Estrogen Receptor Agonist Research Articles

Exposure to ethinyl estradiol during lactation reduces maternal mammary gland complexity and restricts pup growth in mice.

Exposure to ethinyl estradiol during lactation reduces maternal mammary gland complexity and restricts pup growth in mice.

Unraveling the Intricacies: The Role of mRNAs in the Progression and Initiation of Alzheimer's Disease.

This study aims to investigate the molecular mechanisms underlying Alzheimer's disease (AD) by analyzing differentially expressed miRNAs and their target proteins to identify key regulatory networks and therapeutic targets. Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted regulatory mechanisms involving differentially expressed miRNAs. Recent studies suggest that understanding the target proteins of these miRNAs may reveal crucial insights into AD pathology. The objective of this study was to investigate the role of differentially expressed miRNAs in Alzheimer's disease (AD) by identifying their target proteins and exploring the associated regulatory networks. This includes uncovering key hub proteins and their involvement in critical biological pathways linked to AD progression. Additionally, the study aims to identify transcription factors regulating these proteins and evaluate potential therapeutic compounds targeting these molecular players. By integrating these findings, the research seeks to provide a deeper understanding of AD pathogenesis and pave the way for novel therapeutic strategies to mitigate its progression. Differentially expressed miRNAs were collected from reviews, with target proteins identified using MiRDB, STRING, and Cytoscape. Promoter and transcription factor (TF) analyses were performed using Enrichr, and potential therapeutic compounds targeting hub proteins were explored via DrugBank. This study identifies key hub proteins, including TNF, PTEN, KRAS, ESR1, H3-3B, COL25A1, COL19A1, COL13A1, COL27A1, COL5A3, CCND1, FGF2, SMAD2, and PXDN, exploring their roles in AD progression. GO and KEGG pathway analyses revealed that hub proteins, including TNF, PTEN, KRAS, and ESR1, are involved in essential biological processes related to neural differentiation and signaling. Cytocluster analysis identified clusters with significant associations with AD, indicating complex interaction networks among these proteins. Potential therapeutic agents, including TNF inhibitors, estrogen receptor agonists, and KRAS inhibitors, were identified. Promoter and TF analysis further highlighted regulatory factors in AD pathways. This study emphasizes crucial AD-related proteins and pathways, providing insights for future therapeutic targeting of gene expression to mitigate AD progression.

Tamoxifen-induced endometrial hyperplasia

Breast cancer is the most common cancer among the female population. In the adjuvant therapy regimens for hormone-sensitive breast cancer, tamoxifen is one of the most common and cost-effective drugs. Despite the fact that the main therapeutic effect of tamoxifen is associated with its antiestrogenic activity, the drug also acts as an agonist of estrogen receptors in other tissues of the body, such as the endometrium. Side effects of taking tamoxifen may include endometrial proliferation, hyperplasia, polyps, invasive carcinoma, and uterine sarcoma. An outpatient obstetrician-gynecologist most often encounters all these conditions. The main difficulty in managing such patients lies in the absence of uniform algorithms for assessing and further treatment tactics for patients taking tamoxifen, which often leads to unjustified drug withdrawal or numerous surgical manipulations. The literature on the effect of tamoxifen on endometrial tissue and possible algorithms for the management of patients with hyperplastic processes during therapy were analyzed. In the search databases such as Web of Science, eLibrary, Scopus, and PubMed / MEDLINE authors selected articles for the period 1991–2023 devoted to the assessment of the effect of tamoxifen on the endometrial condition using the following keywords: “tamoxifen”, “hyperplasia”, “breast cancer”, “endometrial cancer”, and “assessment”. No methodological filter was used to exclude the omission of suitable articles. This study included full-text sources and literature reviews on the subject under study. Articles that were not directly related to the topic of breast cancer therapy with tamoxifen were excluded from the review. To avoid including duplicate publications therein, if we found two studies by the same authors, the study period of each author was assessed, and if the dates coincided, we selected the most recent publication. It can be concluded that there are restrictions on the management tactics of patients faced with endometrial hyperplastic processes while taking tamoxifen. Many patients included in existing studies and case reports have variable factors that make direct analysis or comparison complicated, such as age, the presence of hypertension, body mass index, various reproductive periods in which patients experienced breast cancer, the duration of tamoxifen intake, and the frequency of pelvic ultrasound. However, this literature review summarizes the data of recent major studies that may clarify the criteria for assessing endometrial thickness while taking tamoxifen and possible options for managing patients during breast cancer therapy. The following steps can improve the quality of medical care for patients with hyperplasia during tamoxifen therapy: awareness of the patient about possible hyperplastic processes during therapy; awareness that any episode of abnormal uterine bleeding is a reason to see a doctor; pelvic ultrasound before starting tamoxifen therapy; the ultrasound thickness of the endometrium is not a reliable criterion, however, elastosonography may be a more promising technique for identifying the risks of malignancy.

Engineering an Estradiol Sensor for Real-Time Detection of Hormones in the Brain

Abstract Text Emerging evidence suggests that estradiol (E2), a potent agonist of estrogen receptors, plays a modulatory role in various brain functions, including mood regulation, cognitive processes, and reproductive behaviors1. Nevertheless, circuit- and cell-type-specific studies of E2 in vivo remain challenging due to the absence of analytical tools capable of precise spatiotemporal detection of E2 in the brain, time-locked with behavior. Here, we present a genetically encoded fluorescent indicator for the real-time detection of estradiol, enabling the study of estradiol dynamics with high spatial specificity and temporal resolution. When expressed in HEK cells, the sensor exhibits a 180% dynamic fluorescence increase in response to E2 at saturation. The sensor also shows high sensitivity to estradiol, responding to concentrations as low as the nanomolar range. Interestingly, the sensor exhibits affinities to other estradiol agonists similar to those of native estrogen receptors, with distinct response characteristics for each ligand. A similar estradiol response profile was observed when the sensor was expressed in primary rat cortical neurons. To further validate the sensor’s compatibility in the brain, we performed stereotactic injection of an AAV1-DIO vector containing the estradiol sensor into the medial preoptic area of the hippocampus in Cre-ESR1 mice. The animals were then sacrificed for ex vivo brain sectioning followed by 2-photon imaging. The sensor expressed in ESR1-positive neurons of the targeted brain region exhibited a 100% fluorescence increase in response to a 300 nM bath application of E2. While comprehensive validation of the sensor, including its functionality, is still in progress, we believe this sensor will be a valuable asset not only for investigating the role of E2 in brain function and behavior but also for addressing broader biological questions that require monitoring of E2 in situ. 1. Taxier LR, Gross KS, Frick KM. Oestradiol as a neuromodulator of learning and memory. Nat Rev Neurosci. 2020;21(10):535-550. doi:10.1038/s41583-020-0362-7 Date of Presentation October 16, 2024

FT-GNN Tool for Bridging HRMS Features and Bioactivity: Uncovering Unidentified Estrogen Receptor Agonists in Sewage.

Identifying primary estrogen receptor (ER) agonists in municipal sewage is essential for ensuring the health of aquatic environments. Given the complex and variable chemical composition of sewage, the predominant ER agonists remain unclear. High-resolution mass spectrometry (HRMS)-based models have been developed to predict compound bioactivity in complex matrices, but further optimization is needed to effectively bridge HRMS features with ER agonists. To address this challenge, an FT-GNN (fragmentation tree-based graph neural network) model was proposed. Given limited data and class imbalance, data augmentation was performed using model predictions within the applicability domain (AD) and oversampling technique (OTE). Model development results demonstrated that integrating the FT-GNN with data augmentation improved the balanced accuracy (bACC) value by 6%-31%. The developed model, with a high bACC to identify more true ER agonists, efficiently classified tens of thousands of unidentified HRMS features in sewage, reducing postprocessing workload in nontargeted screening. Analysis of ER agonist transformation during sewage treatment revealed the anaerobic stage as key to both their removal and formation. Estrogenic effect balance analysis suggests that α-E2 and 9,11-didehydroestriol may be two previously overlooked key ER agonists. Collectively, the development and application of the FT-GNN model are crucial advancements toward credible tracking and efficient control of estrogenic risks in water.

Endocrine disruption potential of dust in children's indoor environments: Associations with multiple chemicals from various compound classes across exposure matrices used for health risk assessment.

Endocrine disruption potential of dust in children's indoor environments: Associations with multiple chemicals from various compound classes across exposure matrices used for health risk assessment.

High-throughput zebrafish screening reveals cardiotoxic effects of organophosphate flame retardants.

High-throughput zebrafish screening reveals cardiotoxic effects of organophosphate flame retardants.

Endocrine-Disrupting Activities of Flavones on Steroid Receptors: Structural Requirements and Synthesis of Novel Flavone with Improved Estrogenic Activity.

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, excessive exposure to some flavonoids comes with a risk of endocrine disruption. Our objective was to define the structural elements of flavones and selected other flavonoids required for endocrine-disrupting activities on each of four steroid receptors, estrogen, androgen, progesterone, and glucocorticoid receptors. Methods: This work presents a systematic screen for the hormone agonist or antagonist activity of a selected panel of flavonoids on estrogen, androgen, progesterone, and glucocorticoid receptors. The screen is focused on the positional requirements of hydroxyl substituents on the flavone backbone. Results: Each receptor exhibited a distinct pattern for structural requirements of the flavones to impact receptor signaling. The most active flavones exhibited antagonist activity on androgen and progesterone receptors with an IC50 of 0.5 and 2 µM, respectively. Flavones only exhibited weak antagonism on glucocorticoid receptors. When active, flavones acted as estrogen receptor agonists. The findings were utilized to design and synthesize a novel flavone, 3-fluoro, 6,4'-dihydroxyflavone 14, that displays increased potency as an estrogen agonist (EC50~30 nM). Modeling of the binding of this novel flavone predicts increased preference for ERα versus ERβ relative to the estrogenic phytoestrogen, genistein. Conclusions: The structural requirements for flavones to act as estrogen agonists and antagonists of other steroid receptors are defined. The synthesis of a novel flavone offers potential for topical applications where systemic estrogen activity is undesired. However, the results highlight the potential for endocrine disruption when certain flavones are consumed in quantity as supplements.

Comprehensive Nontargeted Analysis of Drinking Water Supplies to Identify Chemicals Associated with Estrogen Receptor Agonism or Present in Regions of Elevated Breast Cancer Occurrence.

To explore the hypothesis that differential exposures to estrogen active chemicals may contribute to regional disparities in cancer incidence, a comprehensive targeted and nontargeted analysis was conducted over two seasons (2020) for drinking water samples from 120 households served by 8 public water systems (4 with historically elevated breast cancer incidence) and from 15 brands of retail water. All samples were analyzed using gas and liquid chromatography with high-resolution mass spectrometry and a bioassay for estrogen receptor agonism. Target compounds included disinfection byproducts, per- and polyfluoroalkyl substances (PFAS), trace elements, and compounds selected for their possible relation to breast cancer. Over 7500 GC and LC nontargeted molecular features passed all quality control filters in each sampling season and were prioritized for identification if they were related to measured estrogen receptor agonism or were present at higher levels in areas with high breast cancer incidence (n = 1036). Benzothiazole-2-sulfonic acid, acetyl tributyl citrate, and diphenyl sulfone were among the prioritized and confirmed nontarget compounds. Nine polycyclic aromatic hydrocarbons and two ketone derivatives displayed significant negative correlations with estrogen receptor agonism. Many prioritized compounds remained unidentified, as 84.4% of the LC features and 77.5% of the GC features could not be annotated with high confidence.

Oestrogenic and androgenic activity of oxybenzone and methylparaben in vitro.

Motivated by emerging concerns about health hazards associated with various industrial chemicals, this study investigated the disruption of endocrine system using well established in vitro assays. Due to the lack of scientific data on adverse effects of chemicals used in personal care products (PCPs), the focus was placed on oestrogenic and androgenic action of photostabiliser oxybenzone and preservative methylparaben. To this end we relied on in vitro assays for oestrogen and androgen receptor activation based on HeLa-9903 and AREcoScreen GR KO M1 cell lines to determine dose response according to respective OECD Test Guidelines 455 and 458. Our findings clearly demonstrate that both chemicals act as oestrogen receptor agonists and androgen receptor antagonists, raising additional concerns about health risks for humans posed by excessive and widespread use of such chemicals in PCPs.

Genistein as a Chemo-modulatory Agent: Exploring its Potential in Chemosensitization and Combinatorial Therapeutic Strategies for Cancer Treatment.

Genistein (GEN), a phytoestrogen primarily sourced from soy plants, is recognized for its anticancer properties attributed to its roles as a tyrosine kinase inhibitor, an estrogen receptor agonist, and its influence on various cancer hallmarks by modulating diverse signaling pathways. Recent research has highlighted the considerable potential of GEN in combating drug resistance in cancer cells. This attribute of GEN has been demonstrated by its capacity to modulate tyrosine kinases such as HER2, HER3, and EGFR which are implicated in tumorigenesis, as well as prosurvival signaling pathways including NF-κB and Akt/mTOR. Moreover, GEN impacts drug accumulation, AR-driven transcriptional regulation, ER signaling, and various genes that are involved in autophagy, pro/anti-apoptosis, DNA methylation, and histone acetylation. Further, GEN demonstrated efficacy in combinatorial therapy with various standard anticancer agents like 5-FU, cetuximab, cisplatin, clofarabine, doxorubicin, tamoxifen, TRAIL, trastuzumab, and other agents with anticancer activities such as capsaicin, curcumin, daidzein, lycopene, resveratrol, sulforaphane, etc., across a spectrum of cancers including the cancers of bone, brain, breast, cervix, colorectal, endometrium, esophagus, head and neck, leukemia, liver, lung, ovary, pancreas and stomach. Thus, further clinical validation of these potential combinations involving GEN is warranted to confirm the preclinical findings.

Lessons learned from evaluating defined chemical mixtures in a high-throughput estrogen receptor assay system.

Lessons learned from evaluating defined chemical mixtures in a high-throughput estrogen receptor assay system.

Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling.

Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling.

Asymmetric synthesis of an optically active 1-benzylindane derivative as a selective agonist for estrogen receptor beta

Asymmetric synthesis of an optically active 1-benzylindane derivative as a selective agonist for estrogen receptor beta

Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors.

The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36). In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects. We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity.

Do estrogens receptor agonists have a neuroprotective effect on mouse rgc after optic nerve axotomy?

Aims/Purpose: Estrogens are known to have neuroprotective effects in the central nervous system1‐2 (CNS) and only this steroid hormone has the capability of rescue neuronal cell death caused by an injury. Estrogen receptors (ERs) are expressed in both sexes and are distributed throughout the CNS, while the ER‐β is the most predominant in the brain.The aim of this study is:1. To compare the course of death of RGCs in female and male mice after optic nerve axotomy during the fast (up to 9 days) and slow (from 9 day onwards) phases of RGC loss.2. To analyse the expression of ER‐α and ER‐β in intact retinas.3. To study the neuroprotective effect of ER agonism in the two phases of RGC loss.Methods: Optic nerve crush (ONC) was performed on the left eye of pigmented male and female mice, and the course of retinal ganglion cell3 (RGC) loss analysed up to 21 days after the injury. In intact retinas of both sexes the number of RGCs expressing the estrogen receptors alpha (ER‐α) and beta (ER‐β) was studied. To test the neuroprotective potential of both ERs, ER‐β or ER‐α agonists1‐2 were injected into the vitreous just after ONC and 9 days later, and the retinas analysed at 21 days.Results: The time course of axotomy‐induced RGC death differs between male and female mice. In males, axotomy‐induced RGC loss is significant after 3 days, whereas in females it is delayed until 5 days. In both sexes, ERs are expressed by more than 70% of RGCs. ER‐β agonism neuroprotects axotomised RGCs at 21 days in both sexes: RGC survival in ER‐β treated animals is 19% higher in males and 17% higher in females than in vehicle treated animals.Conclusions: The loss of RGCs following axotomy is significant at an earlier in males than in females. RGCs from both sexes express both ERs. Intravitreal administration of ER‐β agonist delays axotomy‐induced RGCs loss during the second, slow phase of death.References Chakrabarti M., et al. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull. 2014; 109:22‐31. Das A., et al. Estrogen receptor agonists and estrogen attenuate TNF‐α‐induced apoptosis in VSC4.1 motoneurons. J Endocrinol. 2011; 208(2):171‐82. Galindo‐Romero C., et al. Axotomy‐induced retinal ganglion cell death in adult mice: quantitative and topographic time course analyses. Exp Eye Res. 2011; 92(5):377‐87.

Estrogen Alleviates Oxidative Bowel Injury and Neuroinflammation in Necrotizing Enterocolitis.

Estrogen Alleviates Oxidative Bowel Injury and Neuroinflammation in Necrotizing Enterocolitis.

The Molecular Mechanism of Dicofol as an Agonist of the Human Estrogen Receptor: Insights from Molecular Docking and MM-GBSA Studies

The risk to human health has increased worldwide due to the widespread use of organochlorine pesticides. Dicofol (DCF), an organochlorine pesticide, is one of the most contentious endocrine disruptors; it can interact with nuclear receptors and interfere with their regular function. A member of the steroid hormone receptor family, the estrogen receptor (ER) is found in many bodily tissues. It binds to androgens and controls the activity of genes that are responsive to androgens. There is a chance that DCF will disrupt the estrogen receptor. In light of these specifics, we tested the ER disruption and related mechanisms of DCF using Molecular Docking, Generalized Born, and Surface Area Continuum Salvation (MM GBSA) in Molecular Mechanics. Dicofol may bind to the ER with efficiency, according to the docking results that were obtained. The MMGBSA results demonstrated that lipophilic interactions were the primary driver of the stable binding process. The current study supports the structural evidence that DCF is an endocrine disruptor and provides crucial guidance for finding safer alternatives.

Long-term impact of embryonic exposure to ethinylestradiol and clotrimazole on behavior and neuroplasticity in zebrafish (Danio rerio)

Long-term impact of embryonic exposure to ethinylestradiol and clotrimazole on behavior and neuroplasticity in zebrafish (Danio rerio)

Cancer Cells Show Higher Sensitivity to Melatonin-Tamoxifen Drug Conjugates than to Combination of Melatonin and Tamoxifen.

Drug conjugates of tamoxifen and melatonin linked through the amide side chain of melatonin (4a,4b) were reported as promising agents for future treatment of breast cancer, possibly reversing the adverse effects of tamoxifen. Here, we report the synthesis and pharmacological evaluation of a novel series of anticancer drug conjugates linking melatonin with tamoxifen through polymethylene spacers through the ether oxygen of melatonin (16a-c, 19a-c, 21) and compare them to the previously reported amide-linked analogues 4a and 4b. All hybrid ligands are antagonists of estrogen receptor alpha and agonists of the melatonin MT1 receptor with variable potencies. Several drug conjugates including the (CH2)4-linked analogues 4a and 16a and the (CH2)6-linked compound 16c showed higher potency to inhibit cell viability than the combination of melatonin and tamoxifen on at least one cancer cell line including MCF-7, MDA-MB-231, and HT-1080.