of CD4+ T cells from the failing hearts of male mice indicated activation of ER (estrogen receptor)-α signaling. Flow cytometric analysis showed that ERα in CD4+ T cells decreases significantly at 3-day postmyocardial infarction but increases during HF. To antagonize ERα, we tested a novel ERß agonist (OSU-ERb-012) to inhibit T cells and blunt left ventricular remodeling. Proliferation assays showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks postmyocardial infarction and treated with either vehicle or drug (60 mg/kg per day; oral). While vehicle-treated HF mice displayed progressive left ventricular dilatation with significantly increased end-systolic and end-diastolic volumes from 4 to 8 weeks postmyocardial infarction, treatment with OSU-ERb-012 significantly blunted these changes and stopped left ventricular remodeling in both the sexes. Reduction in tibia-normalized heart and left ventricular weights, cardiomyocyte hypertrophy and interstitial fibrosis further supported these results. Additionally, OSU-ERb-012 treatment selectively inhibited cardiac, splenic, and circulating CD4+ T cells without affecting other myeloid and lymphoid cells in the HF mice. CONCLUSIONS: Our studies indicate that ERß agonists and OSU-ERb-012, in particular, could be used as selective immunomodulatory drugs to inhibit CD4+ T cells during chronic HF.
Subject(s)
Heart Failure , Myocardial Infarction , Animals , Chronic Disease , Estrogen Receptor alpha , Estrogen Receptor beta/physiology , Estrogen Receptor beta/therapeutic use , Estrogens/therapeutic use , Female , Lymphocyte Activation , Male , Mice , Myocardial Infarction/metabolism , RNA/therapeutic use , Receptors, Estrogen/therapeutic use , Ventricular Remodeling/physiologyABSTRACT
BACKGROUND: The role of estrogen receptor ß (ERß) in the pathogenesis and development of breast cancer (BC) is controversial, and it is currently considered to play contradictory roles in different phenotypes. ERß2 is thought to promote the BC process, but its role in triple-negative breast cancer (TNBC) has not been reported. METHODS: In this study, we collected tumor tissues from 15 patients with TNBC and obtained a variety of TNBC cell lines as research objects. The plasmid vectors and RNA interference techniques were used to change the level of target genes in cells, quantitative PCR and Western Blots were used to detect gene expression levels, CCK-8 and EdU assay were used to detect cell growth, and Transwell was used to detect cell migration and invasion. Dual-luciferase gene reports and RNA immunoprecipitation (RIP) were used to verify gene targeting relationships. RESULTS: ERß2 was up-regulated in TNBC tissues and promoted the growth, migration, and invasion of TNBC cells. ERß2 regulated hsa_circ_0000732 expression by binding to SCARF1 promoter. Knockdown of hsa_circ_0000732 inhibited TNBC cell proliferation, migration, and invasion by upregulating miR-1184. CONCLUSION: Our present study found that ERß2 is upregulated in some TNBC cells and promotes TNBC cell growth, migration and invasion by regulating hsa_circ_0000732 targeting miR-1184. The special role of ERß2 in TNBC may be the breakthrough of a targeted treatment strategy for TNBC.
Subject(s)
Estrogen Receptor beta/physiology , MicroRNAs/physiology , RNA, Circular/physiology , Triple Negative Breast Neoplasms/etiology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Humans , Neoplasm Invasiveness , Promoter Regions, Genetic , Scavenger Receptors, Class F/genetics , Triple Negative Breast Neoplasms/pathology , Up-RegulationABSTRACT
BACKGROUND: Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor ß (ERß) can be potentially targeted for breast cancer therapy. METHODS AND RESULTS: TAD1822-7 was evaluated for ERß-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERß siRNA, ERß plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERß causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERß. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1ß in the context of hypoxia-induced autophagy. ERß overexpression and ERß agonist showed similar effects, whereas ERß siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells. CONCLUSIONS: These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERß-mediated pathways in breast cancer cells.
Subject(s)
Breast Neoplasms/drug therapy , Estrogen Receptor beta/metabolism , Morpholines/pharmacology , Phenylurea Compounds/pharmacology , Alkaloids , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Autophagy/physiology , Biphenyl Compounds , Breast Neoplasms/metabolism , Cell Hypoxia/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Estrogen Receptor beta/physiology , Female , Humans , Morpholines/metabolism , Phenylurea Compounds/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , UreaABSTRACT
Estrogen is essential for the growth and development of mammary glands and its signaling is associated with breast cancer growth. Estrogen can exert physiological actions via estrogen receptors α/ß (ERα/ß). There is experimental evidence suggesting that in ERα/ß-positive breast cancer, ERα promotes tumor cell proliferation and ERß inhibits ERα-mediated transcriptional activity, resulting in abrogation of cell growth. Therefore, ERß is attracting attention as a potential tumor suppressor, and as a biomarker and therapeutic target in the ERα/ß-positive breast cancer. Based on this information, we have hypothesized that some endocrine-disrupting chemicals (EDCs) that can perturb the balance between ERα and ERß expression levels in breast cancer cells might have effects on the breast cancer proliferation (i.e., down-regulation of the α-type of ER). We have recently reported that 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an active metabolite of bisphenol A, in ERα/ß-positive human breast cancer significantly down-regulates ERα expression, yet stimulates cell proliferation through the activation of ERß-mediated transcription. These results support our hypothesis by demonstrating that exposure to MBP altered the functional role of ERß in breast cancer cells from suppressor to promoter. In contrast, some EDCs, such as Δ9-tetrahydrocannabinol and bisphenol AF, can exhibit anti-estrogenic effects through up-regulation of ERß expression without affecting the ERα expression levels. However, there is no consensus on the correlation between ERß expression levels and clinical prognosis, which might be due to differences in exposed chemicals. Therefore, elucidating the exposure effects of EDCs can reveal the reason for inconsistent functional role of ERß in ERα/ß-positive breast cancer.
Subject(s)
Breast Neoplasms/drug therapy , Endocrine Disruptors/toxicity , Estrogen Receptor beta/drug effects , Animals , Antineoplastic Agents/therapeutic use , Breast Neoplasms/chemically induced , Estrogen Antagonists/therapeutic use , Estrogen Receptor beta/metabolism , Estrogen Receptor beta/physiology , Female , HumansABSTRACT
Estrogen receptors (ERs) are known to play an important role in the proper development of estrogen-sensitive organs, as well as in the development and progression of various types of cancer. ERα, the first ER to be discovered, has been the focus of most cancer research, especially in the context of breast cancer. However, ERß expression also plays a significant role in cancer pathophysiology, notably its seemingly protective nature and loss of expression with oncogenesis and progression. Although ERß exhibits antitumor activity in breast, ovarian, and prostate cancer, its expression is associated with disease progression and worse prognosis in lung cancer. The function of ERß is complicated by the presence of multiple isoforms and single nucleotide polymorphisms, in addition to tissue-specific functions. This mini-review explores current literature on ERß and its mechanism of action and clinical implications in breast, ovarian, prostate, and lung cancer.
Subject(s)
Estrogen Receptor beta/physiology , Neoplasms/genetics , Animals , Cell Proliferation/drug effects , Cell Proliferation/genetics , Disease Progression , Estrogen Receptor beta/genetics , Estrogens/pharmacology , Female , Humans , Male , Neoplasms/pathologySubject(s)
Emotional Regulation/physiology , Estrogen Receptor beta/physiology , Mutation , Social Behavior , Age Factors , Animals , Arginine Vasopressin/genetics , Arginine Vasopressin/metabolism , Behavior, Animal , Depression/drug therapy , Depression/genetics , Estrogen Receptor beta/genetics , Female , Hypothalamus/metabolism , Male , Mice , Neurons/metabolism , Oxytocin/genetics , Oxytocin/metabolism , Sex Factors , Testosterone/metabolism , Tryptophan Hydroxylase/metabolismABSTRACT
Introduction: Sex differences in brain cortical function affect cognition, behaviour and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Oestrogen and oestrogen receptors (ERs), specifically ERß, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERß on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERß affects transcription. Methods: In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ERß knockout mice (n = 4/sex/genotype). We used unbiased clustering to analyse whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results: We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERßKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function 'cation channel activity'. Moreover, within each sex we found only a few DEGs in ERßKO vs WT mice (8 and 5 in males and females, respectively). Conclusions: Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ERß may be largely post-transcriptional.
Subject(s)
Cerebral Cortex/metabolism , Cerebral Cortex/physiology , Estrogen Receptor beta/physiology , Gene Expression/genetics , Sex Characteristics , Animals , Female , Male , Mice, Inbred C57BL , Mice, Knockout , Organ Specificity/genetics , Transcription, Genetic/geneticsABSTRACT
Endometriosis is defined as the presence of endometrial foci, localized beyond their primary site, i.e., the uterine cavity. The etiology of this disease is rather complex. Its development is supported by hormonal, immunological, and environmental factors. During recent years, particular attention has been focused on the genetic mechanisms that may be of particular significance for the increased incidence rates of endometriosis. According to most recent studies, ESR2 and CYP19A1 genes may account for the potential risk factors of infertility associated with endometriosis. The paper presents a thorough review of the latest reports and data concerning the genetic background of the risk for endometriosis development.
Subject(s)
Aromatase/physiology , Endometriosis/genetics , Estrogen Receptor beta/physiology , Genetic Background , Endometriosis/epidemiology , Endometriosis/etiology , Endometrium/metabolism , Endometrium/pathology , Female , Genetic Predisposition to Disease , Humans , Infertility/genetics , Risk FactorsABSTRACT
Estrogens play a key role in the sexual differentiation of the brain and behavior. While early estrogen actions exert masculinizing effects on the brain of male rodents, a diametrically opposite effect is observed in birds where estrogens demasculinize the brain of females. Yet, the two vertebrate classes express similar sex differences in the brain and behavior. Although ERα is thought to play a major role in these processes in rodents, the role of ERß is still controversial. In birds, the identity of the estrogen receptor(s) underlying the demasculinization of the female brain remains unclear. The aim of the present study was thus to determine in Japanese quail the effects of specific agonists of ERα (propylpyrazole triol, PPT) and ERß (diarylpropionitrile, DPN) administered at the beginning of the sensitive period (embryonic day 7, E7) on the sexual differentiation of male sexual behavior and on the density of vasotocin-immunoreactive (VT-ir) fibers, a known marker of the organizational action of estrogens on the quail brain. We demonstrate that estradiol benzoate and the ERß agonist (DPN) demasculinize male sexual behavior and decrease the density of VT-ir fibers in the medial preoptic nucleus and the bed nucleus of the stria terminalis, while PPT has no effect on these measures. These results clearly indicate that ERß, but not ERα, is involved in the estrogen-induced sexual differentiation of brain and sexual behavior in quail.
Subject(s)
Brain/anatomy & histology , Coturnix/physiology , Estrogen Receptor beta/physiology , Sexual Behavior, Animal , Animals , Brain/drug effects , Brain/metabolism , Coturnix/metabolism , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/agonists , Estrogens/pharmacology , Female , Male , Nitriles/pharmacology , Preoptic Area/drug effects , Preoptic Area/metabolism , Propionates/pharmacology , Sex Characteristics , Sex Differentiation/drug effects , Sexual Behavior, Animal/drug effects , Vasotocin/pharmacologyABSTRACT
Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERß) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERß mediates this effect. To investigate the functional role of intestinal ERß during colitis-associated CRC we used intestine-specific ERß knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERß. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERß knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERß protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERß binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERß against colitis-associated CRC, proposing new therapeutic strategies.
Subject(s)
Colitis/prevention & control , Colorectal Neoplasms/prevention & control , Estrogen Receptor beta/physiology , Animals , Cell Line, Tumor , Cell Proliferation , Female , Humans , Intestinal Mucosa/pathology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/physiology , Sex Characteristics , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Estrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients´ blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ERα and ERß expression in UGS-related BlaCa (nâ¯=â¯27), UGS-related non-malignant lesions (nâ¯=â¯35), and noninfected BlaCa (nâ¯=â¯80). We investigated the potential of ERα to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ERα modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ERα was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ERα expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ERα expression correlated with presence of schistosome eggs. ERß was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ERα active state than 17ß-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ERα activation promotes proliferation in ERα expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ERα during UGS and UGS-induced carcinogenesis.
Subject(s)
Estrogen Receptor alpha/physiology , Estrogen Receptor beta/physiology , Female Urogenital Diseases/complications , Female Urogenital Diseases/parasitology , Male Urogenital Diseases/complications , Male Urogenital Diseases/parasitology , Schistosomiasis haematobia/complications , Urinary Bladder Neoplasms/complications , Urinary Bladder Neoplasms/pathology , Cell Proliferation , Female , Humans , MaleABSTRACT
PURPOSE: Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor ß (ERß). However, the antimetastatic effect of the ERß antagonist fulvestrant was still limited in NSCLC patients. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. METHODS: The expression levels of ERß and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERß and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. RESULTS: Here, a positive correlation between ERß and TLR4 expression was observed in both primary NSCLC tissue (Spearman's Rho correlation coefficient = 0.411, p < 0.001) and metastatic lymph node tissue (Spearman's Rho correlation coefficient = 0.374, p = 0.009). The protein levels of ERß in NSCLC cell lines were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p < 0.05). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant + CLI-095 showed the strongest inhibitory effect (p < 0.05). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p < 0.05). CONCLUSIONS: Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Estrogen Receptor Antagonists/therapeutic use , Fulvestrant/therapeutic use , Lung Neoplasms/drug therapy , Neoplasm Metastasis/prevention & control , Sulfonamides/therapeutic use , Toll-Like Receptor 4/antagonists & inhibitors , Adult , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Cell Movement/drug effects , Estrogen Receptor beta/physiology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Invasiveness , Toll-Like Receptor 4/physiologyABSTRACT
Estrogen plays substantial roles in pain modulation; however, studies concerning sex hormones and nociception often yield confusing results. The discrepancy could be a result of lack of consensus to regard estrogen as a variable when working with animal models; thus, the influence of hormones' fluctuations on nociception has continually been neglected. In the present study, we designed a novel hormone substitution model to aid us to evaluate the effects of estrogen's long-term alterations on ovariectomy (OVX)-induced mechanical hyperalgesia and the expression of estrogen receptors(ERs). OVX rats were implanted with slow-release estrogen pellets at differently arranged time points and doses, such that a gradual elevation or decrease of serum estrogen levels following a relatively stable period of estrogen replacement was achieved in rats. Our results demonstrated that gradual estrogen depletion rather than elevation following the stable period of estrogen substitution in OVX rats alleviated OVX-induced mechanical hyperalgesia in a dose-independent manner, and the opposite estrogen increase or decrease paradigms differently regulate the expression of spinal ERs. Specifically, in rats rendered to continuously increased serum estrogen, the early phase estrogen-induced anti-nociception effect in OVX rats was eliminated, which was accompanied by an over-activation of ERα and a strong depression of ERß, while in the OVX rats subject to gradual decrease of estrogen replacement, both ERα and ERß increased modestly compared with the OVX group. Thus, the present study demonstrated that estrogen increase or decrease modulate nociception differently through change of spinal ERs.
Subject(s)
Estradiol/administration & dosage , Estrogens/physiology , Hyperalgesia/physiopathology , Nociception/physiology , Pain Perception/physiology , Animals , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/physiology , Estrogens/blood , Female , Neurons/drug effects , Neurons/physiology , Nociception/drug effects , Ovariectomy , Pain Perception/drug effects , Rats, Sprague-Dawley , Spinal Cord/drug effects , Spinal Cord/physiopathologyABSTRACT
In vertebrates, sex steroids play crucial roles in multiple systems related to reproduction. In females, estrogens and their receptor estrogen receptor (ER or Esr) play indispensable roles in the negative sex steroid feedback regulation of pituitary gonadotropin secretion, which prevents excessive development of ovarian follicles. However, the mechanism of this feedback regulation of a gonadotropin, follicle stimulating hormone (FSH), which is essential for folliculogenesis throughout vertebrates, is poorly understood. In the present study, we generated knockouts of all subtypes of nuclear estrogen receptors in a model teleost medaka, which is suitable for the study of endocrine control and behavioral assays, and analyzed fertility, behavior and functionality of estrogen feedback in each knockout line. Among the estrogen receptors, we revealed that an estrogen receptor Esr2a plays an essential role in this feedback regulation. In addition to this, we also found that esr2a-/- females showed oviduct atresia, which causes complete infertility. Interestingly, esr2a-/- females showed apparently normal sexual behavior but without oviposition in response to male courtship. This phenotype indicates that physical readiness and motivation of sexual behavior is independently controlled.
Subject(s)
Estrogen Receptor beta/physiology , Fertility/physiology , Fish Proteins/physiology , Oryzias/metabolism , Animals , Estrogen Receptor beta/genetics , Female , Fish Proteins/genetics , Gene Knockout Techniques , Male , Oryzias/geneticsABSTRACT
Estrogens receptors (ER) are involved in several sociosexual behaviors and fear responses. In particular, the ERα is important for sexual behaviors, whereas ERß modulates anxiolytic responses. Using shRNA directed either against the ERα or the ERß RNAs (or containing luciferase control) encoded within an adeno-associated viral vector, we silenced these receptors in the ventromedial nucleus of the hypothalamus (VMN) and the central amygdala (CeA). We exposed ovariectomized female rats, sequentially treated with estradiol benzoate and progesterone, to five stimuli, previously reported to elicit positive and negative affect. The subjects were housed in groups of 4 females and 3 males in a seminatural environment for several days before hormone treatment. We analyzed the frequency of a large number of behavior patterns. In addition, we performed analyses of co-occurrence in order to detect changes in the structure of behavior after infusion of the vectors. Silencing the ERα in the VMN disrupted lordosis and showed some anxiolytic properties in aversive situations, whereas silencing of the ERß in this structure had no effect. This was also the case after silencing the ERα in the CeA. Silencing of the ERß in this structure increased risk assessment, an expression of anxiety, and increased olfactory exploration of the environment. We hypothesize that the ERß in the CeA has an important role in the well-established anxiolytic effects of estrogens, and that it may modulate arousal level. Furthermore, it seems that the ERα in the VMN is anxiogenic in aversive or threatening situations, in agreement with other studies.
Subject(s)
Arousal/physiology , Behavior, Animal/physiology , Central Amygdaloid Nucleus/physiology , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/physiology , Fear/physiology , Social Behavior , Ventromedial Hypothalamic Nucleus/physiology , Animals , Central Amygdaloid Nucleus/metabolism , Female , Male , Rats , Sexual Behavior, Animal/physiology , Ventromedial Hypothalamic Nucleus/metabolismABSTRACT
Evidence suggests that airway hyperresponsiveness (AHR) is a characteristic feature of asthma. Epidemiological studies have confirmed that the severity of asthma is greater in women, suggesting a critical role of female sex steroid hormones (especially estrogen). Very few in vivo studies have examined the role of sex steroid hormones in asthma, and the sequence of events that occur through differential activation of estrogen receptors (ERs) remains to be determined in asthmatic airways. Our recent in vitro findings indicated that ERß had increased expression in asthmatic airway smooth muscle (ASM), and that its activation by an ERß-specific agonist downregulated airway remodeling. In this study, we translated the in vitro findings to a murine asthma model and examined the differential role of ER activation in modulating lung mechanics. C57BL/6J male, female, and ovariectomized mice were exposed to mixed allergen (MA) and subcutaneously implanted with sustained-release pellets of placebo, an ERα agonist (4,4',4â³-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [PPT]), and/or an ERß agonist (WAY-200070). We then evaluated the effects of these treatments on airway mechanics, biochemical, molecular, and histological parameters. Mice exposed to MA showed a significant increase in airway resistance, elastance, and tissue damping, and a decrease in compliance; pronounced effects were observed in females. Compared with PPT, WAY treatment significantly reversed the MA-induced changes. The increased mRNA/protein expression of ERα, ERß, and remodeling genes observed in MA-treated mice was significantly reversed in WAY-treated mice. This novel study indicates that activation of ERß signaling downregulates AHR and airway remodeling, and is a promising target in the development of treatments for asthma.
Subject(s)
Airway Remodeling/physiology , Asthma/physiopathology , Bronchial Hyperreactivity/physiopathology , Estrogen Receptor beta/physiology , Estrogens/physiology , Airway Resistance , Allergens/toxicity , Animals , Disease Models, Animal , Drug Implants , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/agonists , Female , Laser Capture Microdissection , Male , Mice , Mice, Inbred C57BL , Ovariectomy , Oxazoles/pharmacology , Phenols/pharmacology , Pyrazoles/pharmacology , Sex CharacteristicsABSTRACT
Vasopressinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei express oestrogen receptor (ER)ß and receive afferent projections from osmosensitive neurones that express ERα. However, which subtype of these receptors mediates the effects of oestradiol on vasopressin (AVP) secretion induced by hydromineral challenge has not yet been demonstrated in vivo. Moreover, AVP secretion induced by hyperosmolality is known to involve activation of TRPV1 (transient receptor potential vanilloid, member 1) in magnocellular neurones, although whether oestradiol modulates expression of this receptor is unknown. Thus, the present study aimed to clarify the mechanisms involved in the modulation exerted by oestradiol on AVP secretion, specifically investigating the involvement of ERß, ERα and TRPV1 receptors in response to water deprivation (WD). We observed that treatment with an ERß agonist potentiated AVP secretion and vasopressinergic neuronal activation induced by WD. This increase in AVP secretion induced by WD was reversed by an ERß antagonist. By contrast to ERß, the ERα agonist did not alter plasma AVP concentrations or activation of AVP neurones in the SON and PVN. Additionally, Fos expression in the subfornical organ was not altered by the ERα agonist. TRPV1 mRNA expression was increased by WD in the SON, although this response was not altered by any treatment. The results of the present study suggest that ERß mediates the effects of oestradiol on AVP secretion in response to WD, indicating that the effects of oestradiol occur directly in AVP neurones without affecting TRPV1.
Subject(s)
Estradiol/pharmacology , Estrogen Receptor beta/physiology , Neurons/physiology , Vasopressins/physiology , Water Deprivation/physiology , Animals , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/agonists , Estrogen Receptor beta/antagonists & inhibitors , Female , Osmolar Concentration , Paraventricular Hypothalamic Nucleus/chemistry , Paraventricular Hypothalamic Nucleus/metabolism , RNA, Messenger/analysis , Rats , Rats, Wistar , Silicone Elastomers , Supraoptic Nucleus/chemistry , Supraoptic Nucleus/metabolism , TRPV Cation Channels/genetics , TRPV Cation Channels/physiology , Vasopressins/analysis , Vasopressins/bloodABSTRACT
INTRODUCTION: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERß) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERß as a therapeutic target. BACKGROUND: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERß shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERß receptor and underscore its therapeutic potential. CONCLUSION: Studies are needed to further elucidate the exact mechanism underlying the role of ERß activation as a therapeutic approach in the management of type 2 diabetes.