Sample records for potential estrogenic effects

  1. Effect of estrogens on skin aging and the potential role of SERMs

    PubMed Central

    Stevenson, Susan; Thornton, Julie

    2007-01-01

    In humans, structural and functional changes attributable to aging are more visibly evident in the skin than in any other organ. Estrogens have significant effects on skin physiology and modulate epidermal keratinocytes, dermal fibroblasts and melanocytes, in addition to skin appendages including the hair follicle and the sebaceous gland. Importantly, skin aging can be significantly delayed by the administration of estrogen. This paper reviews the effects of estrogens on skin and the mechanisms by which estrogens can alleviate the changes due to aging that occur in human skin. The relevance of estrogen replacement therapy (HRT) in post-menopausal women and the potential value of selective estrogen receptor modulators (SERMs) as a therapy for diminishing skin aging are also highlighted. PMID:18044179

  2. Environmental estrogenic effects of alkylphenol ethoxylates.

    PubMed

    Nimrod, A C; Benson, W H

    1996-05-01

    Alkylphenol ethoxylates (APEs) and related compounds recently have been reported to be estrogenic because it has been demonstrated in laboratory studies that they mimic the effects of estradiol both in vitro and in vivo. Chemicals referred to as "environmental estrogens" are suspected of causing health effects in both humans and wildlife through disruption of the endocrine system. In this review, the occurrence, environmental fate, and biological effects of APEs are presented. To provide understanding of the potential for endocrine disruption due to environmental estrogens, the physiology of estrogens in mammals and fish is also reviewed. The estrogenic potency of other environmental estrogens is compared to the potency of APE degradation products. The reproductive effects of estrogenic compounds are considered when evaluating the potential health effects of APEs. Given the reported environmental concentrations and bioconcentration factors of APE products, the potential for these compounds to produce estrogenic effects in the environment appears low. Although questions concerning the physiological effects of APEs and other environmental estrogens remain unanswered, there are indications that research is in progress that will lead to better understanding of the risks to humans and wildlife.

  3. Examining triclosan-induced potentiation of the estrogen uterotrophic effect

    EPA Science Inventory

    Triclosan (TCS), a widely used antibacterial, has been shown to be an endocrine disruptor. We reported previously that TCS potentiated the estrogenic effect of ethinyl estradiol (EE) on uterine growth in rats orally administered 3 μg/kg EE and TCS (2 to 18 mg/kg) in the utero...

  4. Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin.

    PubMed

    Liu, Xuemei; Zhang, Fagen; Liu, Hong; Burdette, Joanna E; Li, Yan; Overk, Cassia R; Pisha, Emily; Yao, Jiaqin; van Breemen, Richard B; Swanson, Steven M; Bolton, Judy L

    2003-06-01

    Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated

  5. Potential Approaches to Enhance the Effects of Estrogen on Senescent Blood Vessels and Postmenopausal Cardiovascular Disease

    PubMed Central

    Khalil, Raouf A.

    2010-01-01

    Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERα, ERβ and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERα such as PPT, ERβ such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD. PMID:20210774

  6. Characterizing the Estrogenic Potential of 1060 Environmental ...

    EPA Pesticide Factsheets

    In order to detect environmental chemicals that pose a risk of endocrine disruption, high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals are needed. Alteration of estrogen signaling has been implicated in a variety of adverse health effects including cancer promotion, reproductive deficits, and vascular effects. Here we investigate the estrogenic potential of 1060 chemicals of environmental relevance using a real-time measure of growth kinetics by electrode impedance in the estrogen-responsive human ductal carcinoma, T47D cell line. Cells were treated in concentration response and measurements of cellular impedance were recorded every hour for six days. Progestens, androgens, and mineralocortocoids (progesterone, dihydrotestosterone, aldosterone) invoked a biphasic impedance signature that contrasted with the anticipated exponential impedance observed in response to known estrogen receptor agonists (17β-estradiol, genestein, bisphenol-A, nonylphenol, 4-tert-octylphenol). Several compounds, including bisphenol-A, and genestein caused impedance comparable to that of 17β-estradiol, although at much higher concentrations. Additionally, trenbolone and cyproterone acetate invoked the characteristic biphasic signature observed with other endogenous steroid hormones. The continuous real-time nature of this assay allows for the rapid detection of differential growth characteristics not easily detected by traditional cell prol

  7. Determination of estrogenic potential in waste water without sample extraction.

    PubMed

    Avberšek, Miha; Žegura, Bojana; Filipič, Metka; Uranjek-Ževart, Nataša; Heath, Ester

    2013-09-15

    This study describes the modification of the ER-Calux assay for testing water samples without sample extraction (NE-(ER-Calux) assay). The results are compared to those obtained with ER-Calux assay and a theoretical estrogenic potential obtained by GC-MSD. For spiked tap and waste water samples there was no statistical difference between estrogenic potentials obtained by the three methods. Application of NE-(ER-Calux) to "real" influent and effluents from municipal waste water treatment plants and receiving surface waters found that the NE-(ER-Calux) assay gave higher values compared to ER-Calux assay and GC-MSD. This is explained by the presence of water soluble endocrine agonists that are usually removed during extraction. Intraday dynamics of the estrogenic potential of a WWTP influent and effluent revealed an increase in the estrogenic potential of the influent from 12.9 ng(EEQ)/L in the morning to a peak value of 40.0 ng(EEQ)/L in the afternoon. The estrogenic potential of the effluent was estrogenic potential was 92-98%. Daytime estrogenic potential values varied significantly. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. An Assessment of Potential Exposure and Risk from Estrogens in Drinking Water

    PubMed Central

    Caldwell, Daniel J.; Mastrocco, Frank; Nowak, Edward; Johnston, James; Yekel, Harry; Pfeiffer, Danielle; Hoyt, Marilyn; DuPlessie, Beth M.; Anderson, Paul D.

    2010-01-01

    prescribed and total estrogens that may potentially be present in drinking water in the United States are not causing adverse effects in U.S. residents, including sensitive subpopulations. PMID:20194073

  9. Estrogen Inhibits Dlk1/FA1 Production: A Potential Mechanism for Estrogen Effects on Bone Turnover

    PubMed Central

    Abdallah, B. M.; Bay-Jensen, A.; Srinivasan, B.; Tabassi, N. C.; Garnero, P.; Delaissé, J.; Khosla, S.; Kassem, M.

    2011-01-01

    We have recently identified Dlk1/FA1 (Delta-like 1/FA1) as a novel regulator of bone mass that functions to mediate bone loss, under estrogen deficiency, in mice. In this report, we investigated the effects of estrogen (E)-deficiency and E replacement on serum (s) levels of Dlk1/FA1 (s-Dlk1FA1) and its correlation with bone turnover markers. s-Dlk1/FA1 and bone turnover markers (s-CTx and s-osteocalcin), were measured in two cohorts: a group of pre- and postmenopausal women (n=100) and a group of postmenopausal women, where half had received estrogen replacement therapy (ERT) (n=166). s-Dlk1/FA1, and s-CTX were elevated in postmenopausal E-deficient compared to premenopausal E-replete women (both; P<0.001). s-Dlk1/FA1 was correlated with s-CTX (r=0.30, P<0.01). ERT, in postmenopausal women, decreased s-Dlk1/FA1, as well as s-CTX and s-osteoclacin (all; P<0.0001). Changes in s-Dlk1 were significantly correlated with those observed in s-CTx (r=0.18, P<0.05) and s-osteocalcin (r=0.28, P<0.001). In conclusion, s-Dlk1/FA1 is influenced by E-deficiency and is correlated with bone turnover. Increased levels of s-Dlk1/FA1 in post-menopausal women may be a mechanism mediating the effects estrogen deficiency on bone turnover. PMID:21681814

  10. Contraceptive, estrogenic and anti-estrogenic potentials of methanolic root extract of Carpolobia lutea in rodents.

    PubMed

    Ettebong, Ette Okon; Nwafor, Paul Alozie; Ekpo, Memfin; Ajibesin, Kola Kayode

    2011-10-01

    Several plants are used in herbal medicine for family planning. Carpolobia lutea is a medicinal plant in South Eastern Nigeria used for family planning. The study was designed to investigate the contraceptive, estrogenic and antiestrogenic potentials of the methanolic root extract of Carpolobia lutea in both rats and mice. The contraceptive effect of extract (7 - 21mg/kg) administered by intraperitoneal route for four days in divided doses was tested in mice and rats. Sexually-active males were introduced on day 5 at the ratio of 3F:1M and kept with these females till the end of the experiment. Investigations on the estrogenic and antiestrogenic property of the extract (7-21mg/kg) were done in immature rats that had undergone surgical removal of both ovaries. The effects of the extract (vaginal opening, vaginal cornification, uterine wet weight) were compared with 17-beta-estradiol (0.1µg/rat/day) as standard drug. Twenty-four hours later, the animals were sacrificed following the last dose and the weights of uterus, kidney, liver and small intestine were recorded. The extract prevented conception in both mice and rats for two gestational periods. Significant changes (p<0.05-0.001) were observed in the length and weight of pups relative to control. There were no abnormalities observed in the pups over thirty days. In ovariectomized immature young rats, the extract showed estrogenic effect (vaginal opening, vaginal cornification and increased uterine wet weight) in low doses while in high doses, it showed anti-estrogenic effect. These findings agree with the traditional use of Carpolobia lutea in the control of fertility. The contraceptive property of the extract may be associated with the direct effects of its chemical constituents.

  11. Synergistic Action of Flavonoids, Baicalein, and Daidzein in Estrogenic and Neuroprotective Effects: A Development of Potential Health Products and Therapeutic Drugs against Alzheimer's Disease

    PubMed Central

    Choi, Roy C. Y.; Zhu, Judy T. T.; Yung, Amanda W. Y.; Lee, Pinky S. C.; Xu, Sherry L.; Guo, Ava J. Y.; Zhu, Kevin Y.; Dong, Tina T. X.; Tsim, Karl W. K.

    2013-01-01

    Despite the classical hormonal effect, estrogen has been reported to mediate neuroprotection in the brain, which leads to the searching of estrogen-like substances for treating neurodegenerative diseases. Flavonoids, a group of natural compounds, are well known to possess estrogenic effects and used to substitute estrogen, that is, phytoestrogen. Flavonoid serves as one of the potential targets for the development of natural supplements and therapeutic drugs against different diseases. The neuroprotection activity of flavonoids was chosen for a possible development of anti-Alzheimer's drugs or food supplements. The estrogenic activity of two flavonoids, baicalein and daidzein, were demonstrated by their strong abilities in stimulating estrogen receptor phosphorylation and transcriptional activation of estrogen responsive element in MCF-7 breast cells. The neuroprotection effects of flavonoids against β-amyloid (Aβ) were revealed by their inhibition effects on in vitro Aβ aggregation and Aβ-induced cytotoxicity in PC12 neuronal cells. More importantly, the estrogenic and neuroprotective activities of individual flavonoid could be further enhanced by the cotreatment in the cultures. Taken together, this synergistic effect of baicalein and daidzein might serve as a method to improve the therapeutic efficacy of different flavonoids against Aβ, which might be crucial in developing those flavonoidsin treating Alzheimer's disease in the future. PMID:24058373

  12. EADB: An Estrogenic Activity Database for Assessing Potential Endocrine Activity

    EPA Science Inventory

    Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body’s endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many ...

  13. Estrogen Effects on Wound Healing

    PubMed Central

    Horng, Huann-Cheng; Chang, Wen-Hsun; Yeh, Chang-Ching; Huang, Ben-Shian; Chang, Chia-Pei; Chen, Yi-Jen; Tsui, Kuan-Hao

    2017-01-01

    Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing. PMID:29099810

  14. [Bone metabolism and cardiovascular function update. Estrogen and its therapeutic potential for bone and vascular health].

    PubMed

    Ohta, Hiroaki

    2014-07-01

    Despite its long-standing role as a "guardian angel" for the female body, estrogen has recently been dethroned from its status as an "elixir" and its use has been restricted due to its oncogenic potential as well as its coagulation system-associated risk. However, it is recognized that estrogen not only works against bone resorption but also improves vascular function. In this regard, it is suggested that estrogen may have a role in improving deteriorated bone quality through its antioxidant action, while this same effect with the SERMs, which may be accounted for by the presence of estrogen, remains yet to be established. Not only evidence needs to be accumulated to support the vascular effects of the SERMs, but their pleiotropic, rather than extra-skeletal, effects, as likely mediated by the estrogen receptors distributed throughout the body, remain to be elucidated.

  15. Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

    PubMed Central

    Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

    2014-01-01

    Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

  16. Vascular Effects of Estrogenic Menopausal Hormone Therapy

    PubMed Central

    Reslan, Ossama M.; Khalil, Raouf A.

    2011-01-01

    Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of

  17. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    PubMed Central

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  18. Src-JNK Potentiation of Estrogen Receptor AF-1; Mechanism, and Role in Estrogen Action in Breast Cancer

    DTIC Science & Technology

    2002-08-01

    an increase in estrogen receptor activity. A second objective is to understand the potential role of Src in estrogen induced mammary ductal development ...bPcis i on to The Ser-ilS-dependent link wt GR- t KaroBio AB, a Swedish pharmaceutical development company with CBP is in addition to the Ser-1l8...the ECL detection kit (Amersham Pharmacia Biotech ). phoresis, stained with Coomassic Blue to monitor expression, and sub- Fluorescence Microscopy

  19. The Distinct Effects of Estrogen and Hydrostatic Pressure on Mesenchymal Stem Cells Differentiation: Involvement of Estrogen Receptor Signaling.

    PubMed

    Zhao, Ying; Yi, Fei-Zhou; Zhao, Yin-Hua; Chen, Yong-Jin; Ma, Heng; Zhang, Min

    2016-10-01

    This study aimed to investigate the differential and synergistic effects of mechanical stimulation and estrogen on the proliferation and osteogenic or chondrogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs) and the roles of estrogen receptor (ER) in them. BMSCs were isolated and cultured using the whole bone marrow adherence method, and flow cytometry was used to identify the surface marker molecules of BMSCs. Cells were pre-treated with 1 nM 17β-estradiol or 1 nM of the estrogen receptor antagonist tamoxifen. Then, the cells were stimulated with hydrostatic pressure. Assessment included flow cytometry analysis of the cell cycle; immunofluorescent staining for F-actin; protein quantification for MAPK protein; and mRNA analysis for Col I, OCN, OPN and BSP after osteogenic induction and Sox-9, Aggrecan and Col-II after chondrogenic induction. Hydrostatic pressure (90 kPa/1 h) and 1 nM 17β-estradiol enhanced the cellular proliferation ability and the cytoskeleton activity but without synergistic biological effects. Estrogen activated ERKs and JNKs simultaneously and promoted the osteogenic differentiation, whereas the pressure just caused JNK-1/2 activation and promoted the chondrogenic differentiation of BMSCs. Estrogen had antagonism effect on chondrogenic promotion of hydrostatic pressure. Mechanobiological effects of hydrostatic pressure are closely associated with ERα activity. MAPK molecules and F-actin were likely to be important mediator molecules in the ER-mediated mechanotransduction of BMSCs.

  20. Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain

    PubMed Central

    Murakami, Gen

    2016-01-01

    Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due

  1. Additive mixture effects of estrogenic chemicals in human cell-based assays can be influenced by inclusion of chemicals with differing effect profiles.

    PubMed

    Evans, Richard Mark; Scholze, Martin; Kortenkamp, Andreas

    2012-01-01

    A growing body of experimental evidence indicates that the in vitro effects of mixtures of estrogenic chemicals can be well predicted from the estrogenicity of their components by the concentration addition (CA) concept. However, some studies have observed small deviations from CA. Factors affecting the presence or observation of deviations could include: the type of chemical tested; number of mixture components; mixture design; and assay choice. We designed mixture experiments that address these factors, using mixtures with high numbers of components, chemicals from diverse chemical groups, assays with different in vitro endpoints and different mixture designs and ratios. Firstly, the effects of mixtures composed of up to 17 estrogenic chemicals were examined using estrogenicity assays with reporter-gene (ERLUX) and cell proliferation (ESCREEN) endpoints. Two mixture designs were used: 1) a 'balanced' design with components present in proportion to a common effect concentration (e.g. an EC(10)) and 2) a 'non-balanced' design with components in proportion to potential human tissue concentrations. Secondly, the individual and simultaneous ability of 16 potential modulator chemicals (each with minimal estrogenicity) to influence the assay outcome produced by a reference mixture of estrogenic chemicals was examined. Test chemicals included plasticizers, phthalates, metals, PCBs, phytoestrogens, PAHs, heterocyclic amines, antioxidants, UV filters, musks, PBDEs and parabens. In all the scenarios tested, the CA concept provided a good prediction of mixture effects. Modulation studies revealed that chemicals possessing minimal estrogenicity themselves could reduce (negatively modulate) the effect of a mixture of estrogenic chemicals. Whether the type of modulation we observed occurs in practice most likely depends on the chemical concentrations involved, and better information is required on likely human tissue concentrations of estrogens and of potential modulators

  2. Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles

    PubMed Central

    Evans, Richard Mark; Scholze, Martin; Kortenkamp, Andreas

    2012-01-01

    A growing body of experimental evidence indicates that the in vitro effects of mixtures of estrogenic chemicals can be well predicted from the estrogenicity of their components by the concentration addition (CA) concept. However, some studies have observed small deviations from CA. Factors affecting the presence or observation of deviations could include: the type of chemical tested; number of mixture components; mixture design; and assay choice. We designed mixture experiments that address these factors, using mixtures with high numbers of components, chemicals from diverse chemical groups, assays with different in vitro endpoints and different mixture designs and ratios. Firstly, the effects of mixtures composed of up to 17 estrogenic chemicals were examined using estrogenicity assays with reporter-gene (ERLUX) and cell proliferation (ESCREEN) endpoints. Two mixture designs were used: 1) a ‘balanced’ design with components present in proportion to a common effect concentration (e.g. an EC10) and 2) a ‘non-balanced’ design with components in proportion to potential human tissue concentrations. Secondly, the individual and simultaneous ability of 16 potential modulator chemicals (each with minimal estrogenicity) to influence the assay outcome produced by a reference mixture of estrogenic chemicals was examined. Test chemicals included plasticizers, phthalates, metals, PCBs, phytoestrogens, PAHs, heterocyclic amines, antioxidants, UV filters, musks, PBDEs and parabens. In all the scenarios tested, the CA concept provided a good prediction of mixture effects. Modulation studies revealed that chemicals possessing minimal estrogenicity themselves could reduce (negatively modulate) the effect of a mixture of estrogenic chemicals. Whether the type of modulation we observed occurs in practice most likely depends on the chemical concentrations involved, and better information is required on likely human tissue concentrations of estrogens and of potential modulators

  3. The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk.

    PubMed

    Williams-Brown, Marian Y; Salih, Sana M; Xu, Xia; Veenstra, Timothy D; Saeed, Muhammad; Theiler, Shaleen K; Diaz-Arrastia, Concepcion R; Salama, Salama A

    2011-09-01

    Western blot analysis. In contrast to TAM, RAL has minimal effect on EM, estrogen-DNA adduct formation, or estrogen-metabolizing enzymes expression. These data show that TAM perturbs the balance of estrogen-metabolizing enzymes and alters the disposition of estrogen metabolites, which can explain, at least in part, the mechanism for TAM-induced EC. These results also implicate the differential effect of TAM and RAL on estrogen metabolism/metabolites as a potential mechanism for their disparate effects on the endometrium. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Estrogenic and anti-estrogenic activity of 23 commercial textile dyes.

    PubMed

    Bazin, Ingrid; Ibn Hadj Hassine, Aziza; Haj Hamouda, Yosra; Mnif, Wissem; Bartegi, Ahgleb; Lopez-Ferber, Miguel; De Waard, Michel; Gonzalez, Catherine

    2012-11-01

    The presence of dyes in wastewater effluent of textile industry is well documented. In contrast, the endocrine disrupting effects of these dyes and wastewater effluent have been poorly investigated. Herein, we studied twenty-three commercial dyes, usually used in the textile industry, and extracts of blue jean textile wastewater samples were evaluated for their agonistic and antagonistic estrogen activity. Total estrogenic and anti-estrogenic activities were measured using the Yeast Estrogen Screen bioassay (YES) that evaluates estrogen receptor binding-dependent transcriptional and translational activities. The estrogenic potencies of the dyes and wastewater samples were evaluated by dose-response curves and compared to the dose-response curve of 17β-estradiol (E2), the reference compound. The dose-dependent anti-estrogenic activities of the dyes and wastewater samples were normalized to the known antagonistic effect of 4-hydroxytamoxifen (4-OHT) on the induction of the lac Z reporter gene by E2. About half azo textile dyes have anti-estrogenic activity with the most active being Blue HFRL. Most azo dyes however have no or weak estrogenic activity. E2/dye or E2/waste water ER competitive binding assays show activity of Blue HFRL, benzopurpurine 4B, Everzol Navy Blue FBN, direct red 89 BNL 200% and waste water samples indicating a mechanism of action common to E2. Our results indicate that several textile dyes are potential endocrine disrupting agents. The presence of some of these dyes in textile industry wastewater may thus impact the aquatic ecosystem. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

    PubMed

    Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

    2014-06-01

    The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

  6. Integral assessment of estrogenic potentials in sediment-associated samples: Part 2: Study of estrogen and anti-estrogen receptor-binding potentials of sediment-associated chemicals under different salinity conditions using the salinity-adapted enzyme-linked receptor assay.

    PubMed

    Kase, Robert; Hansen, Peter D; Fischer, Birgit; Manz, Werner; Heininger, Peter; Reifferscheid, Georg

    2009-01-01

    The enzyme-linked receptor assay (ELRA) detects estrogenic and anti-estrogenic effects at the molecular level of receptor binding and is a useful tool for the integrative assessment of ecotoxicological potentials caused by hormonally active agents (HAA) and endocrine disrupting compounds (EDC). The main advantage of the ELRA is its high sample throughput and its robustness against cytotoxicity and microbial contamination. After a methodological adaptation to salinity of the ELRA, according to the first part of this study, which increased its salinity tolerance and sensitivity for 17-beta-estradiol, the optimised ELRA was used to investigate 13 native sediments characterised by different levels of salinity and chemical contamination. The applicability of the ELRA for routine analysis in environmental assessment was evaluated. Salinity is often a critical factor for bioassays in ecotoxicological sediment assessment. Therefore, salinity of the samples was additionally adjusted to different levels to characterise its influence on elution and binding processes of receptor-binding substances. The ELRA was carried out with the human estrogen receptor alpha (ER) in a 96-well microplate format using the experimental setup known from the competitive immunoassay based on ligand-protein interaction. It is an important improvement that a physiologically relevant receptor was used as a linking protein instead of an antibody. The microplates were coated with a 17-beta-estradiol-BSA conjugate, and dilution series of estradiol and of native sediment samples were added and incubated with the ER. After a washing step, a biotinylated mouse anti-ER antibody was added to each well. Receptor binding to estradiol, agonistic and antagonistic receptor binding, were determined by a streptavidin-POD-biotin complex with subsequent measurement of the peroxidase activity at the wavelength of 450 nm using a commercial ELISA multiplate reader. The sediment elutriates and pore water samples of

  7. MODELING THE EFFECTS OF FLEXIBILITY ON THE BINDING OF ENVIRONMENTAL ESTROGENS TO THE ESTROGEN RECEPTOR

    EPA Science Inventory

    Modeling the effects of flexibility on the binding of environmental estrogens to the estrogen receptor
    There are many reports of environmental endocrine disruption in the literature, yet it has been difficult to identify the specific chemicals responsible for these effects. ...

  8. DEVELOPMENTAL EVALUATION OF A POTENTIAL NON-STEROIDAL ESTROGEN: TRICLOSAN

    EPA Science Inventory

    Triclosan is an antibacterial agent commonly used in industry and often detected in wastewater effluent. The potential of triclosan to act as an endocrine disruptor was examined because its chemical structure closely resembles known non-steroidal estrogens (e.g. DES, bis-phenol A...

  9. Effect-related monitoring: estrogen-like substances in groundwater.

    PubMed

    Kuch, Bertram; Kern, Frieder; Metzger, Jörg W; von der Trenck, Karl Theo

    2010-02-01

    Concentration monitoring as a basis for risk assessment is a valid approach only if there is an unambiguous relation between concentration and effect. In many cases, no such unambiguous relation exists, since various substances can exert the same effect with differing potencies. If some or all of these substances contributing to a biological effect are unknown, effect-related monitoring becomes indispensable. Endocrine-disrupting substances in water bodies, including the groundwater, are a prominent example of such a case. The aim of the investigations described here was to detect hormonally active substances in the groundwater downstream of obsolete landfills by using the E-screen assay and to possibly assign the biological effect to individual chemical compounds by means of instrumental analyses carried out in parallel. Grab samples of the groundwater were collected downstream from abandoned landfills and prepared by liquid/liquid extraction. The total estrogenic activity in these samples was determined in vitro by applying the E-screen assay. The human breast cancer cells (MCF-7) used in the E-screen proliferate in response to the presence of estrogenically active compounds. Expressed in concentration units of the reference substance 17beta-estradiol (E2), the test system allows the quantification of estrogenicity with a limit of detection (LOD) in the range of 0.1 ng/L. Aliquots of the samples were screened using gas chromatography/mass spectrometry (GC/MS) in order to quantify known estrogenically active substances and to identify unknown compounds. Estrogen-positive samples were extracted at different pH values, split into acidic, neutral, and basic fractions and analyzed by GC/MS, searching for individual components that display estrogenic activity. Estrogenic activity exceeding the LOD and the provisional benchmark of 0.5 ng E2/L was found at three out of seven abandoned waste disposal sites tested. The low concentrations of known xenoestrogens such as

  10. Bromine-80m-labeled estrogens: Auger-electron emitting, estrogen receptor-directed ligands with potential for therapy of estrogen receptor positive cancers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    DeSombre, E.R.; Mease, R.C.; Hughes, A.

    1988-01-01

    A triphenylbromoethylene, 1,1-bis(p-hydroxyphenyl)-2-bromo-2-phenylethylene, Br-BHPE, and a bromosteroidal estrogen, 17..cap alpha..- bromovinylestradiol, BrVE/sub 2/, were labeled with the Auger electron emitting nuclide bromine-80m, prepared by the (p,n) reaction with /sup 80/Se. To assess their potential as estrogen receptor (ER) directed therapeutic substrates the bromine-80m labeled estrogens were injected into immature female rats and the tissue distribution studied at 0.5 and 2 hours. Both radiobromoestrogens showed substantial diethylstilbesterol (DES)-inhibitable localization in the ER rich tissues, uterus, pituitary, ovary and vagina at both time points. While the percent dose per gram tissue was higher for the Br-BHPE, the BrVE/sub 2/ showed higher tissuemore » to blood ratios, especially at 2 hr, reflecting the lower blood concentrations of radiobromine following administration of the steroidal bromoestrogen. Comparing intraperitoneal, intravenous and subcutaneous routes of administration for the radiobromine labeled Br-BHPE, the intraperitoneal route was particularly advantageous to provide maximum, DES-inhibitable concentrations in the peritoneal, ER-rich target organs, the uterus, ovary and vagina. While uterine concentrations after BrBHPE were from 10--48% dose/g and after BrVE/sub 2/ were 15--25% dose/g, similar treatment with /sup 80m/Br as sodium bromide showed uniform low concentrations in all tissues at about the levels seen in blood. The effective specific activity of (/sup 80m/Br)BrBHPE, assayed by specific binding to ER in rat uterine cytosol, was 8700 Ci/mmole. 23 refs., 9 figs., 2 tabs.« less

  11. Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

    PubMed Central

    Woolfrey, Kevin M.; Penzes, Peter

    2013-01-01

    Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits

  12. EFFECTS OF EXOGENOUS ESTROGEN ON MATE SELECTION OF HOUSE FINCHES

    EPA Science Inventory

    Concern about the potential for endocrine disrupting chemicals to interfere with normal breeding behaviors of wildlife has prompted this study of effects of exogenous estrogen on mate selection in songbirds. The house finch (Carpodacus mexicanus) was selected as a model as it is ...

  13. EFFECTS OF EXTROGENOUS ESTROGEN ON MATE SELECTION OF HOUSE FINCHES

    EPA Science Inventory

    Effects of exogenous estrogen on mate selection of house finches. Clark, J., Fairbrother, A*. Parametrix, Inc., Corvallis, OR; Brewer, L., EBA, Inc., Sisters, OR; Bennett, R.S., USEPA, Mid-Continent Ecology Division, Duluth, MN.

    Concern about the potential for endocrine...

  14. VASCULAR ACTIONS OF ESTROGENS: FUNCTIONAL IMPLICATIONS

    PubMed Central

    Miller, Virginia M.; Duckles, Sue P.

    2009-01-01

    The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, it is the goal of this review to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared to men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. While consensus opinions are emphasized, controversial views are presented in order to stimulate future research. PMID:18579753

  15. The Estrogen Receptor-α in Osteoclasts Mediates the Protective Effects of Estrogens on Cancellous But Not Cortical Bone

    PubMed Central

    Martin-Millan, Marta; Almeida, Maria; Ambrogini, Elena; Han, Li; Zhao, Haibo; Weinstein, Robert S.; Jilka, Robert L.; O'Brien, Charles A.; Manolagas, Stavros C.

    2010-01-01

    Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)α from the monocyte/macrophage cell lineage in mice (ERαLysM−/−) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERαLysM−/− were resistant to the proapoptotic effect of 17β-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERα knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERα was as effective as 17β-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERα. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERα. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton. PMID:20053716

  16. Impact of smoking on estrogenic efficacy.

    PubMed

    Ruan, X; Mueck, A O

    2015-02-01

    Depending on the type, duration and intensity of cigarette smoking, the efficacy of endogenous and exogenous estrogen can be reduced or completely cancelled. Not only does smoking diminish the beneficial effects of estrogen on hot flushes and urogenital symptoms and its positive effects on lipid metabolism, but smoking also can reduce estrogen's ability to prevent osteoporosis and perhaps also cardiovascular diseases. This is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated so far only with oral estrogen applications. Compensation for the failure of therapeutic action should not be made by increasing the dose in smokers since this might result in the production of potentially mutagenic estrogen metabolites associated with a higher risk of breast cancer. Since the favorable effects of estrogens seem to be not lost in smokers when estrogens are applied transdermally, this route should be preferred in smokers. The most important conclusion from the data presented is that the effects of smoking are very complex and dependent on a multiplicity of factors, so that different types of clinically relevant negative effects must be expected. Women who continue to smoke despite all warnings should be informed that smoking, in addition to all its other negative effects, can also jeopardize the success of hormone replacement therapy.

  17. The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety

    PubMed Central

    Han, Sang Jun; Begum, Khurshida; Foulds, Charles E.; Hamilton, Ross A.; Bailey, Suzanna; Malovannaya, Anna; Chan, Doug; Qin, Jun

    2016-01-01

    The conjugated estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen-target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor α (ERα)–estrogen response element (ERE)–DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry–immunoblotting analyses revealed that, upon TSEC treatment, ERα interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERα-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERα protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERα-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERα interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERα protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERα inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein. PMID:26487511

  18. Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer

    PubMed Central

    Shang, Zhiqun; Li, Yanjun; Hsu, Iawen; Zhang, Minghao; Tian, Jing; Wen, Simeng; Han, Ruifa; Messing, Edward M.; Chang, Chawnshang; Niu, Yuanjie; Yeh, Shuyuan

    2016-01-01

    Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence. PMID:27092883

  19. Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer.

    PubMed

    Shang, Zhiqun; Li, Yanjun; Hsu, Iawen; Zhang, Minghao; Tian, Jing; Wen, Simeng; Han, Ruifa; Messing, Edward M; Chang, Chawnshang; Niu, Yuanjie; Yeh, Shuyuan

    2016-05-10

    Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette-Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.

  20. Postmenopausal estrogen and progestin effects on the serum proteome

    PubMed Central

    2009-01-01

    Background Women's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated. Methods Baseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool. Results In total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways. Conclusions Serum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects. PMID:20034393

  1. Effects of transdermal estrogen replacement therapy on cardiovascular risk factors.

    PubMed

    Menon, Dileep V; Vongpatanasin, Wanpen

    2006-01-01

    The prevalence of hypertension and cardiovascular disease increases dramatically after menopause in women, implicating estrogen as having a protective role in the cardiovascular system. However, recent large clinical trials have failed to show cardiovascular benefit, and have even demonstrated possible harmful effects, of opposed and unopposed estrogen in postmenopausal women. While these findings have led to a revision of guidelines such that they discourage the use of estrogen for primary or secondary prevention of heart disease in postmenopausal women, many investigators have attributed the negative results in clinical trials to several flaws in study design, including the older age of study participants and the initiation of estrogen late after menopause.Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen administration with regards to the cardiovascular outcomes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiologic concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circulation and, thus, avoids the first-pass hepatic effect.Although oral estrogen exerts a more favorable influence than transdermal estrogen on traditional cardiovascular risk factors such as high- and low-density lipoprotein-cholesterol levels, recent studies have indicated that oral estrogen adversely influences many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases levels of acute-phase proteins such as C-reactive protein and serum amyloid A; procoagulant factors such as prothrombin fragments 1+2; and several

  2. Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β

    PubMed Central

    Seeger, Bettina; Klawonn, Frank; Nguema Bekale, Boris; Steinberg, Pablo

    2016-01-01

    Consumers of fruits and vegetables are frequently exposed to small amounts of hormonally active pesticides, some of them sharing a common mode of action such as the activation of the human estrogen receptor α (hERα) or β (hERβ). Therefore, it is of particular importance to evaluate risks emanating from chemical mixtures, in which the individual pesticides are present at human-relevant concentrations, below their corresponding maximum residue levels. Binary and ternary iso-effective mixtures of estrogenic pesticides at effect concentrations eliciting a 1 or 10% effect in the presence or absence of 17β-estradiol were tested experimentally at the hERα in the yeast-based estrogen screen (YES) assay as well as in the human U2-OS cell-based ERα chemical-activated luciferase gene expression (ERα CALUX) assay and at the hERβ in the ERβ CALUX assay. The outcome was then compared to predictions calculated by means of concentration addition. In most cases, additive effects were observed with the tested combinations in all three test systems, an observation that supports the need to expand the risk assessment of pesticides and consider cumulative risk assessment. An additional testing of mixture effects at the hERβ showed that most test substances being active at the hERα could also elicit additive effects at the hERβ, but the hERβ was less sensitive. In conclusion, effects of the same ligands at the hERα and the hERβ could influence the estrogenic outcome under physiological conditions. PMID:26812056

  3. Effects of environmental estrogenic chemicals on AP1 mediated transcription with estrogen receptors alpha and beta.

    PubMed

    Fujimoto, Nariaki; Honda, Hiroaki; Kitamura, Shigeyuki

    2004-01-01

    There has been much discussion concerning endocrine disrupting chemicals suspected of exerting adverse effects in both wildlife and humans. Since the majority of these compounds are estrogenic, a large number of in vitro tests for estrogenic characteristics have been developed for screening purpose. One reliable and widely used method is the reporter gene assay employing estrogen receptors (ERs) and a reporter gene with a cis-acting estrogen responsive element (ERE). Other elements such as AP1 also mediate estrogenic signals and the manner of response could be quite different from that of ERE. Since this has yet to be explored, the ER mediated AP1 activity in response to a series of environmental estrogens was investigated in comparison with ERE findings. All the compounds exhibited estrogenic properties with ERE-luc and their AP1 responses were quite similar. These was one exception, however, p,p'-DDT (1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane) did not exert any AP1-luc activity, while it appeared to be estrogenic at 10(-7) to 10(-5)M with the ERE action. None of the compounds demonstrated ER beta:AP1 activity. These data suggest that significant differences can occur in responses through the two estrogen pathways depending on environmental chemicals.

  4. GPER Mediates Non-Genomic Effects of Estrogen.

    PubMed

    Pupo, Marco; Maggiolini, Marcello; Musti, Anna Maria

    2016-01-01

    Estrogens are important modulators of a broad spectrum of physiological functions in humans. However, despite their beneficial actions, a number of lines of evidence correlate the sustained exposure to exogenous estrogen with increased risk of the onset of various cancers. Mainly these steroid hormones induce their effects by binding and activating estrogen receptors (ERα and ERβ). These receptors belong to the family of ligand-regulated transcription factors, and upon activation they regulate the expression of different target genes by binding directly to specific DNA sequences. On the other hand, in recent years it has become clear that the G protein-coupled estrogen receptor 30 (GPR30/GPER) is able to mediate non-genomic action of estrogens in different cell contexts. In particular, GPER has been shown to specifically bind estrogens, and in turn to functionally cross-react with diverse cell signaling systems such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway and the mitogen-activated protein kinases (MAPK) pathway. In this chapter we will present some of the different experimental techniques currently used to demonstrate the functional role of GPER in mediating non-genomic actions of estrogens, such as the dual luciferase assay, assessment of the involvement of GPER in the stimulation of cell migration in breast cancer cell lines and in cancer-associated fibroblasts, and chromatin immunoprecipitation assay. Overall, the experimental procedures described herein represent key instruments for assessing the biological role of GPER in mediating non-genomic signals of estrogen.

  5. Fluorescent characteristics of estrogenic compounds in landfill leachate.

    PubMed

    Zhanga, Hua; Changb, Cheng-Hsuan; Lü, Fan; Su, Ay; Lee, Duu-Jong; He, Pin-Jing; Shao, Li-Ming

    2009-08-01

    Estrogens in landfill leachate could probably contaminate receiving water sources if not properly polished before discharge. This work measured, using an estrogen receptor-alpha competitor screening assay, the estrogenic potentials of leachate samples collected at a local sanitary landfill in Shanghai, China and their compounds fractionated by molecular weights. The chemical structures of the constituent compounds were characterized using fluorescence excitation and emission matrix (EEM). The organic matters of molecular weight <600 Da and of 3000-14,000 Da contributed most of the estrogenic potentials of the raw leachates. The former were considered as the typical endocrine disrupting compounds in dissolved state; while the latter the fulvic acids with high aromaticity that were readily adsorbed with estrogens (bound state). Statistical analysis on EEM peaks revealed that the chemical structures of noted estrogens in dissolved state and in bound state were not identical. Aerobic treatment effectively removed dissolved estrogens, but rarely removed those bound estrogens.

  6. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Soo Yeun; Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746; Oh, Seung Min

    Chronic exposure to marijuana produces adverse effects on the endocrine and reproductive systems in humans; however, the experimental evidence for this presented thus far has not been without controversy. In this study, the estrogenic effect of marijuana smoke condensate (MSC) was evaluated using in vitro bioassays, viz., the cell proliferation assay, the reporter gene assay, and the ER competitive binding assay. The results of these assays were compared with those of three major cannabinoids, i.e., THC, CBD, and CBN. The estrogenic effect of MSC was further confirmed by the immature female rat uterotrophic assay. MSC stimulated the estrogenicity related tomore » the ER-mediated pathway, while neither THC, CBD, nor CBN did. Moreover, treatment with 10 and 25 mg/kg MSC induced significant uterine response, and 10 mg/kg MSC resulted in an obvious change in the uterine epithelial cell appearance. MSC also enhanced the IGFBP-1 gene expression in a dose-dependent manner. To identify the constituents of MSC responsible for its estrogenicity, the MSC fractionated samples were examined using another cell proliferation assay, and the estrogenic active fraction was analyzed using GC-MS. In the organic acid fraction that showed the strongest estrogenic activity among the seven fractions of MSC, phenols were identified. Our results suggest that marijuana abuse is considered an endocrine-disrupting factor. Furthermore, these results suggest that the phenolic compounds contained in MSC play a role in its estrogenic effect.« less

  7. Biochar as potential adsorptive media for estrogenic compounds

    USDA-ARS?s Scientific Manuscript database

    Endocrine disrupting chemicals are an emerging problem in water pollution due to their toxic effects on humans and wildlife. Estrogenic compounds are a subset of endocrine disrupting chemicals that are particularly dangerous since they are very potent and can affect fish at concentrations as low as ...

  8. Overview of a workshop on screening methods for detecting potential (anti-) estrogenic/androgenic chemicals in wildlife

    USGS Publications Warehouse

    Ankley, Gerald T.; Mihaich, Ellen; Stahl, Ralph G.; Tillitt, Donald E.; Colborn, Theo; McMaster, Suzzanne; Miller, Ron; Bantle, John; Campbell, Pamela; Denslow, Nancy; Dickerson, Richard L.; Folmar, Leroy C.; Fry, Michael; Giesy, John P.; Gray, L. Earl; Guiney, Patrick; Hutchinson, Thomas; Kennedy, Sean W.; Kramer, Vincent; LeBlanc, Gerald A.; Mayes, Monte; Nimrod, Alison; Patino, Reynaldo; Peterson, Richard; Purdy, Richard; Ringer, Robert; Thomas, Peter C.; Touart, Les; Van Der Kraak, Glen; Zacharewski, Tim

    1998-01-01

    The U.S. Congress has passed legislation requiring the U.S. Environmental Protection Agency (U.S. EPA) to develop, validate, and implement screening tests for identifying potential endocrine-disrupting chemicals within 3 years. To aid in the identification of methods suitable for this purpose, the U.S. EPA, the Chemical Manufacturers Association, and the World Wildlife Fund sponsored several workshops, including the present one, which dealt with wildlife species. This workshop was convened with 30 international scientists representing multiple disciplines in March 1997 in Kansas City, Missouri, USA. Participants at the meeting identified methods in terms of their ability to indicate (anti-) estrogenic/androgenic effects, particularly in the context of developmental and reproductive processes. Data derived from structure-activity relationship models and in vitro test systems, although useful in certain contexts, cannot at present replace in vivo tests as the sole basis for screening. A consensus was reached that existing mammalian test methods (e.g., with rats or mice) generally are suitable as screens for assessing potential (anti-) estrogenic/ androgenic effects in mammalian wildlife. However, due to factors such as among-class variation in receptor structure and endocrine function, it is uncertain if these mammalian assays would be of broad utility as screens for other classes of vertebrate wildlife. Existing full and partial life-cycle tests with some avian and fish species could successfully identify chemicals causing endocrine disruption; however, these long-term tests are not suitable for routine screening. However, a number of short-term tests with species from these two classes exist that could serve as effective screening tools for chemicals inducing (anti-) estrogenic/androgenic effects. Existing methods suitable for identifying chemicals with these mechanisms of action in reptiles and amphibians are limited, but in the future, tests with species from

  9. Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

    PubMed

    Grassi, S; Frondaroli, A; Di Mauro, M; Pettorossi, V E

    2010-12-15

    In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Developmental Effects and Estrogenicity of Bisphenol A Alternatives in a Zebrafish Embryo Model.

    PubMed

    Mu, Xiyan; Huang, Ying; Li, Xuxing; Lei, Yunlei; Teng, Miaomiao; Li, Xuefeng; Wang, Chengju; Li, Yingren

    2018-03-06

    In order to understand the negative effects of bisphenol A (BPA) alternatives comprehensively, zebrafish embryos were used to assess the lethality, developmental effects, and estrogenic activity of bisphenol analogues. The in silico estrogenic activities of bisphenol analogues were assayed by binding simulation. According to our results, the lethality of bisphenol analogues decreased in order of bisphenol AF (BPAF) > BPA > bisphenol F (BPF) > bisphenol S (BPS). BPAF and BPF induced significant effects on zebrafish embryos, including decreased heart rate, hatching inhibition, and teratogenic effects. The binding potentials of bisphenol analogues toward zebrafish ERs (zfERS) decreased in the following order: BPAF > BPA > BPF > BPS. Among the three subtypes of zfERs, zfERβ2 showed the highest binding activity toward the bisphenols, followed by zfERα and zfERβ1. In vivo estrogenic activity tests showed that BPAF, BPA, and BPF significantly enhanced the protein levels of ERα along with the mRNA levels of esr1, esr2a, esr2b, and vtg1 in zebrafish embryos. Esr2b showed the strongest response to BPAF and BPA exposure among the three esrs. In contrast, BPS did not significantly regulate ER protein level or ER transcription. In conclusion, BPAF showed the highest lethality, developmental effects, and estrogenic activity (both in silico and in vivo) followed by BPA and BPF. BPS showed the weakest toxicity and estrogenic activity. zfERβ2 might act as the main target among the three ER subtypes of zebrafish after exposure to BPAF and BPA.

  11. Experimental study on the estrogen-like effect of boric Acid.

    PubMed

    Wang, Yadong; Zhao, Yingzheng; Chen, Xiaoyu

    2008-02-01

    There are now considerable evidences that boric acid has reproductive and developmental toxicity, but it is uncertain whether such toxicity is caused by estrogen-like effect. Our objective is to determine the estrogen-like effect of boric acid. Proliferation assay of MCF-7 human breast cancer cells, uterotrophic assay, measure assay of the estradiol (E2), proliferation assay of mucous membrane cells, and assay of estrogen receptor were conducted in this study. Boric acid could increase the weight of uterus of ovariectomized SD rats and the height of epithelium cells of mucous membrane, enhance the expression of the proliferating cell nucleus antigen, and reduce the density of estrogen receptors. However, boric acid could not affect the level of estradiol in serum and stimulate the proliferation of MCF-7 human breast cancer cells. In this study, boric acid exhibited the estrogen-like effect in vivo.

  12. Extracellular matrix integrity: a possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?

    PubMed

    Cox, David A; Helvering, Leah M

    2006-03-09

    Recent gene microarray studies have illustrated heterogeneity in gene expression changes not only between estrogens and selective estrogen receptor modulators (SERMs), but also across different SERM molecules. In ovariectomized rats, this phenomenon was observed with respect to a number of genes involved in collagen turnover and extracellular matrix (ECM) integrity in the uterus and vaginal tissues. Preliminary mechanistic data suggest that these effects on ECM integrity may have relevance in the context of the effect of estrogens and some SERMs to increase the risk of pelvic organ prolapse and the incidence of urinary incontinence in postmenopausal women. Given the pivotal role of ECM integrity and collagen turnover in other tissues and disease states, these processes may provide a fruitful target for future research into the mechanisms for the heterogeneous pharmacology of estrogens and SERMs across different cell types and target tissues.

  13. Rapid effects of estrogens on short-term memory: Possible mechanisms.

    PubMed

    Paletta, Pietro; Sheppard, Paul A S; Matta, Richard; Ervin, Kelsy S J; Choleris, Elena

    2018-06-01

    Estrogens affect learning and memory through rapid and delayed mechanisms. Here we review studies on rapid effects on short-term memory. Estradiol rapidly improves social and object recognition memory, spatial memory, and social learning when administered systemically. The dorsal hippocampus mediates estrogen rapid facilitation of object, social and spatial short-term memory. The medial amygdala mediates rapid facilitation of social recognition. The three estrogen receptors, α (ERα), β (ERβ) and the G-protein coupled estrogen receptor (GPER) appear to play different roles depending on the task and brain region. Both ERα and GPER agonists rapidly facilitate short-term social and object recognition and spatial memory when administered systemically or into the dorsal hippocampus and facilitate social recognition in the medial amygdala. Conversely, only GPER can facilitate social learning after systemic treatment and an ERβ agonist only rapidly improved short-term spatial memory when given systemically or into the hippocampus, but also facilitates social recognition in the medial amygdala. Investigations into the mechanisms behind estrogens' rapid effects on short term memory showed an involvement of the extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) kinase pathways. Recent evidence also showed that estrogens interact with the neuropeptide oxytocin in rapidly facilitating social recognition. Estrogens can increase the production and/or release of oxytocin and other neurotransmitters, such as dopamine and acetylcholine. Therefore, it is possible that estrogens' rapid effects on short-term memory may occur through the regulation of various neurotransmitters, although more research is need on these interactions as well as the mechanisms of estrogens' actions on short-term memory. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Effects of hypoxia on the response of fish to estrogen exposure

    EPA Science Inventory

    Natural and synthetic estrogens are common contaminants in surface waters and have the potential to affect reproduction in fish. Estrogens are likely to co-occur with low dissolved oxygen (DO) levels, which result from inputs of organic material in wastewater effluents or from an...

  15. DEVELOPMENTAL EVALUATION OF A POTENTIAL NON-STEROIDAL ESTROGEN: TRICLOSAN. (R827098)

    EPA Science Inventory

    Abstract

    Triclosan is an antibacterial agent commonly used in industry and often detected in wastewater effluent. The potential of triclosan to act as an endocrine disruptor was examined because its chemical structure closely resembles known non-steroidal estrogens (e....

  16. Facile screening of potential xenoestrogens by an estrogen receptor-based reusable optical biosensor.

    PubMed

    Liu, Lanhua; Zhou, Xiaohong; Lu, Yun; Shan, Didi; Xu, Bi; He, Miao; Shi, Hanchang; Qian, Yi

    2017-11-15

    The apparent increase in hormone-induced cancers and disorders of the reproductive tract has led to a growing demand for new technologies capable of screening xenoestrogens. We reported an estrogen receptor (ER)-based reusable fiber biosensor for facile screening estrogenic compounds in environment. The bioassay is based on the competition of xenoestrogens with 17β-estradiol (E 2 ) for binding to the recombinant receptor of human estrogen receptor α (hERα) protein, leaving E 2 free to bind to fluorophore-labeled anti-E 2 monoclonal antibody. Unbound anti-E 2 antibody then binds to the immobilized E 2 -protein conjugate on the fiber surface, and is detected by fluorescence emission induced by evanescent field. As expected, the stronger estrogenic activity of xenoestrogen would result in the weaker fluorescent signal. Three estrogen-agonist compounds, diethylstilbestrol (DES), 4-n-nonylphenol (NP) and 4-n-octylphenol (OP), were chosen as a paradigm for validation of this assay. The rank order of estrogenic potency determined by this biosensor was DES>OP>NP, which were consistent with the published results in numerous studies. Moreover, the E 2 -protein conjugate modified optical fiber was robust enough for over 300 sensing cycles with the signal recoveries ranging from 90% to 100%. In conclusion, the biosensor is reusable, reliable, portable and amenable to on-line operation, providing a facile, efficient and economical alternative to screen potential xenoestrogens in environment. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Health Impacts of Estrogens in the Environment, Considering Complex Mixture Effects

    PubMed Central

    Filby, Amy L.; Neuparth, Teresa; Thorpe, Karen L.; Owen, Richard; Galloway, Tamara S.; Tyler, Charles R.

    2007-01-01

    Background Environmental estrogens in wastewater treatment work (WwTW) effluents are well established as the principal cause of reproductive disruption in wild fish populations, but their possible role in the wider health effects of effluents has not been established. Objectives We assessed the contribution of estrogens to adverse health effects induced in a model fish species by exposure to WwTW effluents and compared effects of an estrogen alone and as part of a complex mixture (i.e., spiked into effluent). Methods Growth, genotoxic, immunotoxic, metabolic, and endocrine (feminized) responses were compared in fathead minnows (Pimephales promelas) exposed for 21 days to a potent estrogenic effluent, a weakly estrogenic effluent before and after spiking with a steroidal estrogen [17α-ethinyl-estradiol (EE2)], and to EE2 alone. Results In addition to endocrine disruption, effluent exposure induced genotoxic damage, modulated immune function, and altered metabolism; many of these effects were elicited in a sex-specific manner and were proportional to the estrogenic potencies of the effluents. A key finding was that some of the responses to EE2 were modified when it was present in a complex mixture (i.e., spiked into effluent), suggesting that mixture effects may not be easily modeled for effluent discharges or when the chemicals impact on a diverse array of biological axes. Conclusion These data reveal a clear link between estrogens present in effluents and diverse, adverse, and sex-related health impacts. Our findings also highlight the need for an improved understanding of interactive effects of chemical toxicants on biological systems for understanding health effects of environmental mixtures. PMID:18087587

  18. Interactions between estrogen effects and hunger effects in ovariectomized female mice. I. Measures of arousal

    PubMed Central

    Shelley, Deborah N.; Dwyer, EvaRose; Johnson, Carolyn; Wittkowski, Knut M.; Pfaff, Donald W.

    2007-01-01

    Measures of arousal were used to study effects of estradiol and food restriction, and their potential interactions, in ovariectomized female C57Bl/6 mice. It was hypothesized based on a proposed theoretical equation (Pfaff, 2006) that each treatment would increase arousal-related behaviors and that their combination would further increase arousal behavior. Following baseline testing, animals (n = 28) were divided into 3 groups that, in different experimental phases, received either estradiol (in subcutaneous capsules), restricted diet (a liquid diet providing 60% of daily caloric requirements) or a combination of those two. An automated arousal behavior monitoring system was used to measure home cage voluntary motor activity and sensory responsiveness, these being components of a new operational definition of ‘generalized arousal’. Key findings: (1) During the light, all treatments reduced voluntary activity. (2) In the dark, estrogens increased, while estrogens in combination with restricted diet decreased, horizontal activity. (3) In the dark, restricted diet alone had little effect on voluntary activity, but reduced it when combined with estrogen treatment. (4) All treatments reduced responses to the olfactory stimulus. The dependence of results on time of day was unexpected. Further, different patterns of results for the three treatments suggest that estrogens and food restriction did not have equivalent or additive effects on arousal. While contrary to the main prediction, these findings are discussed in terms of the animals’ adaptive preparations for reproduction (Schneider, 2006). PMID:17868674

  19. Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory.

    PubMed

    Korol, Donna L; Pisani, Samantha L

    2015-08-01

    This article is part of a Special Issue "Estradiol and cognition". Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings showing that the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging.

    PubMed

    Wend, Korinna; Wend, Peter; Krum, Susan A

    2012-01-01

    The roles of estrogens have been best studied in the breast, breast cancers, and in the female reproductive tract. However, estrogens have important functions in almost every tissue in the body. Recent clinical trials such as the Women's Health Initiative have highlighted both the importance of estrogens and how little we know about the molecular mechanism of estrogens in these other tissues. In this review, we illustrate the diverse functions of estrogens in the bone, adipose tissue, skin, hair, brain, skeletal muscle and cardiovascular system, and how the loss of estrogens during aging affects these tissues. Early transcriptional targets of estrogen are reviewed in each tissue. We also describe the tissue-specific effects of selective estrogen receptor modulators (SERMs) used for the treatment of breast cancers and postmenopausal symptoms.

  1. Examining triclosan-induced estrogenic and androgenic effects on the rat reproductive system

    EPA Science Inventory

    Background: Triclosan (TCS), a widely used antibacterial, has been shown to be an endocrine disruptor. We reported previously that TCS potentiated the estrogenic effect of ethinyl estradiol (EE) on uterine growth in female rats co-administered EE (3 μg/kg) and TCS (2 to 18 m...

  2. Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat

    PubMed Central

    Deer, Rachel R.

    2016-01-01

    In the present study, interactions of age and estrogen in the modulation of cerebrovascular function were examined in small arteries <150 μM. The hypothesis tested was that age enhances deleterious effects of exogenous estrogen by augmenting constrictor prostanoid (CP)-potentiated reactivity of the female (F) cerebrovasculature. F Sprague-Dawley rats approximating key stages of “hormonal aging” in humans were studied: perimenopausal (mature multi-gravid, MA, cyclic, 5–6 mo of age) and postmenopausal (reproductively senescent, RS, acyclic 10–12 mo of age). Rats underwent bilateral ovariectomy and were given estrogen replacement therapy (E) or placebo (O) for 14–21 days. Vasopressin reactivity (VP, 10−12–10−7 M) was measured in pressurized middle cerebral artery segments, alone or in the presence of COX-1- (SC560, 1 μM) or COX-2- (NS398, 10 μM) selective inhibitors. VP-stimulated release of prostacyclin (PGI2) and thromboxane (TXA2) were assessed by radioimmunoassay of 6-keto-PGF1α and TXB2 (stable metabolites). VP-induced vasoconstriction was attenuated in ovariectomized + estrogen-replaced, multigravid adult rats (5–6 mo; MAE) but potentiated in older ovariectomized + estrogen-replaced, reproductively senescent rats (12–14 mo; RSE). SC560 and NS398 reduced reactivity similarly in ovariectomized multigravid adult rats (5–6 mo; MAO) and ovariectomized reproductively senescent rat (12–14 mo; RSO). In MAE, reactivity to VP was reduced to a greater extent by SC560 than by NS398; however, in RSE, this effect was reversed. VP-stimulated PGI2 was increased by estrogen, yet reduced by age. VP-stimulated TXA2 was increased by estrogen and age in RSE but did not differ in MAO and RSO. Taken together, these data reveal that the vascular effects of estrogen are distinctly age-dependent in F rats. In younger MA, beneficial and protective effects of estrogen are evident (decreased vasoconstriction, increased dilator prostanoid function). Conversely, in

  3. EADB: An Estrogenic Activity Database for Assessing ...

    EPA Pesticide Factsheets

    Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body’s endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; http://www.fda.gov/ScienceResearch/ BioinformaticsTools/EstrogenicActivityDatabaseEADB/default. htm) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of

  4. [The estrogenic effect of formononetin and its effect on the expression of rats' atrium estrogen receptors].

    PubMed

    Xing, Dian-Xia; Liu, Xian-Ling; Xue, Cun-Kuan; Huang, Qi; Liu, Zhi-Gao; Xiong, Liang

    2010-09-01

    To observe the estrogenic effect of formononetin and its effect on the expressions of atrial estrogen receptor subtypes alpha and beta (ERalpha and ERbeta). 50 femal rats were randomly divided into five groups: sham group, model group, nilestriol group, formononetin groups of low and high dose. Rats in sham group were cut a piece of fat before closing the abdomen, the others were ovariectomized. Vaginal exfoliated cell were observed from the fifth day to the tenth after operation to test if the model is successful. The sham and model group were given nomal saline in 10 mL/kg by gavage, the remaining three groups were given nilestriol 2.5 mg/(kg x w), low [20 mg/(kg x d) land high dose [100 mg/(kg x d)) of formononetin by gavage respectively. In the 8th week, vaginal exfoliated cell were observed, then decapitated the rats, removed the uterus, weighed and take wright staining microscopy. The relative expressions of ERalpha and ERbeta of right atrium were detected by RT-PCR. The vaginal cells exhibit a change of estrus after had been fed with high dose of formononetin after 8 weeks. Formononetin increase the uterus coefficient and the expression of atrial ERbeta (P < 0.01), but it dose not have any effect on the expression of ERalpha (P > 0.05). Formononetin have estrogenic effect in ovariectomized rats, and it can markedly upregulate the expression of rats' atrial ERbeta.

  5. Treatment of BG-1 Ovarian Cancer Cells Expressing Estrogen Receptors with Lambda-cyhalothrin and Cypermethrin Caused a Partial Estrogenicity Via an Estrogen Receptor-dependent Pathway

    PubMed Central

    Kim, Cho-Won; Go, Ryeo-Eun

    2015-01-01

    Synthetic pyrethroids (SPs) are the most common pesticides which are recently used for indoor pest control. The widespread use of SPs has resulted in the increased exposure to wild animals and humans. Recently, some SPs are suspected as endocrine disrupting chemicals (EDCs) and have been assessed for their potential estrogenicity by adopting various analyzing assays. In this study, we examined the estrogenic effects of lambda-cyhalothrin (LC) and cypermethrin (CP), the most commonly used pesticides in Korea, using BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To evaluate the estrogenic activities of two SPs, LC and CP, we employed MTT assay and reverse-transcription polymerase chain reaction (RT-PCR) in LC or CP treated BG-1 ovarian cancer cells. In MTT assay, LC (10−6 M) and CP (10−5 M) significantly induced the growth of BG-1 cancer cells. LC or CP-induced cell growth was antagonized by addition of ICI 182,720 (10−8 M), an ER antagonist, suggesting that this effect appears to be mediated by an ER-dependent manner. Moreover, RT-PCR results showed that transcriptional level of cyclin D1, a cell cycle-regulating gene, was significantly up-regulated by LC and CP, while these effects were reversed by co-treatment of ICI 182,780. However, p21, a cyclin D-ckd-4 inhibitor gene, was not altered by LC or CP. Moreover, ERα expression was not significantly changed by LC and CP, while downregulated by E2. Finally, in xenografted mouse model transplanted with human BG-1 ovarian cancer cells, E2 significantly increased the tumor volume compare to a negative control, but LC did not. Taken together, these results suggest that LC and CP may possess estrogenic potentials by stimulating the growth of BG-1 ovarian cancer cells via partially ER signaling pathway associated with cell cycle as did E2, but this estrogenic effect was not found in in vivo mouse model. PMID:26877835

  6. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover).

    PubMed

    Mu, H; Bai, Y-H; Wang, S-T; Zhu, Z-M; Zhang, Y-W

    2009-04-01

    Antioxidant and estrogenic effects of formononetin on ovariectomized mice have been investigated in the present study. The adult female Kunming mice were divided into 5 groups: sham-operated group, ovariectomized group, stilbestrol replacement therapy group (0.20 mg/kg day), low-dose formononetin group (0.05 g/kg day) and high-dose formononetin group (0.5 g/kg day). The mice in the latter 4 groups were ovariectomized. The drug was given by oral administration for 6 months. Estrogenic effect was determined by the change of uterine weight, and oxidant effects were determined by the content of SOD, GSH-Px, CAT and MDA. The intake of formononetin increased the uterine weight of the mice significantly as well as the content of SOD, GSH-Px, CAT, and reduced MDA in body. Formononetin had obvious antioxidant effects and estrogenic effect, and the estrogenic effect was not dosage-related.

  7. Estrogen-Cholinergic Interactions: Implications for Cognitive Aging

    PubMed Central

    Newhouse, Paul; Dumas, Julie

    2015-01-01

    While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

  8. Inhibitory effect of luteolin on estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19).

    PubMed

    Lu, Dan-feng; Yang, Li-juan; Wang, Fei; Zhang, Guo-lin

    2012-08-29

    Inhibition of aromatase, the key enzyme in estrogen biosynthesis, is an important strategy in the treatment of breast cancer. Several dietary flavonoids show aromatase inhibitory activity, but their tissue specificity and mechanism remain unclear. This study found that the dietary flavonoid luteolin potently inhibited estrogen biosynthesis in a dose- and time-dependent manner in KGN cells derived from human ovarian granulosa cells, the major source of estrogens in premenopausal women. Luteolin decreased aromatase mRNA and protein expression in KGN cells. Luteolin also promoted aromatase protein degradation and inhibited estrogen biosynthesis in aromatase-expressing HEK293A cells, but had no effect on recombinant expressed aromatase. Estrogen biosynthesis in KGN cells was inhibited with differing potencies by extracts of onion and bird chili and by four other dietary flavonoids: kaempferol, quercetin, myricetin, and isorhamnetin. The present study suggests that luteolin inhibits estrogen biosynthesis by decreasing aromatase expression and destabilizing aromatase protein, and it warrants further investigation as a potential treatment for estrogen-dependent cancers.

  9. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1.

    PubMed

    Pelekanou, Vasiliki; Kampa, Marilena; Kiagiadaki, Foteini; Deli, Alexandra; Theodoropoulos, Panayiotis; Agrogiannis, George; Patsouris, Efstratios; Tsapis, Andreas; Castanas, Elias; Notas, George

    2016-02-01

    Estrogens are known modulators of monocyte/macrophage functions; however, the underlying mechanism has not been clearly defined. Recently, a number of estrogen receptor molecules and splice variants were identified that exert different and sometimes opposing actions. We assessed the expression of estrogen receptors and explored their role in mediating estrogenic anti-inflammatory effects on human primary monocytes. We report that the only estrogen receptors expressed are estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30/G-protein estrogen receptor 1, in a sex-independent manner. 17-β-Estradiol inhibits the LPS-induced IL-6 inflammatory response, resulting in inhibition of NF-κB transcriptional activity. This is achieved via a direct physical interaction of ligand-activated estrogen receptor-α 36-kDa splice variant with the p65 component of NF-κB in the nucleus. G-protein coupled receptor 30/G-protein estrogen receptor 1, which also physically interacts with estrogen receptor-α 36-kDa splice variant, acts a coregulator in this process, because its inhibition blocks the effect of estrogens on IL-6 expression. However, its activation does not mimic the effect of estrogens, on neither IL-6 nor NF-κB activity. Finally, we show that the estrogen receptor profile observed in monocytes is not modified during their differentiation to macrophages or dendritic cells in vitro and is shared in vivo by macrophages present in atherosclerotic plaques. These results position estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30 as important players and potential therapeutic targets in monocyte/macrophage-dependent inflammatory processes. © Society for Leukocyte Biology.

  10. Rapid effects of estrogens on behavior: environmental modulation and molecular mechanisms.

    PubMed

    Laredo, Sarah A; Villalon Landeros, Rosalina; Trainor, Brian C

    2014-10-01

    Estradiol can modulate neural activity and behavior via both genomic and nongenomic mechanisms. Environmental cues have a major impact on the relative importance of these signaling pathways with significant consequences for behavior. First we consider how photoperiod modulates nongenomic estrogen signaling on behavior. Intriguingly, short days permit rapid effects of estrogens on aggression in both rodents and song sparrows. This highlights the importance of considering photoperiod as a variable in laboratory research. Next we review evidence for rapid effects of estradiol on ecologically-relevant behaviors including aggression, copulation, communication, and learning. We also address the impact of endocrine disruptors on estrogen signaling, such as those found in corncob bedding used in rodent research. Finally, we examine the biochemical mechanisms that may mediate rapid estrogen action on behavior in males and females. A common theme across these topics is that the effects of estrogens on social behaviors vary across different environmental conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰

    PubMed Central

    Liu, Ran; Yang, Shao-Hua

    2013-01-01

    The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. PMID:23340160

  12. Estrogenic Environmental Chemicals and Drugs: Mechanisms for Effects on the Developing Male Urogenital System

    PubMed Central

    Taylor, Julia A.; Richter, Catherine A.; Ruhlen, Rachel L.; vom Saal, Frederick S.

    2011-01-01

    Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID:21827855

  13. Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice.

    PubMed

    Song, Yan; Santen, Richard J; Wang, Ji-ping; Yue, Wei

    2012-12-01

    A tissue-selective estrogen complex (TSEC), combining a selective estrogen receptor modulator, bazedoxifene (BZA), with conjugated equine estrogen (CEE), represents a novel strategy of menopausal hormone therapy without involving a progestin. We hypothesized that the antiestrogenic properties of BZA can also block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer in women. To test our hypothesis, the effects of estradiol (E(2)), CEE, and BZA on mammary gland and breast cancer xenografts were assessed in mouse models. In immature castrate mice, BZA completely blocked CEE- or E(2)-stimulated ductal and terminal end bud growth of mammary gland as well as estrogen-responsive gene expression. As a positive control, E(2) stimulated tumor growth in nude mice bearing MCF-7 xenografts. This effect was completely blocked by BZA as were E(2)-stimulated expression of PR, pS2 (trefoil factor 1), cMyc, and AREG; the enhancement of Ki67 and proliferating cell nuclear antigen (PCNA); and the antiapoptotic effect. CEE was much less potent than E(2) in stimulating Ki67, reducing apoptosis, and stimulating gene expression, but all effects were blocked by BZA. Unexpectedly, CEE alone, even at high doses, did not stimulate tumor growth. As confirmation of its absorption and deconjugation, CEE caused a 6-fold increase in uterine weight and stimulation of gene expression. These data support our hypothesis that the net effect of the CEE/BZA TSEC is to block estrogen action in benign and malignant breast tissue. These findings provide a rationale for a clinical study to determine whether this TSEC prevents breast cancer in women.

  14. Estrogen-cholinergic interactions: Implications for cognitive aging.

    PubMed

    Newhouse, Paul; Dumas, Julie

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. Published by Elsevier Inc.

  15. Estrogen-dependent changes in serum iron levels as a translator of the adverse effects of estrogen during infection: a conceptual framework.

    PubMed

    Hamad, Mawieh; Awadallah, Samir

    2013-12-01

    Elevated levels of estrogen often associate with increased susceptibility to infection. This has been attributed to the ability of estrogen to concomitantly enhance the growth and virulence of pathogens and suppress host immunity. But the exact mechanism of how estrogen mediates such effects, especially in cases where the pathogen and/or the immune components in question do not express estrogen receptors, has yet to be elucidated. Here we propose that translating the adverse effects of estrogen during infection is dependent to a significant degree upon its ability to manipulate iron homeostasis. For elevated levels of estrogen alter the synthesis and/or activity of several factors involved in iron metabolism including hypoxia inducible factor 1α (HIF-1α) and hepcidin among others. This leads to the inhibition of hepcidin synthesis in hepatocytes and the maintenance of ferroportin (FPN) integrity on the surface of iron-releasing duodenal enterocytes, hepatocytes, and macrophages. Intact FPN permits the continuous efflux of dietary and stored iron into the circulation, which further enhances pathogen growth and virulence on the one hand and suppresses host immunity on the other. This new conceptual framework may help explain a multitude of disparate clinical and experimental observations pertinent to the relationship between estrogen and infection. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis.

    PubMed

    Farris, Manuela; Bastianelli, Carlo; Rosato, Elena; Brosens, Ivo; Benagiano, Giuseppe

    2017-10-01

    The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.

  17. Estrogenic activity, estrogens, and calcium in runoff post-layer litter application from rainfall simulated events

    USDA-ARS?s Scientific Manuscript database

    Estrogens in runoff from fields fertilized with animal wastes have been implicated as endocrine disruptors of fish in recipient surface waters. The goal of this study was to measure estrogenic activity in runoff post-application of animal waste with the greatest potential for estrogenic activity - ...

  18. The role of estrogen in cutaneous ageing and repair.

    PubMed

    Wilkinson, Holly N; Hardman, Matthew J

    2017-09-01

    Combined advances in modern medical practice and increased human longevity are driving an ever-expanding elderly population. Females are particularly at risk of age-associated pathology, spending more of their lives in a post-menopausal state. Menopause, denoted by a rapid decline in serum sex steroid levels, accelerates biological ageing across the body's tissues. Post-menopause physiological changes are particularly noticeable in the skin, which loses structural architecture and becomes prone to damage. The sex steroid most widely discussed as an intrinsic contributor to skin ageing and pathological healing is 17β-estradiol (or estrogen), although many others are involved. Estrogen deficiency is detrimental to many wound-healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment widely reverses these effects. Over recent decades, many of the molecular and cellular correlates to estrogen's beneficial effect on normal skin homeostasis and wound healing have been reported. However, disparities still exist, particularly in the context of mechanistic studies investigating estrogen receptor signalling and its potential cellular effects. New molecular techniques, coupled with increased understanding of estrogen in skin biology, will provide further opportunities to develop estrogen receptor-targeted therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Effects of Estrogen in Gender-dependent Fetal Programming of Adult Cardiovascular Dysfunction.

    PubMed

    Chen, Zewen; Wang, Lei; Ke, Jun; Xiao, DaLiao

    2018-03-01

    Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of cardiovascular disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Estrogen receptor-independent catechol estrogen binding activity: protein binding studies in wild-type, Estrogen receptor-alpha KO, and aromatase KO mice tissues.

    PubMed

    Philips, Brian J; Ansell, Pete J; Newton, Leslie G; Harada, Nobuhiro; Honda, Shin-Ichiro; Ganjam, Venkataseshu K; Rottinghaus, George E; Welshons, Wade V; Lubahn, Dennis B

    2004-06-01

    Primary evidence for novel estrogen signaling pathways is based upon well-documented estrogenic responses not inhibited by estrogen receptor antagonists. In addition to 17beta-E2, the catechol estrogen 4-hydroxyestradiol (4OHE2) has been shown to elicit biological responses independent of classical estrogen receptors in estrogen receptor-alpha knockout (ERalphaKO) mice. Consequently, our research was designed to biochemically characterize the protein(s) that could be mediating the biological effects of catechol estrogens using enzymatically synthesized, radiolabeled 4-hydroxyestrone (4OHE1) and 4OHE2. Scatchard analyses identified a single class of high-affinity (K(d) approximately 1.6 nM), saturable cytosolic binding sites in several ERalphaKO estrogen-responsive tissues. Specific catechol estrogen binding was competitively inhibited by unlabeled catechol estrogens, but not by 17beta-E2 or the estrogen receptor antagonist ICI 182,780. Tissue distribution studies indicated significant binding differences both within and among various tissues in wild-type, ERalphaKO, and aromatase knockout female mice. Ligand metabolism experiments revealed extensive metabolism of labeled catechol estrogen, suggesting that catechol estrogen metabolites were responsible for the specific binding. Collectively, our data provide compelling evidence for the interaction of catechol estrogen metabolites with a novel binding protein that exhibits high affinity, specificity, and selective tissue distribution. The extensive biochemical characterization of this binding protein indicates that this protein may be a receptor, and thus may mediate ERalpha/beta-independent effects of catechol estrogens and their metabolites.

  1. Estrogen in cardiovascular disease during systemic lupus erythematosus.

    PubMed

    Gilbert, Emily L; Ryan, Michael J

    2014-12-01

    Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in

  2. Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

    PubMed Central

    Gilbert, Emily L.; Ryan, Michael J.

    2015-01-01

    Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against

  3. Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system.

    PubMed

    Segura-Uribe, Julia J; Pinto-Almazán, Rodolfo; Coyoy-Salgado, Angélica; Fuentes-Venado, Claudia E; Guerra-Araiza, Christian

    2017-08-01

    Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1 (MAP1), MAP2, neurofilament 38 (NF38) by different mechanisms of action and at different levels: neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.

  4. Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system

    PubMed Central

    Segura-Uribe, Julia J.; Pinto-Almazán, Rodolfo; Coyoy-Salgado, Angélica; Fuentes-Venado, Claudia E.; Guerra-Araiza, Christian

    2017-01-01

    Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1 (MAP1), MAP2, neurofilament 38 (NF38) by different mechanisms of action and at different levels: neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects. PMID:28966632

  5. Computational estimation of rainbow trout estrogen receptor binding affinities for environmental estrogens

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shyu, Conrad; Cavileer, Timothy D.; Nagler, James J.

    2011-02-01

    Environmental estrogens have been the subject of intense research due to their documented detrimental effects on the health of fish and wildlife and their potential to negatively impact humans. A complete understanding of how these compounds affect health is complicated because environmental estrogens are a structurally heterogeneous group of compounds. In this work, computational molecular dynamics simulations were utilized to predict the binding affinity of different compounds using rainbow trout (Oncorhynchus mykiss) estrogen receptors (ERs) as a model. Specifically, this study presents a comparison of the binding affinity of the natural ligand estradiol-17{beta} to the four rainbow trout ER isoformsmore » with that of three known environmental estrogens 17{alpha}-ethinylestradiol, bisphenol A, and raloxifene. Two additional compounds, atrazine and testosterone, that are known to be very weak or non-binders to ERs were tested. The binding affinity of these compounds to the human ER{alpha} subtype is also included for comparison. The results of this study suggest that, when compared to estradiol-17{beta}, bisphenol A binds less strongly to all four receptors, 17{alpha}-ethinylestradiol binds more strongly, and raloxifene has a high affinity for the {alpha} subtype only. The results also show that atrazine and testosterone are weak or non-binders to the ERs. All of the results are in excellent qualitative agreement with the known in vivo estrogenicity of these compounds in the rainbow trout and other fishes. Computational estimation of binding affinities could be a valuable tool for predicting the impact of environmental estrogens in fish and other animals.« less

  6. Membrane estrogen receptors - is it an alternative way of estrogen action?

    PubMed

    Soltysik, K; Czekaj, P

    2013-04-01

    The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERα and ERβ which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non-classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far-reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.

  7. Estrogen effects of Daldinia concentrica and Psathyrella efflorescens extracts in vitro.

    PubMed

    Benie, Tanon; Kouakou, Koffi; Thieulant, Marie-Lise

    2008-02-28

    Daldinia concentrica and Psathyrella efflorescens are two fungi used in African traditional medicine. In the present study, their extracts were evaluated for their steroid activities in estrogen- or androgen-dependent cell lines using as endpoints steroid-dependent transcriptional activity and cell proliferation. Treatment of human breast cancer MCF-7 cells with 15 or 30 microg/ml of Daldinia concentrica or Psathyrellaefflorescens extracts in the absence of 17beta-estradiol (E2) significantly increased the transcriptional activity of an estrogen receptor (ER)-dependent reporter gene, in the same range as E2. Similar data were obtained in gonadotrope cell line alpha-T3-1. All the effects were prevented by the pure estrogen antagonist, ICI 182,780. In the absence of steroid addition, the two extracts induced cell proliferation of ER-dependent MCF-7 and Ishikawa Var-I cell lines by approximately 100% of the E2 response. Combination treatments with E2 showed no competitive or additive effects in the two latter cell lines. Interestingly, the extracts had no androgen-like response in androgen receptor (AR)-positive and ER-negative MDA-MB231 cells, suggesting that fungi effects are estrogen specific and extracts are not toxic at used concentrations. Results provided evidence that Daldinia concentrica or Psathyrellaefflorescens extracts induce estrogen-like effects in ER-positive cell lines, which could be responsible of the effects observed in vivo.

  8. Bisphenol AF and Bisphenol B Exert Higher Estrogenic Effects than Bisphenol A via G Protein-Coupled Estrogen Receptor Pathway.

    PubMed

    Cao, Lin-Ying; Ren, Xiao-Min; Li, Chuan-Hai; Zhang, Jing; Qin, Wei-Ping; Yang, Yu; Wan, Bin; Guo, Liang-Hong

    2017-10-03

    Numerous studies have indicated estrogenic disruption effects of bisphenol A (BPA) analogues. Previous mechanistic studies were mainly focused on their genomic activities on nuclear estrogen receptor pathway. However, their nongenomic effects through G protein-coupled estrogen receptor (GPER) pathway remain poorly understood. Here, using a SKBR3 cell-based fluorescence competitive binding assay, we found six BPA analogues bound to GPER directly, with bisphenol AF (BPAF) and bisphenol B (BPB) displaying much higher (∼9-fold) binding affinity than BPA. Molecular docking also demonstrated the binding of these BPA analogues to GPER. By measuring calcium mobilization and cAMP production in SKBR3 cells, we found the binding of these BPA analogues to GPER lead to the activation of subsequent signaling pathways. Consistent with the binding results, BPAF and BPB presented higher agonistic activity than BPA with the lowest effective concentration (LOEC) of 10 nM. Moreover, based on the results of Boyden chamber and wound-healing assays, BPAF and BPB displayed higher activity in promoting GPER mediated SKBR3 cell migration than BPA with the LOEC of 100 nM. Overall, we found two BPA analogues BPAF and BPB could exert higher estrogenic effects than BPA via GPER pathway at nanomolar concentrations.

  9. Effect of Topical Estrogen in the Mangement of Traumatic Facial Wounds

    PubMed Central

    Ghazizadeh Hashemi, Seyed Amirhosein; Barati, Behrooz; Mohammadi, Hosein; Saeidi, Masumeh; Bahreini, Abbas; Kiani, Mohammad Ali

    2016-01-01

    Introduction: Acute skin wound healing is a complicated process comprising various phases. Recent animal studies have shown that steroid sex hormones such as estrogen maybe helpful in the regulation of several pathophysiologic stages that are involved in wound healing. In this study we examined the effects of topical estrogen in the treatment of traumatic facial wounds. Materials and Methods: Patients referred to Luqman Hospital, Tehran with traumatic wounds were enrolled in this case-control study into two groups of equal size. From the second week of the study, topical estrogen (0.625 mg conjugated topical estrogen ointment) was administered in the case group, while the control group received a Eucerin dressing only. The two groups were then compared in terms of wound healing rate on Day 7,14, and 30. Results: Thirty patients with mean age of 16.02+36.23 years were compared in the control and estrogen-treated groups. After treatment, no scars or keloids were observed in either group. The wound area in the estrogen group was lower than that in the control group on Day 14 and 30, but the difference was not significant (P>0.05). Healing rates in the control group on Day 14 (7.1+42.3 vs.50.3+4.9 mm2) and Day 30 (1.9+93.5 vs. + 97.3+0.6 mm2) (were lower than those in the estrogen group, but the differences were not significant (P>0.05). Findings show that the required time for wound healing in the estrogen-treated group was lower than that in the control group, but the difference was not significant (P>0.05). Conclusion: Based on this study, topical estrogen has no effect on the rate of wound healing or the rate of wound area. PMID:26878003

  10. Effect of Topical Estrogen in the Mangement of Traumatic Facial Wounds.

    PubMed

    Ghazizadeh Hashemi, Seyed Amirhosein; Barati, Behrooz; Mohammadi, Hosein; Saeidi, Masumeh; Bahreini, Abbas; Kiani, Mohammad Ali

    2016-01-01

    Acute skin wound healing is a complicated process comprising various phases. Recent animal studies have shown that steroid sex hormones such as estrogen maybe helpful in the regulation of several pathophysiologic stages that are involved in wound healing. In this study we examined the effects of topical estrogen in the treatment of traumatic facial wounds. Patients referred to Luqman Hospital, Tehran with traumatic wounds were enrolled in this case-control study into two groups of equal size. From the second week of the study, topical estrogen (0.625 mg conjugated topical estrogen ointment) was administered in the case group, while the control group received a Eucerin dressing only. The two groups were then compared in terms of wound healing rate on Day 7,14, and 30. Thirty patients with mean age of 16.02+36.23 years were compared in the control and estrogen-treated groups. After treatment, no scars or keloids were observed in either group. The wound area in the estrogen group was lower than that in the control group on Day 14 and 30, but the difference was not significant (P>0.05). Healing rates in the control group on Day 14 (7.1+42.3 vs.50.3+4.9 mm2) and Day 30 (1.9+93.5 vs. + 97.3+0.6 mm2) (were lower than those in the estrogen group, but the differences were not significant (P>0.05). Findings show that the required time for wound healing in the estrogen-treated group was lower than that in the control group, but the difference was not significant (P>0.05). Based on this study, topical estrogen has no effect on the rate of wound healing or the rate of wound area.

  11. Effects of estrogens and progestins on high density lipoproteins

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Krauss, R.M.; Lindgren, F.T.; Wingerd, J.

    High density lipoprotein (HDL) levels are knwon to be higher in women than in men, and to increase with estrogen use. To assess the effects of estrogens on HDL subspecies, analytic ultracentrifuge measurements of HDL were compared in 11 menopausal estrogen users and 16 controls. The difference in mean schlieren patterns between the groups showed a significantly higher level of HDL with flotation rate (F/sub 1/ /sub 20//sup 0/) > 1.5 (predominantly HDL/sub 2/) in the users. This was similar to the difference in HDL seen between nonusers of hormones and age-matched males. A previous study had shown that usersmore » of combination oral contraceptives had increased levels of HDL with F/sub 1/ /sub 20//sup 0/ less than or equal to 3.5 (primarily HDL/sub 3/) suggesting that the estrogen effect on HDL is altered by the presence of added progestin. The progestin effect was studied here in detail in two women with type V hyperlipoproteinemia treated with norethindrone acetate. Reduction in serum triglyceride was accompanied by a reduction in HDL, predominantly in the less dense species (HDL/sub 2/). Among groups of oral contraceptive and noncontraceptive estrogen and progestin users whose HDL-cholesterol levels have been reported recently, there was a direct correlation (r = 0.86, p < .001) between mean HDL-cholesterol and triglyceride levels. Endogenous hormonal influences on HDL were assessed by serum hormone and lipoprotein measurements at weekly intervals during two consecutive menstrual cycles in four healthy females. An increase in HDL of highest flotation rate (F/sub 1/ /sub 20//sup 0/ 5 to 9) was seen, which corresponded with the time of ovulation, raising the possibility of pituitary as well as gonadal hormone effects on HDL.« less

  12. Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer

    PubMed Central

    Lecomte, Sylvain; Charlier, Thierry D.; Pakdel, Farzad

    2017-01-01

    The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens. PMID:28914763

  13. Pathway Analysis Revealed Potential Diverse Health Impacts of Flavonoids that Bind Estrogen Receptors

    PubMed Central

    Ye, Hao; Ng, Hui Wen; Sakkiah, Sugunadevi; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao

    2016-01-01

    Flavonoids are frequently used as dietary supplements in the absence of research evidence regarding health benefits or toxicity. Furthermore, ingested doses could far exceed those received from diet in the course of normal living. Some flavonoids exhibit binding to estrogen receptors (ERs) with consequential vigilance by regulatory authorities at the U.S. EPA and FDA. Regulatory authorities must consider both beneficial claims and potential adverse effects, warranting the increases in research that has spanned almost two decades. Here, we report pathway enrichment of 14 targets from the Comparative Toxicogenomics Database (CTD) and the Herbal Ingredients’ Targets (HIT) database for 22 flavonoids that bind ERs. The selected flavonoids are confirmed ER binders from our earlier studies, and were here found in mainly involved in three types of biological processes, ER regulation, estrogen metabolism and synthesis, and apoptosis. Besides cancers, we conjecture that the flavonoids may affect several diseases via apoptosis pathways. Diseases such as amyotrophic lateral sclerosis, viral myocarditis and non-alcoholic fatty liver disease could be implicated. More generally, apoptosis processes may be importantly evolved biological functions of flavonoids that bind ERs and high dose ingestion of those flavonoids could adversely disrupt the cellular apoptosis process. PMID:27023590

  14. Behaviour of estrogenic endocrine-disrupting chemicals in permeable carbonate sands.

    PubMed

    Shepherd, Benjamin O; Erler, Dirk V; Tait, Douglas R; van Zwieten, Lukas; Kimber, Stephen; Eyre, Bradley D

    2015-08-01

    The remediation of four estrogenic endocrine-disrupting compounds (EDCs), estrone (E1), estradiol (E2), ethinylestradiol (EE2) and estriol (E3), was measured in saturated and unsaturated carbonate sand-filled columns dosed with wastewater from a sewage treatment plant. The estrogen equivalency (EEQ) of inlet wastewater was 1.2 ng L(-1) and was remediated to an EEQ of 0.5 ng L(-1) through the unsaturated carbonate sand-filled columns. The high surface area of carbonate sand and associated high microbial activity may have assisted the degradation of these estrogens. The fully saturated sand columns showed an increase in total estrogenic potency with an EEQ of 2.4 ng L(-1), which was double that of the inlet wastewater. There was a significant difference (P < 0.05) in total estrogenic potency between aerobic and anaerobic columns. The breakdown of conjugated estrogens to estrogenic EDCs formed under long residence time and reducing conditions may have been responsible for the increase in the fully saturated columns. This may also be explained by the desorption of previously sorbed estrogenic EDCs. The effect of additional filter materials, such as basalt sediment and coconut fibre, on estrogenic EDC reduction was also tested. None of these amendments provided improvements in estrogen remediation relative to the unamended unsaturated carbonate sand columns. Aerobic carbonate sand filters have good potential to be used as on-site wastewater treatment systems for the reduction of estrogenic EDCs. However, the use of fully saturated sand filters, which are used to promote denitrification, and the loss of nitrogen as N2 were shown to cause an increase in EEQ. The potential for the accumulation of estrogenic EDCs under anaerobic conditions needs to be considered when designing on-site sand filtration systems required to reduce nitrogen. Furthermore, the accumulation of estrogens under anaerobic conditions such as under soil absorption systems or leachate fields has the

  15. Selective estrogen receptor modulator effects of epimedium extracts on breast cancer and uterine growth in nude mice.

    PubMed

    Indran, Inthrani Raja; Zhang, Shi-Jun; Zhang, Zhi Wei; Sun, Feng; Gong, Yinhan; Wang, Xiaochong; Li, Jun; Erdelmeier, Clemens A J; Koch, Egon; Yong, Eu Leong

    2014-01-01

    Epimedium is popularly used in traditional Chinese medicine to treat sexual dysfunction, menstrual irregularity, and osteoporosis. The estrogenic effects of the prenylated flavonoids of Epimedium make it an attractive alternative for hormone replacement therapy. Here, we examined the therapeutic potential of the estrogenic herb extract of Epimedium brevicornum as an alternative to hormone replacement therapy in a breast cancer mouse model. To that end, athymic and ovariectomized female nude mice were subcutaneously injected into the mammary fat pads with MCF-7 breast cancer cells, randomly grouped and fed with soy-free feeds, alone or in combination with ethinyl estradiol or different doses of the estrogenic herb extract of E. brevicornum. Our findings demonstrate that unlike ethinyl estradiol, it did not promote the growth of breast cancer xenograft volume and weight, with the highest dose showing a significant reduction in growth and ERα protein content. Moreover, the extract increased uterine weight at the lowest dose, while higher doses had no effects. Put together, our data shows for the first time that despite the estrogenic activity of E. brevicornum, its action is largely tissue specific and dose-dependent. Our data on E. brevicornum presents in vivo evidence for its selective estrogen receptor modulator effect and warrants exploration of its use as an alternative to hormone replacement therapy in menopausal women. Georg Thieme Verlag KG Stuttgart · New York.

  16. Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle.

    PubMed

    Trenti, Annalisa; Tedesco, Serena; Boscaro, Carlotta; Trevisi, Lucia; Bolego, Chiara; Cignarella, Andrea

    2018-03-15

    Estrogen plays an important role in the regulation of cardiovascular physiology and the immune system by inducing direct effects on multiple cell types including immune and vascular cells. Sex steroid hormones are implicated in cardiovascular protection, including endothelial healing in case of arterial injury and collateral vessel formation in ischemic tissue. Estrogen can exert potent modulation effects at all levels of the innate and adaptive immune systems. Their action is mediated by interaction with classical estrogen receptors (ERs), ERα and ERβ, as well as the more recently identified G-protein coupled receptor 30/G-protein estrogen receptor 1 (GPER1), via both genomic and non-genomic mechanisms. Emerging data from the literature suggest that estrogen deficiency in menopause is associated with an increased potential for an unresolved inflammatory status. In this review, we provide an overview through the puzzle pieces of how 17β-estradiol can influence the cardiovascular and immune systems.

  17. Effects of triclosan on hormones and reproductive axis in female Yellow River carp (Cyprinus carpio): Potential mechanisms underlying estrogen effect.

    PubMed

    Wang, Fan; Guo, Xiangmeng; Chen, Wanguang; Sun, Yaowen; Fan, Chaojie

    2017-12-01

    Triclosan (TCS), a member of the class of compounds called pharmaceutical and personal care products (PPCPs), is a broad antibacterial and antifungal agent found in a lot of consumer products. However, TCS hormone effect mechanism in teleost female fish is not clear. Female Yellow River carp (Cyprinus carpio) were exposed to 1/20, 1/10 and 1/5 LC 50 TCS (96h LC 50 of TCS to carp) under semi-static conditions for 42days. Vitellogenin (Vtg), 17β-estradiol (E 2 ), testosterone(T), estrogen receptor (Er), gonadotropin (GtH), and gonadotropin-releasing hormone (GnRH) levels were measured by enzyme-linked immunosorbent assay (ELISA). Meanwhile, we also examined the mRNA expressions of aromatase, GtHs-β, GnRH, and Er by quantitative real-time PCR (qRT-PCR). The results indicated that 1/5 LC 50 TCS induced Vtg in hepatopancreas of female carps by interference with the hypothalamic-pituitary-gonadal (HPG) axis at multiple potential loci through three mechanisms: (a) TCS exposure enhanced the mRNA expression of hypothalamus and gonadal aromatase which converts androgens into estrogens, subsequently increasing serum concentrations of E 2 to induce Vtg in hepatopancreas; (b) TCS treatment increased GnRH and GtH-β mRNA expression and secretion, causing the disturbance of reproductive endocrine and the increase of E 2 to induce Vtg in hepatopancreas; (c) TCS exposure enhanced synthesis and secretion of Er, then it bound to Er to active Vtg synthesis. These mechanisms showed that TCS may induce Vtg production in female Yellow River carp by Er-mediated and non-Er-mediated pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Glyphosate induces human breast cancer cells growth via estrogen receptors.

    PubMed

    Thongprakaisang, Siriporn; Thiantanawat, Apinya; Rangkadilok, Nuchanart; Suriyo, Tawit; Satayavivad, Jutamaad

    2013-09-01

    Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1.

    PubMed

    Treas, Justin; Tyagi, Tulika; Singh, Kamaleshwar P

    2013-11-01

    Chronic exposure to arsenic and estrogen is associated with risk of prostate cancer, but their mechanism is not fully understood. Additionally, the carcinogenic effects of their co-exposure are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic, estrogen, and their combination, on cell growth and transformation, and identify the mechanism behind these effects. RWPE-1 human prostate epithelial cells were chronically exposed to arsenic and estrogen alone and in combination. Cell growth was measured by cell count and cell cycle, whereas cell transformation was evaluated by colony formation assay. Gene expression was measured by quantitative real-time PCR and confirmed at protein level by Western blot analysis. MLH1 promoter methylation was determined by pyrosequencing method. Exposure to arsenic, estrogen, and their combinations increases cell growth and transformation in RWPE-1 cells. Increased expression of Cyclin D1 and Bcl2, whereas decreased expression of mismatch repair genes MSH4, MSH6, and MLH1 was also observed. Hypermethylation of MLH1 promoter further suggested the epigenetic inactivation of MLH1 expression in arsenic and estrogen treated cells. Arsenic and estrogen combination caused greater changes than their individual treatments. Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1-mediated apoptotic response, and consequently increased cellular transformation. © 2013 Wiley Periodicals, Inc.

  20. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    PubMed

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Estrogen, Vascular Estrogen Receptor and Hormone Therapy in Postmenopausal Vascular Disease

    PubMed Central

    Khalil, Raouf A.

    2013-01-01

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

  2. Mouse Leydig Cells with Different Androgen Production Potential Are Resistant to Estrogenic Stimuli but Responsive to Bisphenol A Which Attenuates Testosterone Metabolism

    PubMed Central

    Savchuk, Iuliia; Söder, Olle; Svechnikov, Konstantin

    2013-01-01

    It is well known that estrogens and estrogen-like endocrine disruptors can suppress steroidogenic gene expression, attenuate androgen production and decrease differentiation of adult Leydig cell lineage. However, there is no information about the possible link between the potency of Leydig cells to produce androgens and their sensitivity to estrogenic stimuli. Thus, the present study explored the relationship between androgen production potential of Leydig cells and their responsiveness to estrogenic compounds. To investigate this relationship we selected mouse genotypes contrasting in sex hormone levels and differing in testosterone/estradiol (T/E2) ratio. We found that two mouse genotypes, CBA/Lac and C57BL/6j have the highest and the lowest serum T/E2 ratio associated with increased serum LH level in C57BL/6j compared to CBA/Lac. Analysis of steroidogenic gene expression demonstrated significant upregulation of Cyp19 gene expression but coordinated suppression of LHR, StAR, 3βHSDI and Cyp17a1 in Leydig cells from C57BL/6j that was associated with attenuated androgen production in basal and hCG-stimulated conditions compared to CBA/Lac mice. These genotype-dependent differences in steroidogenesis were not linked to changes in the expression of estrogen receptors ERα and Gpr30, while ERβ expression was attenuated in Leydig cells from C57BL/6j compared to CBA/Lac. No effects of estrogenic agonists on steroidogenesis in Leydig cells from both genotypes were found. In contrast, xenoestrogen bisphenol A significantly potentiated hCG-activated androgen production by Leydig cells from C57BL/6j and CBA/Lac mice by suppressing conversion of testosterone into corresponding metabolite 5α-androstane-3α,17β-diol. All together our data indicate that developing mouse Leydig cells with different androgen production potential are resistant to estrogenic stimuli, while xenoestrogen BPA facilitates hCG-induced steroidogenesis in mouse Leydig cells via attenuation of

  3. Estrogens and aging skin.

    PubMed

    Thornton, M Julie

    2013-04-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. Its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer.   Skin aging can be significantly delayed by the administration of estrogen. This paper reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SERMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. Understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies.

  4. Effect of blood estrogen and progesterone on severity of minor RAS

    NASA Astrophysics Data System (ADS)

    Utami, S.; Rahardjo, T. W. B.; Baziad, A.; Alwadris, T. T.; Auerkari, E. I.

    2018-05-01

    Recurrent Aphthous Stomatitis (RAS) is a chronic inflammatory disease that attacks oral mucosa. Estrogen stimulates proliferation and buccal mucosa cornification and generally acts as an immunoinhibitor that can increase antibody synthesis through humoral response, while progesterone has immunosuppressive potential. This study aimed to examine the levels of blood estrogen and progesterone in females with Minor RAS of varying severity. Subjects were 42 women, 17–40 years old, with Minor RAS but without hormonal therapy or hysterectomy. They were investigated to see whether the severity of pain was related to condition of onset, recurrence and site or amount of lesions. Blood was taken on the 21st – 22nd day of the menstrual cycle to test both hormone levels, using Microparticle Enzyme Immunoassay for the estrogen level, and Competitive Radioimmunoassay for the progesterone level. There was no significant relation between estrogen (p=0.530) or progesterone (p=0.717) level and the severity of Minor RAS. There is a tendency of normal estrogen level on both mild (62.5%) and severe (37.5%) Minor RAS. However, the progesterone level tends to be low both in mild (61.3%) and severe (38.7%) Minor RAS. It is assumed that the decrease of progesterone level also decreases the anti-inflammation function.

  5. Estrogen and Osteoporosis.

    ERIC Educational Resources Information Center

    Lindsay, Robert

    1987-01-01

    This article reviews the use of estrogen in the prevention and treatment of osteoporosis. Dosage levels, interactions with other factors, side effects, and the mechanism of estrogen action are discussed. (Author/MT)

  6. Histopathologic Effects of Estrogens on Marine Fishes

    EPA Science Inventory

    Endocrine-disrupting chemicals (EDCs), such as estrogens estradiol (E2) and ethinylestradiol (EE2) have been reported to affect fish reproduction. This study histologically compared and evaluated effects of EDCs in two species of treated fish. Juvenile male summer flounder (Paral...

  7. Estrogens and development

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McLachlan, J.A.; Newbold, R.R.

    1987-11-01

    The normal development of the genital organs of mammals, including humans, is under hormonal control. A role for the female sex hormone estrogen in this process is still unclear. However, exposure of experimental animals or humans to the potent exogenous estrogen, diethylstilbestrol (DES), results in persistent differentiation effects. Since many chemicals in the environment are weakly estrogenic, the possibility of hormonally altered differentiation must be considered.

  8. ANALYSIS OF LAGOON SAMPLES FROM DIFFERENT CONCENTRATED ANIMAL FEEDING OPERATIONS FOR ESTROGENS AND ESTROGEN CONJUGATES

    EPA Science Inventory

    Although Concentrated Animal Feeding Operations CAFOs) have been identified as potentially important sources for the release of estrogens into the environment, information is lacking on the concentrations of estrogens in whole lagoon effluents (including suspended solids)which ar...

  9. Estrogen, aging and the cardiovascular system

    PubMed Central

    Stice, James P.; Lee, Jennifer S.; Pechenino, Angela S.; Knowlton, Anne A.

    2014-01-01

    Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFκB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone. PMID:19371207

  10. Estrogenic Compounds, Estrogen Receptors and Vascular Cell Signaling in the Aging Blood Vessels

    PubMed Central

    Smiley, Dia A.; Khalil, Raouf A.

    2010-01-01

    The cardiovascular benefits of menopausal hormone therapy (MHT) remain controversial. The earlier clinical observations that cardiovascular disease (CVD) was less common in MHT users compared to non-users suggested cardiovascular benefits of MHT. Also, experimental studies have identified estrogen receptors ERα, ERβ and GPR30, which mediate genomic or non-genomic effects in vascular endothelium, smooth muscle, and extracellular matrix (ECM). However, data from randomized clinical trials (RCTs), most notably the Women's Health Initiative (WHI) study, have challenged the cardiovascular benefits and highlighted adverse cardiovascular events with MHT. The discrepancies have been attributed to the design of RCTs, the subjects' advanced age and preexisting CVD, and the form of estrogen used. The discrepancies may also stem from age-related changes in vascular ER amount, distribution, integrity, and post-receptor signaling pathways as well as structural changes in the vasculature. Age-related changes in other sex hormones such as testosterone may also alter the hormonal environment and influence the cardiovascular effects of estrogen. Investigating the chemical properties, structure-activity relationship and pharmacology of natural and synthetic estrogens should improve the effectiveness of conventional MHT. Further characterization of phytoestrogens, selective estrogen-receptor modulators (SERMs), and specific ER agonists may provide substitutes to conventional MHT. Conditions with excess or low estrogen levels such as polycystic ovary syndrome (PCOS) and Turner syndrome may provide insight into the development and regulation of ER and the mechanisms of aberrant estrogen-ER interactions. The lessons learned from previous RCTs have led to more directed studies such as the Kronos Early Estrogen Prevention Study (KEEPS). Careful design of experimental models and RCTs, coupled with the development of specific ER modulators, hold the promise of improving the actions of

  11. Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β

    PubMed Central

    Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

    2017-01-01

    Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ. PMID:28404976

  12. Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β.

    PubMed

    Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

    2017-06-13

    Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ.

  13. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products.

    PubMed

    Myers, Sharon L; Yang, Chun Z; Bittner, George D; Witt, Kristine L; Tice, Raymond R; Baird, Donna D

    2015-05-01

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products.

  14. Effect of protracted estrogen administration on the thyroid of Ames dwarf mice.

    PubMed

    Vidal, S; Cameselle-Teijeiro, J; Horvath, E; Kovacs, K; Bartke, A

    2001-04-01

    The effect of protracted estrogen administration on estrogen receptor expression and cellular composition of the thyroid was examined in genetically thyrotropin (TSH)-deficient female Ames dwarf mice (df/df) to reveal whether estrogen might act independently from TSH. inducing changes in thyroid morphology and function. To evaluate such changes, the thyroid from four estrogen-implanted Ames dwarf mice, four sham-implanted Ames dwarf mice and four sham-implanted normal littermate mice were investigated histologically, immunohistochemically and morphometrically. Our morphologic study demonstrated significant differences in the colloid areas of normal and dwarf mice (P<0.001). The correlation observed between this parameter and body weights (r=0.610, P<0.05) and thyroid weights (r=0.729, P<0.01) suggests that the decrease in the colloid areas is not a result of abnormal folliculogenesis but is in direct correlation with the small thyroid and body size of dwarf mice. Although two types of estrogen receptors are known to exist in the present study, only the alpha (ERalpha) variant was found in the thyroid. ERalpha immunoreactivity was detected in the nuclei of parafollicular cells but not of the follicular epithelium. No significant differences were reported in ER expression between estrogen-implanted dwarf mice and sham-implanted dwarf mice, suggesting that estrogen receptor expression in the thyroid is independent of circulating estrogen levels. In spite of the absence of ERalpha in follicular cells, protracted estrogen administration affected mainly the follicular cells. Our results suggest that when TSH is absent estrogens may exert a negative feedback on the activity of follicular cells.

  15. Neuroprotective Effects of Nonfeminizing Estrogens in Retinal Photoreceptor Neurons

    PubMed Central

    Nixon, Everett; Simpkins, James W.

    2012-01-01

    Purpose. Retinal diseases such as macular degeneration and glaucoma are disorders that target specific retinal neurons that can ultimately lead to vision loss. Under these conditions and pathologies, retinal neurons can die via apoptosis that may be due to increased oxidative stress. The neuroprotective effects of 17β-estradiol (E2) and three synthetic nonfeminizing estrogen analogs (ZYC-26, ZYC-23, and ZYC-3) were investigated to examine their abilities to protect retinal neurons against glutamate toxicity. Methods. Using an in vitro model of glutamate-induced cell death in 661W cells, a mouse cone photoreceptor cell line, shown to express both estrogen receptors (ERs) via immunoblotting, was pretreated with E2 and its analogs and cell viability were assessed. Results. It was observed that E2 and estrogen analogs, ZYC-26 and ZYC-3, were protective against a 5 mM glutamate insult in 661W cells. The neuroprotective abilities of ZYC-26 and ZYC-3 were autonomous of estrogen receptor-α (ERα) and ERβ demonstrated by their ability to protect in the presence of ICI 182780, a pan-ER antagonist with a high affinity for the estrogen receptor. Treatment with PPT and DPN, ERα- and ERβ-specific agonists, respectively, did not protect the 661W cells from the glutamate insult. Studying the membrane ER (mER) or GPR30 did show that activation of the receptor by G1 protected the retinal neuron from insult, whereas G15, an antagonist of the mER was not able to antagonize the protection previously seen. Conclusions. These data demonstrate that nonfeminizing estrogens may emerge as useful compounds for neuroprotection of retinal cells. PMID:22700711

  16. Content-specific activational effects of estrogen on working memory performance.

    PubMed

    Vranić, Andrea; Hromatko, Ivana

    2008-07-01

    The authors explored the influence of task content and the menstrual cycle phase on working memory (WM) performance. They addressed the content specificity of WM in the framework of evolutionary psychology, proposing a hormone-mediated adaptive design governing face perception. The authors tested 2 groups of healthy young women (n = 66 women with regular menstrual cycle, n = 27 oral contraceptive users) on a WM task with adult male or infant face photographs. Analyses of variance showed significant interaction between task content and estrogen level. Women were more efficient in solving the male faces task during high-estrogen phase of the cycle than during low-estrogen phase. No differences were found in the efficacy of solving the infant faces task between different phases of the cycle. Results suggest content-specific activational effects of estrogen on the WM performance and are consistent with the notion of a hormonal mechanism underlying adaptive shifts in cognition related to mating motivation.

  17. Identification, contribution, and estrogenic activity of potential EDCs in a river receiving concentrated livestock effluent in Southern Taiwan.

    PubMed

    Liu, Yung-Yu; Lin, Yi-Siou; Yen, Chia-Hung; Miaw, Chang-Ling; Chen, Ting-Chien; Wu, Meng-Chun; Hsieh, Chi-Ying

    2018-04-27

    We assessed 22 selected endocrine-disrupting compounds (EDCs) and other emerging, potentially endocrine-active compounds with estrogenic activity from the waters of the Wuluo River, southern Taiwan. This watershed receives high amounts of livestock and untreated household wastewaters. The river is surrounded by concentrated animal feedlot operations (CAFOs). River water samples were analyzed for selected compounds by liquid chromatography-tandem mass spectrometry (LC-MS/MS), T47D-KBluc reporter gene assay, and E-screen cell proliferation in vitro bioassay. Total concentrations of ∑alkylphenolic compounds (bisphenol A, 4-nonylphenol, t-nonylphenol, octylphenol, nonylphenol mono-ethoxylate, nonylphenol di-ethoxylate) were much higher than ∑estrogens (estrone, 17 β-estradiol, estriol, 17ß-ethynylestradiol, diethylstilbestrol), ∑preservatives (methyl paraben, ethyl paraben, propyl paraben, butyl paraben), ∑UV-filters (benzophenone, methyl benzylidene camphor, benzophenone-3), ∑antimicrobials (triclocarben, triclosan, chloroxylenol), and an insect repellent (diethyltoluamide) over four seasonal sampling periods. The highest concentration was found for bisphenol A with a mean of 302 ng/L. However, its contribution to estrogenic activity was not significant due to its relatively low estrogenic potency. Lower detection rates were found for BP, EE2, TCS, and PCMX, while DES and EP were not detected. E1 and E2 levels in raw water samples were 50% higher than the predicted no-effect concentrations (PNEC) for aquatic organisms of 6 and 2 ng/L, respectively. The potency of estrogenic activity ranged from 11.7 to 190.1 ng/L E2 T47D-Kbluc and 6.63 to 84.5 ng/L E2 E-Screen for extracted samples. Importantly, estrone contributed 50% of the overall activity in 60% and 44% of the samples based on T47D-KBluc and MCF-7 bioassays, followed by 17 ß-estradiol, highlighting the importance of total steroid estrogen loading. This study demonstrates that the estrogenic

  18. Effects of watershed densities of animal feeding operations on nutrient concentrations and estrogenic activity in agricultural streams.

    PubMed

    Ciparis, Serena; Iwanowicz, Luke R; Voshell, J Reese

    2012-01-01

    Application of manures from animal feeding operations (AFOs) as fertilizer on agricultural land can introduce nutrients and hormones (e.g. estrogens) to streams. A landscape-scale study was conducted in the Shenandoah River watershed (Virginia, USA) in order to assess the relationship between densities of AFOs in watersheds of agricultural streams and in-stream nutrient concentrations and estrogenic activity. The effect of wastewater treatment plants (WWTPs) on nutrients and estrogenic activity was also evaluated. During periods of high and low flow, dissolved inorganic nitrogen (DIN) and orthophosphate (PO(4)-P) concentrations were analyzed and estrogens/estrogenic compounds were extracted and quantified as17β-estradiol equivalents (E2Eq) using a bioluminescent yeast estrogen screen. Estrogenic activity was measurable in the majority of collected samples, and 20% had E2Eq concentrations >1 ng/L. Relatively high concentrations of DIN (>1000 μg/L) were also frequently detected. During all sampling periods, there were strong relationships between watershed densities of AFOs and in-stream concentrations of DIN (R(2) = 0.56-0.81) and E2Eq (R(2) = 0.39-0.75). Relationships between watershed densities of AFOs and PO(4)-P were weaker, but were also significant (R(2) = 0.27-0.57). When combined with the effect of watershed AFO density, streams receiving WWTP effluent had higher concentrations of PO(4)-P than streams without WWTP discharges, and PO(4)-P was the only analyte with a consistent relationship to WWTPs. The results of this study suggest that as the watershed density of AFOs increases, there is a proportional increase in the potential for nonpoint source pollution of agricultural streams and their receiving waters by nutrients, particularly DIN, and compounds that can cause endocrine disruption in aquatic organisms. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Effects of watershed densities of animal feeding operations on nutrient concentrations and estrogenic activity in agricultural streams

    USGS Publications Warehouse

    Ciparis, S.; Iwanowicz, L.R.; Voshell, J.R.

    2012-01-01

    Application of manures from animal feeding operations (AFOs) as fertilizer on agricultural land can introduce nutrients and hormones (e.g. estrogens) to streams. A landscape-scale study was conducted in the Shenandoah River watershed (Virginia, USA) in order to assess the relationship between densities of AFOs in watersheds of agricultural streams and in-stream nutrient concentrations and estrogenic activity. The effect of wastewater treatment plants (WWTPs) on nutrients and estrogenic activity was also evaluated. During periods of high and low flow, dissolved inorganic nitrogen (DIN) and orthophosphate (PO 4-P) concentrations were analyzed and estrogens/estrogenic compounds were extracted and quantified as17??-estradiol equivalents (E2Eq) using a bioluminescent yeast estrogen screen. Estrogenic activity was measurable in the majority of collected samples, and 20% had E2Eq concentrations >1ng/L. Relatively high concentrations of DIN (>1000??g/L) were also frequently detected. During all sampling periods, there were strong relationships between watershed densities of AFOs and in-stream concentrations of DIN (R 2=0.56-0.81) and E2Eq (R 2=0.39-0.75). Relationships between watershed densities of AFOs and PO 4-P were weaker, but were also significant (R 2=0.27-0.57). When combined with the effect of watershed AFO density, streams receiving WWTP effluent had higher concentrations of PO 4-P than streams without WWTP discharges, and PO 4-P was the only analyte with a consistent relationship to WWTPs. The results of this study suggest that as the watershed density of AFOs increases, there is a proportional increase in the potential for nonpoint source pollution of agricultural streams and their receiving waters by nutrients, particularly DIN, and compounds that can cause endocrine disruption in aquatic organisms. ?? 2011 Elsevier B.V.

  20. Effects of watershed densities of animal feeding operations on nutrient concentrations and estrogenic activity in agricultural streams

    USGS Publications Warehouse

    Ciparis, Serena; Iwanowicz, Luke R.; Voshell, J. Reese

    2012-01-01

    Application of manures from animal feeding operations (AFOs) as fertilizer on agricultural land can introduce nutrients and hormones (e.g. estrogens) to streams. A landscape-scale study was conducted in the Shenandoah River watershed (Virginia, USA) in order to assess the relationship between densities of AFOs in watersheds of agricultural streams and in-stream nutrient concentrations and estrogenic activity. The effect of wastewater treatment plants (WWTPs) on nutrients and estrogenic activity was also evaluated. During periods of high and low flow, dissolved inorganic nitrogen (DIN) and orthophosphate (PO4-P) concentrations were analyzed and estrogens/estrogenic compounds were extracted and quantified as17β-estradiol equivalents (E2Eq) using a bioluminescent yeast estrogen screen. Estrogenic activity was measurable in the majority of collected samples, and 20% had E2Eq concentrations > 1 ng/L. Relatively high concentrations of DIN (> 1000 μg/L) were also frequently detected. During all sampling periods, there were strong relationships between watershed densities of AFOs and in-stream concentrations of DIN (R2 = 0.56–0.81) and E2Eq (R2 = 0.39–0.75). Relationships between watershed densities of AFOs and PO4-P were weaker, but were also significant (R2 = 0.27–0.57). When combined with the effect of watershed AFO density, streams receiving WWTP effluent had higher concentrations of PO4-P than streams without WWTP discharges, and PO4-P was the only analyte with a consistent relationship to WWTPs. The results of this study suggest that as the watershed density of AFOs increases, there is a proportional increase in the potential for nonpoint source pollution of agricultural streams and their receiving waters by nutrients, particularly DIN, and compounds that can cause endocrine disruption in aquatic organisms.

  1. Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner.

    PubMed

    Katchy, Anne; Pinto, Caroline; Jonsson, Philip; Nguyen-Vu, Trang; Pandelova, Marchela; Riu, Anne; Schramm, Karl-Werner; Samarov, Daniel; Gustafsson, Jan-Åke; Bondesson, Maria; Williams, Cecilia

    2014-03-01

    Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

  2. Coexposure to Phytoestrogens and Bisphenol A Mimics Estrogenic Effects in an Additive Manner

    PubMed Central

    Katchy, Anne; Pinto, Caroline; Williams, Cecilia

    2014-01-01

    Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER–mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer. PMID:24284790

  3. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.

    PubMed

    Somerville, B W

    1975-03-01

    The minimum exposure to estrogen required to cause estrogen-withdrawal migraine has been studied by giving long-acting estradiol valerate to four women and short-acting estradiol benzoate to two women. It was found that several days of exposure to high estrogen levels were needed to cause migraine on estrogen withdrawal. Oral administration of estrogen supplements in the form of estradiol valerate or as conjugated equine estrogens during the premenstrual phase in four women did not significantly affect plasma levels of estradiol, nor was it effective in preventing menstrual migraine.

  4. Estrogen action and prostate cancer

    PubMed Central

    Nelles, Jason L; Hu, Wen-Yang; Prins, Gail S

    2011-01-01

    Early work on the hormonal basis of prostate cancer focused on the role of androgens, but more recently estrogens have been implicated as potential agents in the development and progression of prostate cancer. In this article, we review the epidemiological, laboratory and clinical evidence that estrogen may play a causative role in human prostate cancer, as well as rodent and grafted in vivo models. We then review recent literature highlighting potential mechanisms by which estrogen may contribute to prostate cancer, including estrogenic imprinting and epigenetic modifications, direct genotoxicity, hyperprolactinemia, inflammation and immunologic changes, and receptor-mediated actions. We discuss the work performed so far separating the actions of the different known estrogen receptors (ERs), ERα and ERβ, as well as G-protein-coupled receptor 30 and their specific roles in prostate disease. Finally, we predict that future work in this field will involve more investigations into epigenetic changes, experiments using new models of hormonal dysregulation in developing human prostate tissue, and continued delineation of the roles of the different ER subtypes, as well as their downstream signaling pathways that may serve as therapeutic targets. PMID:21765856

  5. Effect of vaginal estrogen on pessary use

    PubMed Central

    Dessie, Sybil G.; Armstrong, Katherine; Modest, Anna M.; Hacker, Michele R.

    2016-01-01

    Introduction and hypothesis Many providers recommend concurrent estrogen therapy with pessary use to limit complications; however, limited data exist to support this practice. We hypothesized that vaginal estrogen supplementation decreases incidence of pessary-related complications and discontinuation. Methods We performed a retrospective cohort study of women who underwent a pessary fitting from 1 January 2007 through 1 September 2013 at one institution; participants were identified by billing code and were eligible if they were post-menopausal and had at least 3 months of pessary use and 6 months of follow-up. All tests were two sided, and P values < 0.05 were considered statistically significant. Results Data from 199 women were included; 134 used vaginal estrogen and 65 did not. Women who used vaginal estrogen had a longer median follow-up time (29.5 months) compared with women who did not (15.4 months) and were more likely to have at least one pessary check (98.5 % vs 86.2 %, P < 0.001). Those in the estrogen group were less likely to discontinue using their pessary (30.6 % vs 58.5 %, P < 0.001) and less likely to develop increased vaginal discharge than women who did not [hazard ratio (HR) 0.31, 95 % confidence interval (CI) 0.17–0.58]. Vaginal estrogen was not protective against erosions (HR 0.93, 95 % CI 0.54–1.6) or vaginal bleeding (HR 0.78, 95 % CI 0.36–1.7). Conclusions Women who used vaginal estrogen exhibited a higher incidence of continued pessary use and lower incidence of increased vaginal discharge than women who did not. PMID:26992727

  6. Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture.

    PubMed Central

    Zava, D T; Blen, M; Duwe, G

    1997-01-01

    We investigated the estrogenic activity of various environmental pollutants (xenobiotics), in particular the xenoestrogen o,p-DDT, and compared their effects with those of endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding capacity, induction of estrogen end products, and activation of cell proliferation in estrogen-sensitive human breast cancer cells in monolayer culture. We also quantified the levels of phytoestrogens in extracts of some common foods, herbs, and spices and in human saliva following consumption of a high phytoestrogen food source (soy milk) to compare phytoestrogen abundance and bioavailability relative to the reported xenoestrogen burden in humans. Results show that natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind estrogen receptor (ER) in intact cells, but demonstrate marked differences in their ability to induce end products of estrogen action and to regulate cell proliferation. All of the different classes of estrogens stimulated cell proliferation at concentrations that half-saturated ER, but only some classes were able to induce estrogen-regulated end products. Genistein, a common phytoestrogen found in soy foods, differed from the xenoestrogen DDT in its effects on cell proliferation and ability to induce estrogen-regulated end products. Moreover, we found that many of the foods, herbs, and spices commonly consumed by humans contain significant amounts of phytoestrogens, and consumption of soy milk, a phytoestrogen-rich food, markedly increases the levels of phytoestrogens in saliva. In conclusion, our in vitro results predict that a diet high in phytoestrogens would significantly reduce the binding of weak xenoestrogens to ER in target tissues in vivo. PMID:9168008

  7. Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation.

    PubMed

    Benoit, Thibaut; Valera, Marie-Cecile; Fontaine, Coralie; Buscato, Melissa; Lenfant, Francoise; Raymond-Letron, Isabelle; Tremollieres, Florence; Soulie, Michel; Foidart, Jean-Michel; Game, Xavier; Arnal, Jean-Francois

    2017-11-01

    The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Estrogen and the female heart.

    PubMed

    Knowlton, A A; Korzick, D H

    2014-05-25

    Estrogen has a plethora of effects in the cardiovascular system. Studies of estrogen and the heart span human clinical trials and basic cell and molecular investigations. Greater understanding of cell and molecular responses to estrogens can provide further insights into the findings of clinical studies. Differences in expression and cellular/intracellular distribution of the two main receptors, estrogen receptor (ER) α and β, are thought to account for the specificity and differences in responses to estrogen. Much remains to be learned in this area, but cellular distribution within the cardiovascular system is becoming clearer. Identification of GPER as a third ER has introduced further complexity to the system. 17β-estradiol (E2), the most potent human estrogen, clearly has protective properties activating a signaling cascade leading to cellular protection and also influencing expression of the protective heat shock proteins (HSP). E2 protects the heart from ischemic injury in basic studies, but the picture is more involved in the whole organism and clinical studies. Here the complexity of E2's widespread effects comes into play and makes interpretation of findings more challenging. Estrogen loss occurs primarily with aging, but few studies have used aged models despite clear evidence of differences between the response to estrogen deficiency in adult and aged animals. Thus more work is needed focusing on the effects of aging vs. estrogen loss on the cardiovascular system. Published by Elsevier Ireland Ltd.

  9. Estrogenic activity of osthole and imperatorin in MCF-7 cells and their osteoblastic effects in Saos-2 cells.

    PubMed

    Jia, Min; Li, Yuan; Xin, Hai-Liang; Hou, Ting-Ting; Zhang, Nai-Dai; Xu, Hong-Tao; Zhang, Qiao-Yan; Qin, Lu-Ping

    2016-06-01

    There is an increasing interest in phytoestrogens due to their potential medical usage in hormone replacement therapy (HRT). The present study was designed to investigate the in vitro effects of estrogen-like activities of two widespread coumarins, osthole and imperatorin, using the MCF-7 cell proliferation assay and their alkaline phosphatase (ALP) activities in osteoblasts Saos-2 cells. The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERα, progesterone receptor (PR) and PS2 mRNA levels were increased by treatment with osthole and imperatorin. All these effects were significantly inhibited by the specific estrogen receptor antagonist ICI182, 780. Cell cycle analysis revealed that their proliferation stimulatory effect was associated with a marked increase in the number of MCF-7 cells in S phase, which was similar to that observed with estradiol. It was also observed that they significantly increased ALP activity, which was reversed by ICI182,780. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway. In conclusion, osthole and imperatorin may represent new pharmacological tools for the treatment of osteoporosis. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  10. The role of selective estrogen receptor modulators in the treatment of schizophrenia.

    PubMed

    Bratek, Agnieszka; Krysta, Krzysztof; Drzyzga, Karolina; Barańska, Justyna; Kucia, Krzysztof

    2016-09-01

    Gender differences in schizophrenia have been recognized for a long time and it has been widely accepted that sex steroid hormones, especially estradiol, are strongly attributed to this fact. Two hypotheses regarding estradiol action in psychoses gained special research attention - the estrogen protection hypothesis and hypoestrogenism hypothesis. A growing number of studies have shown benefits in augmenting antipsychotic treatment with estrogens or selective estrogen receptor modulators (SERM). This review is focused on the role of selective estrogen receptor modulators in the treatment of schizophrenic patients. In order to achieve this result PubMed was searched using the following terms: schizophrenia, raloxifene, humans. We reviewed only randomized, placebo-controlled studies. Raloxifene, a selective estrogen receptor modulator was identified as useful to improve negative, positive, and general psychopathological symptoms, and also cognitive functions. All reviewed studies indicated improvement in at least one studied domain. Augmentation with raloxifene was found to be a beneficial treatment strategy for chronic schizophrenia both in female and male patients, however potential side effects (a small increase in the risk of venous thromboembolism and endometrial cancer) should be carefully considered. SERMs could be an effective augmentation strategy in the treatment of both men women with schizophrenia, although further research efforts are needed to study potential long-term side effects.

  11. Characterizing the Growth Kinetics in Estrogen Responsive ...

    EPA Pesticide Factsheets

    There is a need to develop high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals for endocrine disrupting potential. The estrogen signaling pathway is a known xenobiotic target that has been implicated in a variety of adverse health effects including reproductive deficits and cancer promotion. Using real-time measurements of growth kinetics by electrode impedance, the estrogen-responsive human ductal carcinoma cell line, T47D, was treated with 2000 chemicals of environmental relevance. Cells were treated in concentration response and measurements of cellular impedance were recorded every hour for six days. Exponential impedance, signifying increased proliferation, was observed by prototypical estrogen receptor agonists (17β-estradiol, genestein, bisphenol-A, nonylphenol, 4-tert-octylphenol). Several compounds, including bisphenol-A and genestein, induced cell proliferation at comparable levels to 17β-estradiol, although at much higher concentrations. Progestins, and mineralocortocoids (progesterone, dihydrotestosterone, aldosterone) invoked a biphasic impedance signature. In conclusion, the real-time nature of this assay allows for rapid detection of differential growth characteristics shows potential, in combination with other ToxCast HTS assays, to detect environmental chemicals with potential endocrine activity. [This abstract does not necessarily reflect Agency policy]. Several compounds, including bisphenol-A and

  12. Gene expression profiling in Ishikawa cells: A fingerprint for estrogen active compounds

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boehme, Kathleen; Simon, Stephanie; Mueller, Stefan O.

    2009-04-01

    Several anthropogenous and naturally occurring substances, referred to as estrogen active compounds (EACs), are able to interfere with hormone and in particular estrogen receptor signaling. EACs can either cause adverse health effects in humans and wildlife populations or have beneficial effects on estrogen-dependent diseases. The aim of this study was to examine global gene expression profiles in estrogen receptor (ER)-proficient Ishikawa plus and ER-deficient Ishikawa minus endometrial cancer cells treated with selected well-known EACs (Diethylstilbestrol, Genistein, Zearalenone, Resveratrol, Bisphenol A and o,p'-DDT). We also investigated the effect of the pure antiestrogen ICI 182,780 (ICI) on the expression patterns caused bymore » these compounds. Transcript levels were quantified 24 h after compound treatment using Illumina BeadChip Arrays. We identified 87 genes with similar expression changes in response to all EAC treatments in Ishikawa plus. ICI lowered the magnitude or reversed the expression of these genes, indicating ER dependent regulation. Apart from estrogenic gene regulation, Bisphenol A, o,p'-DDT, Zearalenone, Genistein and Resveratrol displayed similarities to ICI in their expression patterns, suggesting mixed estrogenic/antiestrogenic properties. In particular, the predominant antiestrogenic expression response of Resveratrol could be clearly distinguished from the other test compounds, indicating a distinct mechanism of action. Divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals Bisphenol A and o,p'-DDT, warrants a careful assessment of potential detrimental and/or beneficial effects of EACs. The characteristic expression fingerprints and the identified subset of putative marker genes can be used for screening chemicals with an unknown mode of action and for predicting their potential to exert endocrine disrupting effects.« less

  13. Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats

    NASA Technical Reports Server (NTRS)

    Brooks-Asplund, Esther M.; Shoukas, Artin A.; Kim, Soon-Yul; Burke, Sean A.; Berkowitz, Dan E.

    2002-01-01

    We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17beta-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.

  14. Bioassay of estrogenicity and chemical analyses of estrogens in streams across the United States associated with livestock operations

    USGS Publications Warehouse

    Alvarez, David A.; Shappell, Nancy W.; Billey, L.O.; Bermudez, Dietrich S.; Wilson, Vickie S.; Kolpin, Dana W.; Perkins, Stephanie D.; Evans, Nicola; Foreman, William T.; Gray, James L.; Shipitalo, J.M.; Meyer, Michael T.

    2013-01-01

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentrations of estrogens in streams from these manures also are of concern due to potential endocrine disruption in aquatic species. Streams associated with livestock operations were sampled by discrete samples (n = 38) or by time-integrated polar organic chemical integrative samplers (POCIS,n = 19). Samples were analyzed for estrogens by gas chromatography-tandem mass spectrometry (GC-MSM2) and estrogenic activity was assessed by three bioassays: Yeast Estrogen Screen (YES), T47D-KBluc Assay, MCF-7 Estrogenicity Screen (E-Screen). Samples were collected from 19 streams within small (∼1-30 km2) watersheds in 12 U.S. states representing a range of hydrogeologic conditions, dominated by: dairy (3), grazing beef (3), feedlot cattle (1); swine (5); poultry (3); and 4 areas where no livestock were raised or manure was applied. Water samples were consistently below the United Kingdom proposed Lowest Observable Effect Concentration for 17b-estradiol in fish (10 ng/L) in all watersheds, regardless of land use. Estrogenic activity was often higher in samples during runoff conditions following a period of manure application. Estrone was the most commonly detected estrogen (13 of 38 water samples, mean 1.9, maximum 8.3 ng/L). Because of the T47D-KBluc assay’s sensitivity towards estrone (1.4 times 17β-estradiol) it was the most sensitive method for detecting estrogens, followed by the E-Screen, GC-MS2, and YES. POCIS resulted in more frequent detections of estrogens than discrete water samples across all sites, even when applying the less-sensitive YES bioassay to the POCIS extracts.

  15. Environmental transport of endogenous dairy manure estrogens.

    PubMed

    Popova, Inna E; Morra, Matthew J

    2017-11-02

    Although estrogens originating from dairy manure applied to agricultural soils as a fertilizer can potentially contaminate surface water and groundwater, the variables that control transport are poorly understood. Our objective was to assess the potential for off-site movement of endogenous dairy cattle estrogens when manure is applied on fields at agronomically relevant fertilization rates. Estrone (E1), 17α-estradiol (α-E2), and 17β-estradiol (β-E2) were used in laboratory sorption, desorption, and transformation incubations with both manure and an agriculturally relevant soil. Sorption on manure containing 44% organic carbon exceeded sorption on soil containing 0.8% organic carbon by 20 to 150 times, following the pattern of β-E2 > α-E2 > E1. Approximately 20% of E1 and 17% of α-E2 were desorbed from manure, whereas only about 4% of β-E2 was desorbed. Thirty to seventy percent of α-E2 and β-E2 were converted to E1 in soil and manure, making it imperative that transformation reactions be considered when predicting transport and potential biological effects in the environment. Overall results indicate that high organic carbon concentrations and relatively low amounts of desorption inhibit the potential for off-site transport of endogenous dairy manure estrogens.

  16. ANALYSIS OF LAGOON SAMPLES FROM DIFFERENT CONCENTRATED ANIMAL FEEDING OPERATIONS (CAFOS) FOR ESTROGENS AND ESTROGEN CONJUGATES (PRESENTATION)

    EPA Science Inventory

    Although Concentrated Animal Feeding Operations (CAFOs) have been identified as potentially important sources for the release of estrogens into the environment, information is lacking on the concentrations of estrogens in whole lagoon effluents (including suspended solids) which ...

  17. Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol.

    PubMed

    Patisaul, H B; Whitten, P L; Young, L J

    1999-04-06

    Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen-dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders. Copyright 1999 Elsevier Science B.V.

  18. Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers

    PubMed Central

    Raj, Ganesh V; Sareddy, Gangadhara Reddy; Ma, Shihong; Lee, Tae-Kyung; Viswanadhapalli, Suryavathi; Li, Rui; Liu, Xihui; Murakami, Shino; Chen, Chien-Cheng; Lee, Wan-Ru; Mann, Monica; Krishnan, Samaya Rajeshwari; Manandhar, Bikash; Gonugunta, Vijay K; Strand, Douglas; Tekmal, Rajeshwar Rao; Ahn, Jung-Mo; Vadlamudi, Ratna K

    2017-01-01

    The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers. DOI: http://dx.doi.org/10.7554/eLife.26857.001 PMID:28786813

  19. Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lecomte, Sylvain; Lelong, Marie; Bourgine, Gaëlle

    Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as amore » model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases. - Highlights: • SERM activity of dietary compounds on proliferation and differentiation is studied. • All the dietary compounds tested transactivate estrogen receptors. • Apigenin and

  20. Dissolved organic matter and estrogen interactions regulate estrogen removal in the aqueous environment: A review.

    PubMed

    Ma, Li; Yates, Scott R

    2018-06-03

    This review summarizes the characterization and quantification of interactions between dissolved organic matter (DOM) and estrogens as well as the effects of DOM on aquatic estrogen removal. DOM interacts with estrogens via binding or sorption mechanisms like π-π interaction and hydrogen bonding. The binding affinity is evaluated in terms of organic-carbon-normalized sorption coefficient (Log K OC ) which varies with types and composition of DOM. DOM has been suggested to be a more efficient sorbent compared with other matrices, such as suspended particulate matter, sediment and soil; likely associated with its large surface area and concentrated carbon content. As a photosensitizer, DOM enhanced estrogen photodegradation when the concentration of DOM was below a threshold value, and when above, the acceleration effect was not observed. DOM played a dual role in affecting biodegradation of estrogens depending on the recalcitrance of the DOM and the nutrition status of the degraders. DOM also acted as an electron shuttle (redox mediator) mediating the degradation of estrogens. DOM hindered enzyme-catalyzed removal of estrogens while enhanced their transformation during the simultaneous photo-enzymatic process. Membrane rejection of estrogens was pronounced for hydrophobic DOM with high aromaticity and phenolic moiety content. Elimination of estrogens via photolysis, biodegradation, enzymolysis and membrane rejection in the presence of DOM is initiated by sorption, accentuating the role of DOM as a mediator in regulating aquatic estrogen removal. Published by Elsevier B.V.

  1. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products

    PubMed Central

    Myers, Sharon L.; Yang, Chun Z.; Bittner, George D.; Witt, Kristine L.; Tice, Raymond R.; Baird, Donna D.

    2014-01-01

    Use of personal care products is widespread in the United States but tends to be greater among African Americans than whites. Of special concern is the possible hazard of absorption of chemicals with estrogenic activity (EA) or anti-EA (AEA) in these products. Such exposure may have adverse health effects, especially when it occurs during developmental windows (e.g., prepubertally) when estrogen levels are low. We assessed the ethanol extracts of eight commonly used hair and skin products popular among African Americans for EA and AEA using a cell proliferation assay with the estrogen sensitive MCF-7:WS8 cell line derived from a human breast cancer. Four of the eight personal care products tested (Oil Hair Lotion, Extra-dry Skin Lotion, Intensive Skin Lotion, Petroleum Jelly) demonstrated detectable EA, whereas three (Placenta Hair Conditioner, Tea-Tree Hair Conditioner, Cocoa Butter Skin Cream) exhibited AEA. Our data indicate that hair and skin care products can have EA or AEA, and suggest that laboratory studies are warranted to investigate the in vivo activity of such products under chronic exposure conditions as well as epidemiologic studies to investigate potential adverse health effects that might be associated with use of such products. PMID:24849798

  2. The estrogen-related receptors (ERRs): potential targets against bone loss.

    PubMed

    Zhang, Ling; Wong, Jiemin; Vanacker, Jean-Marc

    2016-10-01

    Bone loss and the resulting skeletal fragility is induced by several pathological or natural conditions, the most prominent of which being aging as well as the decreased levels of circulating estrogens in post-menopause females. To date, most treatments against bone loss aim at preventing excess bone resorption. We here summarize data indicating that the estrogen-related receptors (ERRs) α and γ prevent bone formation. Inhibiting these receptors may thus constitute an anabolic approach by increasing bone formation.

  3. Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism

    PubMed Central

    2017-01-01

    Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women’s health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in “normal” vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast

  4. Estrogen supports urothelial defense mechanisms.

    PubMed

    Lüthje, Petra; Brauner, Hanna; Ramos, Nubia L; Ovregaard, Amanda; Gläser, Regine; Hirschberg, Angelica Lindén; Aspenström, Pontus; Brauner, Annelie

    2013-06-19

    Epidemiological data imply a role of estrogen in the pathogenesis of urinary tract infections (UTIs), although the underlying mechanisms are not well understood. However, it is thought that estrogen supplementation after menopause decreases the risk of recurrent infections. We sought to investigate the influence of estrogen on host-pathogen interactions and the consequences for UTI pathogenesis. We analyzed urothelial cells from menstruating and postmenopausal women before and after a 2-week period of estrogen supplementation, and also studied the influence of estradiol during Escherichia coli UTI in a mouse infection model. Important findings were confirmed in two human urothelial cell lines. We identified two epithelial defense mechanisms modulated by estrogen. Estrogen induced the expression of antimicrobial peptides, thereby enhancing the antimicrobial capacity of the urothelium and restricting bacterial multiplication. In addition, estrogen promoted the expression and redistribution of cell-cell contact-associated proteins, thereby strengthening the epithelial integrity and preventing excessive loss of superficial cells during infection. These two effects together may prevent bacteria from reaching deeper layers of the urinary tract epithelium and developing reservoirs that can serve as a source for recurrent infections. Thus, this study presents some underlying mechanisms for the beneficial effect of estradiol after menopause and supports the application of estrogen in postmenopausal women suffering from recurrent UTI.

  5. Effect of vaginal or systemic estrogen on dynamics of collagen assembly in the rat vaginal wall.

    PubMed

    Montoya, T Ignacio; Maldonado, P Antonio; Acevedo, Jesus F; Word, R Ann

    2015-02-01

    The objective of this study was to compare the effects of systemic and local estrogen treatment on collagen assembly and biomechanical properties of the vaginal wall. Ovariectomized nulliparous rats were treated with estradiol or conjugated equine estrogens (CEEs) either systemically, vaginal CEE, or vaginal placebo cream for 4 wk. Low-dose local CEE treatment resulted in increased vaginal epithelial thickness and significant vaginal growth without uterine hyperplasia. Furthermore, vaginal wall distensibility increased without compromise of maximal force at failure. Systemic estradiol resulted in modest increases in collagen type I with no change in collagen type III mRNA. Low-dose vaginal treatment, however, resulted in dramatic increases in both collagen subtypes whereas moderate and high dose local therapies were less effective. Consistent with the mRNA results, low-dose vaginal estrogen resulted in increased total and cross-linked collagen content. The inverse relationship between vaginal dose and collagen expression may be explained in part by progressive downregulation of estrogen receptor-alpha mRNA with increasing estrogen dose. We conclude that, in this menopausal rat model, local estrogen treatment increased total and cross-linked collagen content and markedly stimulated collagen mRNA expression in an inverse dose-effect relationship. High-dose vaginal estrogen resulted in downregulation of estrogen receptor-alpha and loss of estrogen-induced increases in vaginal collagen. These results may have important clinical implications regarding the use of local vaginal estrogen therapy and its role as an adjunctive treatment in women with loss of vaginal support. © 2015 by the Society for the Study of Reproduction, Inc.

  6. Modulation of pain by estrogens.

    PubMed

    Craft, Rebecca M

    2007-11-01

    It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

  7. Removal of estrogens and estrogenicity through drinking water treatment.

    PubMed

    Schenck, Kathleen; Rosenblum, Laura; Wiese, Thomas E; Wymer, Larry; Dugan, Nicholas; Williams, Daniel; Mash, Heath; Merriman, Betty; Speth, Thomas

    2012-03-01

    Estrogenic compounds have been shown to be present in surface waters, leading to concerns over their possible presence in finished drinking waters. In this work, two in vitro human cell line bioassays for estrogenicity were used to evaluate the removal of estrogens through conventional drinking water treatment using a natural water. Bench-scale studies utilizing chlorine, alum coagulation, ferric chloride coagulation, and powdered activated carbon (PAC) were conducted using Ohio River water spiked with three estrogens, 17β-estradiol, 17α-ethynylestradiol, and estriol. Treatment of the estrogens with chlorine, either alone or with coagulant, resulted in approximately 98% reductions in the concentrations of the parent estrogens, accompanied by formation of by-products. The MVLN reporter gene and MCF-7 cell proliferation assays were used to characterize the estrogenic activity of the water before and after treatment. The observed estrogenic activities of the chlorinated samples showed that estrogenicity of the water was reduced commensurate with removal of the parent estrogen. Therefore, the estrogen chlorination by-products did not contribute appreciably to the estrogenic activity of the water. Coagulation alone did not result in significant removals of the estrogens. However, addition of PAC, at a typical drinking water plant dose, resulted in removals ranging from approximately 20 to 80%.

  8. Estrogen Enhances Malignant Phenotypes in Human Salivary Adenoid Cystic Carcinoma Cells.

    PubMed

    Sumida, Tomoki; Ishikawa, Akiko; Kamata, Y U; Nakano, Hiroyuki; Yamada, Tomohiro; Mori, Yoshihide

    2016-06-01

    Adenoid cystic carcinoma (SGC) is a common type of salivary gland cancer (SGC). Surgery is the first treatment choice because chemoradiotherapy is usually not effective. Therefore, new treatment modalities are urgently needed. In this study, it was investigated whether the estrogen axis could be a treatment target or not. Adenoid cystic carcinoma (ACC) ACCM cells, were used. The specific cell line lacks estrogen receptor (ER). ER was introduced in ACCM cells, and the effect of 17β-estradiol (E2) was investigated on cell proliferation, cell-cycle distribution, and cell motility. E2 induced cell proliferation, and the S-phase fraction increased in a dose-dependent manner. Cell motility was also up-regulated compared to control cells. The estrogen/ER system up-regulated malignant phenotypes in ER-positive ACC, and hormone therapy may have a potential as effective treatment for this malignancy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Acute Toxicity, Teratogenic, and Estrogenic Effects of Bisphenol A and Its Alternative Replacements Bisphenol S, Bisphenol F, and Bisphenol AF in Zebrafish Embryo-Larvae.

    PubMed

    Moreman, John; Lee, Okhyun; Trznadel, Maciej; David, Arthur; Kudoh, Tetsuhiro; Tyler, Charles R

    2017-11-07

    Bisphenol A (BPA), a chemical incorporated into plastics and resins, has estrogenic activity and is associated with adverse health effects in humans and wildlife. Similarly structured BPA analogues are widely used but far less is known about their potential toxicity or estrogenic activity in vivo. We undertook the first comprehensive analysis on the toxicity and teratogenic effects of the bisphenols BPA, BPS, BPF, and BPAF in zebrafish embryo-larvae and an assessment on their estrogenic mechanisms in an estrogen-responsive transgenic fish Tg(ERE:Gal4ff)(UAS:GFP). The rank order for toxicity was BPAF > BPA > BPF > BPS. Developmental deformities for larval exposures included cardiac edema, spinal malformation, and craniofacial deformities and there were distinct differences in the effects and potencies between the different bisphenol chemicals. These effects, however, occurred only at concentrations between 1.0 and 200 mg/L which exceed those in most environments. All bisphenol compounds induced estrogenic responses in Tg(ERE:Gal4ff)(UAS:GFP) zebrafish that were inhibited by coexposure with ICI 182 780, demonstrating an estrogen receptor dependent mechanism. Target tissues included the heart, liver, somite muscle, fins, and corpuscles of Stannius. The rank order for estrogenicity was BPAF > BPA = BPF > BPS. Bioconcentration factors were 4.5, 17.8, 5.3, and 0.067 for exposure concentrations of 1.0, 1.0, 0.10, and 50 mg/L for BPA, BPF, BPAF, and BPS, respectively. We thus show that these BPA alternatives induce similar toxic and estrogenic effects to BPA and that BPAF is more potent than BPA, further highlighting health concerns regarding the use of BPA alternatives.

  10. Estrogen signaling through the G protein-coupled estrogen receptor regulates granulocyte activation in fish.

    PubMed

    Cabas, Isabel; Rodenas, M Carmen; Abellán, Emilia; Meseguer, José; Mulero, Victoriano; García-Ayala, Alfonsa

    2013-11-01

    Neutrophils are major participants in innate host responses. It is well known that estrogens have an immune-modulatory role, and some evidence exists that neutrophil physiology can be altered by these molecules. Traditionally, estrogens act via classical nuclear estrogen receptors, but the identification of a G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor that binds estradiol and other estrogens, has opened up the possibility of exploring additional estrogen-mediated effects. However, information on the importance of GPER for immunity, especially, in neutrophils is scant. In this study, we report that gilthead seabream (Sparus aurata L.) acidophilic granulocytes, which are the functional equivalent of mammalian neutrophils, express GPER at both mRNA and protein levels. By using a GPER selective agonist, G1, it was found that GPER activation in vitro slightly reduced the respiratory burst of acidophilic granulocytes and drastically altered the expression profile of several genes encoding major pro- and anti-inflammatory mediators. In addition, GPER signaling in vivo modulated adaptive immunity. Finally, a cAMP analog mimicked the effects of G1 in the induction of the gene coding for PG-endoperoxide synthase 2 and in the induction of CREB phosphorylation, whereas pharmacological inhibition of protein kinase A superinduced PG-endoperoxide synthase 2. Taken together, our results demonstrate for the first time, to our knowledge, that estrogens are able to modulate vertebrate granulocyte functions through a GPER/cAMP/protein kinase A/CREB signaling pathway and could establish therapeutic targets for several immune disorders in which estrogens play a prominent role.

  11. Distinct Hypothalamic Neurons Mediate Estrogenic Effects on Energy Homeostasis and Reproduction

    PubMed Central

    Xu, Yong; Nedungadi, Thekkethil P.; Zhu, Liangru; Sobhani, Nasim; Irani, Boman G.; Davis, Kathryn E.; Zhang, Xiaorui; Zou, Fang; Gent, Lana M.; Hahner, Lisa D.; Khan, Sohaib A.; Elias, Carol F.; Elmquist, Joel K.; Clegg, Deborah J.

    2011-01-01

    Summary Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-α (ERα). However, ERα-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERα in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERα in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERα from both SF1 and POMC neurons causes hypometabolism, hyperphagia and increased visceral adiposity. Additionally, female mice lacking ERα in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERα inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERα neurons to regulate different aspects of energy homeostasis and reproduction. PMID:21982706

  12. Effects of phytoestrogens and environmental estrogens on osteoblastic differentiation in MC3T3-E1 cells.

    PubMed

    Kanno, Sanae; Hirano, Seishiro; Kayama, Fujio

    2004-03-01

    Phytoestrogens and environmental estrogens, which have in part some structural similarity to 17beta-estradiol, are reported to act as agonists/antagonists of estrogen in animals and humans. Estrogen is known to play an important role in maintaining bone mass, since the concentration of serum estrogen decreases after menopause and the estrogen deficiency results in bone loss. In this study, we report the effects of phytoestrogens (genistein, daidzein, and coumestrol) and environmental estrogens (bisphenol A (BPA), p-n-nonylphenol (NP) and bis(2-ethylhexyl)phthalate (DEHP)) on osteoblast differentiation using MC3T3-E1 cells, a mouse calvaria osteoblast-like cell line. Coumestrol (10(-10) to 10(-6)M) slightly enhanced cell proliferation, while neither the other phytoestrogens (daidzein, genistein) nor environmental estrogens increased cell proliferation. Alkaline phosphatase (ALP) activity and cellular calcium (Ca) and phosphorus (P) contents were increased by phytoestrogens and BPA; however, neither NP nor DEHP affected those osteoblastic indicators. The effects of estrogenic potency, using the cell proliferation of MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line, indicate that coumestrol has the highest estrogenic potency among those phytoestrogens and environmental estrogens. The estrogenic potency of NP and DEHP were lower than the others. In conclusion, phytoestrogens, such as coumestrol, genistein and daidzein, and BPA increased ALP activity and enhanced bone mineralization in MC3T3-E1 cells, suggesting that not only phytoestrogen but also BPA, an environmental estrogen, is implicated in bone metabolism.

  13. Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pinto, Caroline; Grimaldi, Marina; Boulahtouf, Abdelhay

    2014-10-01

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared tomore » 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater

  14. Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals.

    PubMed

    Miles, Clare; Green, Richard; Hines, Melissa

    2006-12-01

    Gonadal hormones, particularly estrogens, have been suggested to influence memory and cognitive tasks that show sex differences. Previously, we reported that male-to-female (M-F) transsexuals undergoing estrogen treatment for sex re-assignment scored higher on verbal Paired Associate Learning (PAL) than a transsexual control group awaiting estrogen treatment. The present study used a more robust design to examine further associations between estrogen and cognition. We assessed additional aspects of memory, including visual, spatial, object and location memory, other cognitive abilities that show reliable sex differences, including verbal and visual-spatial abilities, and mood variables that could mediate associations between estrogen and cognition. In addition to comparing groups of individuals on and off estrogen, we used two repeated measures designs (AB and BA). The AB group was tested prior to hormone treatment and then again after treatment had begun; the BA group was tested while on estrogen treatment and then again when hormones had been withdrawn prior to surgery. Few changes in memory or cognition were observed, and changes that were observed were not consistent across study designs. The lack of significant effects did not relate to mood changes or to the sexual orientation of participants. These findings suggest that estrogen treatment associated with sex change for M-F transsexuals has little or no influence on sex-typed aspects of cognition or memory.

  15. The E-screen assay as a tool to identify estrogens: An update on estrogenic environmental pollutants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Soto, A.M.; Sonnenschein, C.; Chung, K.L.

    1995-10-01

    Estrogens are defined by their ability to induce the proliferation of cells of the female genital tract. The wide chemical diversity of estrogenic compounds precludes an accurate prediction of estrogenic activity on the basis of chemical structure. Rodent bioassays are not suited for the large-scale screening of chemicals before their release into the environment because of their cost, complexity, and ethical concerns. The E-SCREEN assay was developed to assess the estrogenicity of environmental chemicals using the proliferative effect of estrogens on their target cells as an end point. This quantitative assay compares the cell number achieved by similar inocula ofmore » MCF-7 cells in the absence of estrogens (negative control) and in the presence of 17{beta}-estradiol (positive control) and a range of concentrations of chemicals suspected to be estrogenic. Among the compounds tested, several {open_quotes}new{close_quotes} estrogens were found; alkylphenols, phthalates, some PCB congeners and hydroxylated PCBs, and the insecticides dieldrin, endosulfan, and toxaphene were estrogenic by the E-SCREEN assay. In addition, these compounds competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics. Recombinant human growth factors (bFGF, EGF, IGF-1) and insulin did not increase cell yields. The aims of the work summarized in this paper were (a) to validate the E-SCREEN assay; (b) to screen a variety of chemicals present in the environment to identify those that may be causing reproductive effects in wildlife and humans; (c) to assess whether environmental estrogens may act cumulatively; and finally (d) to discuss the reliability of this and other assays to screen chemicals for their estrogenicity before they are released into the environment. 57 refs., 3 figs., 9 tabs.« less

  16. Melatonin decreases estrogen receptor binding to estrogen response elements sites on the OCT4 gene in human breast cancer stem cells

    PubMed Central

    Lopes, Juliana; Arnosti, David; Trosko, James E.; Tai, Mei-Hui; Zuccari, Debora

    2016-01-01

    Cancer stem cells (CSCs) pose a challenge in cancer treatment, as these cells can drive tumor growth and are resistant to chemotherapy. Melatonin exerts its oncostatic effects through the estrogen receptor (ER) pathway in cancer cells, however its action in CSCs is unclear. Here, we evaluated the effect of melatonin on the regulation of the transcription factor OCT4 (Octamer Binding 4) by estrogen receptor alpha (ERα) in breast cancer stem cells (BCSCs). The cells were grown as a cell suspension or as anchorage independent growth, for the mammospheres growth, representing the CSCs population and treated with 10 nM estrogen (E2) or 10 μM of the environmental estrogen Bisphenol A (BPA) and 1 mM of melatonin. At the end, the cell growth as well as OCT4 and ERα expression and the binding activity of ERα to the OCT4 was assessed. The increase in number and size of mammospheres induced by E2 or BPA was reduced by melatonin treatment. Furthermore, binding of the ERα to OCT4 was reduced, accompanied by a reduction of OCT4 and ERα expression. Thus, melatonin treatment is effective against proliferation of BCSCs in vitro and impacts the ER pathway, demonstrating its potential therapeutic use in breast cancer. PMID:27551335

  17. Effects of Millettia macrophylla (Fabaceae) extracts on estrogen target organs of female wistar rat.

    PubMed

    Zingue, Stéphane; Njamen, Dieudonné; Tchoumtchoua, Job; Halabalaki, Maria; Simpson, Evan; Clyne, Colin; Magne Nde, Chantal Beatrice

    2013-01-01

    The present study aims to determine the estrogenicity of Millettia macrophylla, a Cameroonian medicinal plant, in ovariectomized rats and to investigate the underlying mechanisms, in order to justify scientifically its traditional use. To accomplish this objective, we used dichloromethane (DCM) and methanol (MeOH) extracts of the stem bark of M. macrophylla. In the cell culture based assay, the MeOH extract significantly transactivated estrogen receptor α (ERα) and estrogen receptor β (ERβ); in addition, the estrogen-like effects of both, DCM and MeOH extracts, could be inhibited in vitro by the pure ER antagonist ICI 182,780, indicating that these effects were primarily mediated through ERs. In animal experiments, both DCM and MeOH extracts significantly increased the uterine and vaginal epithelial heights in the 3-day treatment assay, while only the MeOH extract exhibited such effects in the sub-chronic treatment regimen. Furthermore, the MeOH extract significantly decreased fasting serum triglycerides, total cholesterol levels and artherogenic risk in the sub-chronic treatment. These results indicate that M. macrophylla extracts have estrogen-like effects supporting their traditional use in Cameroon to alleviate some menopausal problems (See graphical abstract in Supplementary Fig. 1, available in the online version only).

  18. Estrogen regulates histone deacetylases to prevent cardiac hypertrophy

    PubMed Central

    Pedram, Ali; Razandi, Mahnaz; Narayanan, Ramesh; Dalton, James T.; McKinsey, Timothy A.; Levin, Ellis R.

    2013-01-01

    The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease. PMID:24152730

  19. Effects of essential oil exposure on salivary estrogen concentration in perimenopausal women.

    PubMed

    Shinohara, Kazuyuki; Doi, Hirokazu; Kumagai, Chizu; Sawano, Erika; Tarumi, Wataru

    2017-01-01

    The menopausal transition is the time from the onset of menstrual changes until one year after the final menstrual period. During this phase, perimenopausal women experience a variety of health-related symptoms, which seemingly derive from declining level of estrogen secretion. It has long been recognized that some essential oils have the efficacy of alleviating menopausal symptoms. On the basis of this, it is possible that these essential oils have the potency to facilitate estrogen secretion in women. The present study investigated this possibility by examining if the olfactory exposure to the essential oil increase salivary estrogen concentration. We tested the effect of ten essential oils; clary sage, frankincense, geranium, lavender, jasmine absolute, neroli, rose otto, ylang ylang, orange and roman chamomile, which are thought to relieve perimenopasal symptoms. The results have shown increase of salivary estrogen concentration induced by exposure to geranium and rose otto compared to control odor. Together with the previous studies, the present study may give support to the notion that olfactory exposure to some essential oils can influence salivary concentration of estrogen.

  20. Effects of advanced treatments of wastewater effluents on estrogenic and reproductive health impacts in fish.

    PubMed

    Filby, Amy L; Shears, Janice A; Drage, Briane E; Churchley, John H; Tyler, Charles R

    2010-06-01

    Whether the implementation of additional treatments for the removal of estrogens from wastewater treatment works (WwTWs) effluents will eliminate their feminizing effects in exposed wildlife has yet to be established, and this information is crucial for future decisions on investment into WwTWs. Here, granular activated carbon (GAC), ozone (O(3)), and chlorine dioxide (ClO(2)) were investigated for their effectiveness in reducing steroidal estrogen levels in a WwTW effluent and assessments made on the associated estrogenic and reproductive responses in fathead minnows (Pimephales promelas) exposed for 21 days. All treatments reduced the estrogenicity of the standard-treated (STD) effluent, but with different efficacies; ranging between 70-100% for total estrogenicity and 53-100% for individual steroid estrogens. In fish exposed to the GAC- and ClO(2)- (but not O(3)-) treated effluents, there was no induction of plasma vitellogenin (VTG) or reduction in the weight of the fatpad, a secondary sex character in males, as occurred for fish exposed to STD effluent. This finding suggests likely benefits of employing these treatment processes for the reproductive health in wild fish populations living in rivers receiving WwTW discharges. Exposure of pair-breeding minnows to the GAC-treated effluent, however, resulted in a similar inhibition of egg production to that occurring for exposure to the STD effluent (34-40%). These data, together with a lack of effect on egg production of the estrogen, ethinylestradiol (10 ng/L), alone, suggest that chemical/physical properties of the effluents rather than their estrogenicity were responsible for the reproductive effect and that these factor(s) were not remediated for through GAC treatment. Collectively, our findings illustrate the importance of assessing integrative biological responses, rather than biomarkers alone, in the assessment and improvement of WwTW technologies for the protection of wild fish populations.

  1. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action.

    PubMed

    Bhavnani, Bhagu R; Stanczyk, Frank Z

    2014-07-01

    Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50-59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD. CEE is a natural formulation of an extract prepared from pregnant mares' urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17β-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17β-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor β and not the estrogen receptor α. All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17β-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins. Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer

  2. Combinations of Physiologic Estrogens with Xenoestrogens Alter ERK Phosphorylation Profiles in Rat Pituitary Cells

    PubMed Central

    Jeng, Yow-Jiun; Watson, Cheryl S.

    2011-01-01

    Background Estrogens are potent nongenomic phospho-activators of extracellular-signal–regulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously. Objectives We examined estrogen-induced ERK activation, comparing the abilities of structurally related XEs (alkylphenols and bisphenol A) to alter ERK responses induced by physiologic concentrations (1 nM) of estradiol (E2), estrone (E1), and estriol (E3). Methods We quantified hormone/mimetic-induced ERK phosphorylations in the GH3/B6/F10 rat pituitary cell line using a plate immunoassay, comparing effects with those on cell proliferation and by estrogen receptor subtype-selective ligands. Results Alone, these structurally related XEs activate ERKs in an oscillating temporal pattern similar (but not identical) to that with physiologic estrogens. The potency of all estrogens was similar (active between femtomolar and nanomolar concentrations). XEs potently disrupted physiologic estrogen signaling at low, environmentally relevant concentrations. Generally, XEs potentiated (at the lowest, subpicomolar concentrations) and attenuated (at the highest, picomolar to 100 nM concentrations) the actions of the physiologic estrogens. Some XEs showed pronounced nonmonotonic responses/inhibitions. The phosphorylated ERK and proliferative responses to receptor-selective ligands were only partially correlated. Conclusions XEs are both imperfect potent estrogens and endocrine disruptors; the more efficacious an XE, the more it disrupts actions of physiologic estrogens. This ability to disrupt physiologic estrogen signaling suggests that XEs may disturb normal functioning at life stages where actions of particular estrogens are important (e.g., development, reproductive cycling, pregnancy, menopause). PMID:20870566

  3. Analytical techniques for steroid estrogens in water samples - A review.

    PubMed

    Fang, Ting Yien; Praveena, Sarva Mangala; deBurbure, Claire; Aris, Ahmad Zaharin; Ismail, Sharifah Norkhadijah Syed; Rasdi, Irniza

    2016-12-01

    In recent years, environmental concerns over ultra-trace levels of steroid estrogens concentrations in water samples have increased because of their adverse effects on human and animal life. Special attention to the analytical techniques used to quantify steroid estrogens in water samples is therefore increasingly important. The objective of this review was to present an overview of both instrumental and non-instrumental analytical techniques available for the determination of steroid estrogens in water samples, evidencing their respective potential advantages and limitations using the Need, Approach, Benefit, and Competition (NABC) approach. The analytical techniques highlighted in this review were instrumental and non-instrumental analytical techniques namely gas chromatography mass spectrometry (GC-MS), liquid chromatography mass spectrometry (LC-MS), enzyme-linked immuno sorbent assay (ELISA), radio immuno assay (RIA), yeast estrogen screen (YES) assay, and human breast cancer cell line proliferation (E-screen) assay. The complexity of water samples and their low estrogenic concentrations necessitates the use of highly sensitive instrumental analytical techniques (GC-MS and LC-MS) and non-instrumental analytical techniques (ELISA, RIA, YES assay and E-screen assay) to quantify steroid estrogens. Both instrumental and non-instrumental analytical techniques have their own advantages and limitations. However, the non-instrumental ELISA analytical techniques, thanks to its lower detection limit and simplicity, its rapidity and cost-effectiveness, currently appears to be the most reliable for determining steroid estrogens in water samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Mixture interactions of xenoestrogens with endogenous estrogens.

    EPA Science Inventory

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. These environmental estrogens originate from various sources including concentrated animal feedlot operations (CAFO), m...

  5. “Rapid Estrogen Signaling in the Brain: Implications for the Fine-Tuning of Neuronal Circuitry”

    PubMed Central

    Srivastava, Deepak P.; Waters, Elizabeth M.; Mermelstein, Paul G.; Kramár, Enikö A.; Shors, Tracey J.; Liu, Feng

    2011-01-01

    Rapid actions of estrogens were first described over 40 years ago. However, the importance of rapid estrogen-mediated actions in the central nervous system (CNS) has only now becoming apparent. Several lines of evidence demonstrate that rapid estrogen-mediated signaling elicits potent effects on molecular and cellular events, resulting in the fine-tuning of neuronal circuitry. At an ultrastructural level, the details of estrogen receptor localization and how these are regulated by the circulating hormone and age, are now becoming evident. Furthermore, the mechanisms that allow membrane-associated estrogen receptors to couple with intracellular signaling pathways are also now being revealed. Elucidation of complex actions of rapid estrogen-mediated signaling on synaptic proteins, connectivity and synaptic function in pyramidal neurons has demonstrated that this neurosteroid engage specific mechanisms in different areas of the brain. The regulation of synaptic properties most likely underlies the ‘fine-tuning’ of neuronal circuitry. This in turn may influence how learned behaviors are encoded by different circuitry in male and female subjects. Importantly, as estrogens have been suggested as potential treatments of a number of disorders of the CNS, advancements in our understanding of rapid estrogen signaling in the brain will serve to aid in the development of potential novel estrogen-based treatments. PMID:22072656

  6. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens.

    PubMed Central

    Newbold, R

    1995-01-01

    Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors. PMID:8593881

  7. Loss of ERβ expression as a common step in estrogen-dependent tumor progression

    PubMed Central

    Bardin, Allison; Boulle, Nathalie; Lazennec, Gwendal; Vignon, Françoise; Pujol, Pascal

    2004-01-01

    The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues and the mitogenic effects of estrogen in these tissues (e.g. breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared to benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ, or ERβ specific gene induction could indicate that ERβ has a differential effect on proliferation as compared to ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, e.g. via ligand specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review. PMID:15369453

  8. Environmental impact of estrogens on human, animal and plant life: A critical review.

    PubMed

    Adeel, Muhammad; Song, Xiaoming; Wang, Yuanyuan; Francis, Dennis; Yang, Yuesuo

    2017-02-01

    Since the inception of global industrialization, steroidal estrogens have become an emerging and serious concern. Worldwide, steroid estrogens including estrone, estradiol and estriol, pose serious threats to soil, plants, water resources and humans. Indeed, estrogens have gained notable attention in recent years, due to their rapidly increasing concentrations in soil and water all over the world. Concern has been expressed regarding the entry of estrogens into the human food chain which in turn relates to how plants take up and metabolism estrogens. In this review we explore the environmental fate of estrogens highlighting their release through effluent sources, their uptake, partitioning and physiological effects in the ecological system. We draw attention to the potential risk of intensive modern agriculture and waste disposal systems on estrogen release and their effects on human health. We also highlight their uptake and metabolism in plants. We use MEDLINE and other search data bases for estrogens in the environment from 2005 to the present, with the majority of our sources spanning the past five years. Published acceptable daily intake of estrogens (μg/L) and predicted no effect concentrations (μg/L) are listed from published sources and used as thresholds to discuss reported levels of estrogens in the aquatic and terrestrial environments. Global levels of estrogens from river sources and from Waste Water Treatment Facilities have been mapped, together with transport pathways of estrogens in plants. Estrogens at polluting levels have been detected at sites close to waste water treatment facilities and in groundwater at various sites globally. Estrogens at pollutant levels have been linked with breast cancer in women and prostate cancer in men. Estrogens also perturb fish physiology and can affect reproductive development in both domestic and wild animals. Treatment of plants with steroid estrogen hormones or their precursors can affect root and shoot

  9. Effect of Vaginal or Systemic Estrogen on Dynamics of Collagen Assembly in the Rat Vaginal Wall1

    PubMed Central

    Montoya, T. Ignacio; Maldonado, P. Antonio; Acevedo, Jesus F.; Word, R. Ann

    2014-01-01

    ABSTRACT The objective of this study was to compare the effects of systemic and local estrogen treatment on collagen assembly and biomechanical properties of the vaginal wall. Ovariectomized nulliparous rats were treated with estradiol or conjugated equine estrogens (CEEs) either systemically, vaginal CEE, or vaginal placebo cream for 4 wk. Low-dose local CEE treatment resulted in increased vaginal epithelial thickness and significant vaginal growth without uterine hyperplasia. Furthermore, vaginal wall distensibility increased without compromise of maximal force at failure. Systemic estradiol resulted in modest increases in collagen type I with no change in collagen type III mRNA. Low-dose vaginal treatment, however, resulted in dramatic increases in both collagen subtypes whereas moderate and high dose local therapies were less effective. Consistent with the mRNA results, low-dose vaginal estrogen resulted in increased total and cross-linked collagen content. The inverse relationship between vaginal dose and collagen expression may be explained in part by progressive downregulation of estrogen receptor-alpha mRNA with increasing estrogen dose. We conclude that, in this menopausal rat model, local estrogen treatment increased total and cross-linked collagen content and markedly stimulated collagen mRNA expression in an inverse dose-effect relationship. High-dose vaginal estrogen resulted in downregulation of estrogen receptor-alpha and loss of estrogen-induced increases in vaginal collagen. These results may have important clinical implications regarding the use of local vaginal estrogen therapy and its role as an adjunctive treatment in women with loss of vaginal support. PMID:25537371

  10. Estrogen enhances the bone regeneration potential of periodontal ligament stem cells derived from osteoporotic rats and seeded on nano-hydroxyapatite/collagen/poly(L-lactide)

    PubMed Central

    E, LING-LING; XU, WEN-HUAN; FENG, LIN; LIU, YI; CAI, DONG-QING; WEN, NING; ZHENG, WEN-JIE

    2016-01-01

    This study investigated the effects of estrogen on the bone regeneration potential of periodontal ligament stem cells (PDLSCs) derived from osteoporotic rats and seeded on a collagen-based composite scaffold [nano-hydroxyapatite/collagen/poly(L-lactide) (nHAC/PLA)]. For this purpose, 48 healthy 3-month-old Sprague-Dawley female rats were divided into 2 groups as follows: the bilaterally ovariectomized (OVX) rats and sham-operated rats. The PDLSCs were isolated at 3 months after surgery (by which time postmenopausal osteoporosis had developed). The effects of estrogen on the characteristics of these cells seeded in a culture plate and of the cells seeded on nHAC/PLA were then investigated. The PDLSC + nHAC/PLA constructs were implanted subcutaneously into the backs of severe combined immunodeficient (SCID) mice for 12 weeks in order to examine the role of estrogen in the bone formation ability of PDLSCs derived from osteoporotic rats. The results from methyl thiazolyl tetrazolium (MTT) assay revealed that the proliferation of the cells derived from the rats in the OVX group was significantly higher than that of the cells derived from the rats in the sham-operated group at the stage of logarithmic growth. The staining intensity of alkaline phosphatase (ALP) and the mineralization of the cells derived from the rats in the OVX group was significantly weaker than that of the cells from the rats in the sham-operated group. When the PDLSCs were seeded on nHAC/PLA, ALP activity, osteocalcin (OCN) secretion, mineral formation and the mRNA expression levels of ALP, OCN, estrogen receptor (ER)α and ERβ in the cells derived from the rats in the OVX group were markedly decreased. Treatment with 17β-estradiol (E2) significantly weakened the proliferative ability of the cells derived from the OVX group rats, and enhanced their osteogenic differentiation ability and the mRNA expression levels of ALP, OCN, ERα and ERβ. When the constructs were implanted into the backs of SCID

  11. Perfluorinated chemicals, PFOS and PFOA, enhance the estrogenic effects of 17β-estradiol in T47D human breast cancer cells.

    PubMed

    Sonthithai, Pacharapan; Suriyo, Tawit; Thiantanawat, Apinya; Watcharasit, Piyajit; Ruchirawat, Mathuros; Satayavivad, Jutamaad

    2016-06-01

    Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most popular surfactants among perfluorinated compounds (PFCs), with a wide range of uses. Growing evidence suggests that PFCs have the potential to interfere with estrogen homeostasis, posing a risk of endocrine-disrupting effects. This in vitro study aimed to investigate the estrogenic effect of these compounds on T47D hormone-dependent breast cancer cells. PFOS and PFOA (10(-12) to 10(-4)  M) were not able to induce estrogen response element (ERE) activation in the ERE luciferase reporter assay. The ERE activation was induced when the cells were co-incubated with PFOS (10(-10) to 10(-7)  M) or PFOA (10(-9) to 10(-7)  M) and 1 nM of 17β-estradiol (E2). PFOS and PFOA did not modulate the expression of estrogen-responsive genes, including progesterone (PR) and trefoil factor (pS2), but these compounds enhanced the effect of E2-induced pS2 gene expression. Neither PFOS nor PFOA affected T47D cell viability at any of the tested concentrations. In contrast, co-exposure with PFOS or PFOA and E2 resulted in an increase of E2-induced cell viability, but no effect was found with 10 ng ml(-1) EGF co-exposure. Both compounds also intensified E2-dependent growth in the proliferation assay. ERK1/2 phosphorylation was increased by co-exposure with PFOS or PFOA and E2, but not with EGF. Collectively, this study shows that PFOS and PFOA did not possess estrogenic activity, but they enhanced the effects of E2 on estrogen-responsive gene expression, ERK1/2 activation and the growth of the hormone-deprived T47D cells. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Endocrine disruptive estrogens role in electron transfer: bio-electrochemical remediation with microbial mediated electrogenesis.

    PubMed

    Kumar, A Kiran; Reddy, M Venkateswar; Chandrasekhar, K; Srikanth, S; Mohan, S Venkata

    2012-01-01

    Bioremediation of selected endocrine disrupting compounds (EDCs)/estrogens viz. estriol (E3) and ethynylestradiol (EE2) was evaluated in bio-electrochemical treatment (BET) system with simultaneous power generation. Estrogens supplementation along with wastewater documented enhanced electrogenic activity indicating their function in electron transfer between biocatalyst and anode as electron shuttler. EE2 addition showed more positive impact on the electrogenic activity compared to E3 supplementation. Higher estrogen concentration showed inhibitory effect on the BET performance. Poising potential during start up phase showed a marginal influence on the power output. The electrons generated during substrate degradation might have been utilized for the EDCs break down. Fuel cell behavior and anodic oxidation potential supported the observed electrogenic activity with the function of estrogens removal. Voltammetric profiles, dehydrogenase and phosphatase enzyme activities were also found to be in agreement with the power generation, electron discharge and estrogens removal. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

    PubMed

    Duarte-Guterman, Paula; Yagi, Shunya; Chow, Carmen; Galea, Liisa A M

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Estrogen and the aging brain: an elixir for the weary cortical network.

    PubMed

    Dumitriu, Dani; Rapp, Peter R; McEwen, Bruce S; Morrison, John H

    2010-08-01

    The surprising discovery in 1990 that estrogen modulates hippocampal structural plasticity launched a whole new field of scientific inquiry. Over the past two decades, estrogen-induced spinogenesis has been described in several brain areas involved in cognition in a number of species, in both sexes and on multiple time scales. Exploration into the interaction between estrogen and aging has illuminated some of the hormone's neuroprotective effects, most notably on age-related cognitive decline in nonhuman primates. Although there is still much to be learned about the mechanisms by which estrogen exerts its actions, key components of the signal transduction pathways are beginning to be elucidated and nongenomic actions via membrane bound estrogen receptors are of particular interest. Future studies are focused on identifying the most clinically relevant hormone treatment, as well as the potential identification of new therapeutics that can prevent or reverse age-related cognitive impairment by intercepting specific signal transduction pathways initiated by estrogen.

  15. The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines.

    PubMed

    Sandra, Niro; Ester, Pereira; Marie-Agnès, Pélissier; Robert, Morfin; Olivier, Hennebert

    2012-04-01

    7β-Hydroxy-epiandrosterone (7β-OH-EpiA), an endogenous androgenic derivative of dehydroepiandrosterone, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-Δ(12,14)-PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7β-OH-EpiA (1-100nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogen-dependent mammary cancers. Estrogen induced PGE2 production and cell proliferation via its binding to estrogen receptors (ERs) in these tumors. Our objective was to test the effects of 7β-OH-EpiA on the proliferation (by counting with trypan blue exclusion), cell cycle and cell apoptosis (by flow cytometry) of breast cancer cell lines MCF-7 (ERα+, ERβ+, G-protein coupled receptor 30: GPR30+) and MDA-MB-231 (ERα-, ERβ+, GPR30+) and to identify a potential target of this steroid in these cell lineages (by transactivations) and in the nuclear ER-negative SKBr3 cells (GPR30+) (by proliferation assays). 7β-OH-EpiA exerted anti-estrogenic effects in MCF-7 and MDA-MB-231 cells associated with cell proliferation inhibition and cell cycle arrest. Moreover, transactivation and proliferation with ER agonists assays indicated that 7β-OH-EpiA interacted with ERβ. Data from proliferation assays on the MCF-7, MDA-MB-231 and SKBr3 cell lines suggested that 7β-OH-EpiA may also act through the membrane GPR30 receptor. These results support that this androgenic steroid acts as an anti-estrogenic compound. Moreover, this is the first evidence that low doses of androgenic steroid exert antiproliferative effects in these mammary cancer cells. Further investigations are needed to improve understanding of the observed actions of endogenous 7β-OH-EpiA. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Activation of Estrogen Receptor Transfected into a Receptor-Negative Brest Cancer Cell Line Decreases the Metastatic and Invasive Potential of the Cells

    NASA Astrophysics Data System (ADS)

    Garcia, Marcel; Derocq, Danielle; Freiss, Gilles; Rochefort, Henri

    1992-12-01

    Breast cancers containing estrogen receptors are responsive to antiestrogen treatment and have a better prognosis than estrogen receptor-negative tumors. The loss of estrogen and progesterone receptors appears to be associated with a progression to less-differentiated tumors. We transfected the human estrogen receptor into the estrogen receptor-negative metastatic breast cancer cell line MDA-MB-231 in an attempt to restore their sensitivity to antiestrogens. Two stable sublines of MDA-MB-231 cells (HC1 and HE5) expressing functional estrogen receptors were studied for their ability to grow and invade in vitro and to metastasize in athymic nude mice. The number and size of lung metastases developed by these two sublines in ovariectomized nude mice was not markedly altered by tamoxifen but was inhibited 3-fold by estradiol. Estradiol also significantly inhibited in vitro cell proliferation of these sublines and their invasiveness in Matrigel, a reconstituted basement membrane, whereas the antiestrogens 4-hydroxytamoxifen and ICI 164,384 reversed these effects. These results show that estradiol inhibits the metastatic ability of estrogen receptornegative breast cancer cells following transfection with the estrogen receptor, whereas estrogen receptor-positive breast cancers are stimulated by estrogen, indicating that factors other than the estrogen receptor are involved in progression toward hormone independence. Reactivation or transfer of the estrogen receptor gene can therefore be considered as therapeutic approaches to hormone-independent cancers

  17. Estrogen via estrogen receptor beta partially inhibits mandibular condylar cartilage growth.

    PubMed

    Chen, J; Kamiya, Y; Polur, I; Xu, M; Choi, T; Kalajzic, Z; Drissi, H; Wadhwa, S

    2014-11-01

    Temporomandibular joint (TMJ) diseases predominantly afflict women, suggesting a role for female hormones in the disease process. However, little is known about the role of estrogen receptor (ER) signaling in regulating mandibular condylar cartilage growth. Therefore, the goal of this study was to examine the effects of altered estrogen levels on the mandibular condylar cartilage in wild type (WT) and ER beta Knockout (KO) mice. 21-day-old female WT (n = 37) and ER beta KO mice (n = 36) were either sham operated or ovariectomized, and treated with either placebo or estradiol. The mandibular condylar cartilage was evaluated by histomorphometry, proliferation was analyzed by double ethynyl-2'-deoxyuridine/bromodeoxyuridine (EdU/BrdU) labeling, and assays on gene and protein expression of chondrocyte maturation markers were performed. In WT mice, ovariectomy caused a significant increase in mandibular condylar cartilage cell numbers, a significant increase in Sox9 expression and a significant increase in proliferation compared with sham operated WT mice. In contrast, ovariectomy did not cause any of these effects in the ER beta KO mice. Estrogen replacement treatment in ovariectomized WT mice caused a significant decrease in ER alpha expression and a significant increase in Sost expression compared with ovariectomized mice treated with placebo. Estrogen replacement treatment in ovariectomized ER beta KO mice caused a significant increase in Col2 expression, no change in ER alpha expression, and a significant increase in Sost expression. Estrogen via ER beta inhibits proliferation and ER alpha expression while estrogen independent of ER beta induces Col2 and Sost expression. Copyright © 2014 China University of Geosciences (Beijing) and Peking University. Published by Elsevier Ltd. All rights reserved.

  18. Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER.

    PubMed

    Zekas, Erin; Prossnitz, Eric R

    2015-10-15

    Estrogen (17β-estradiol) promotes the survival and proliferation of breast cancer cells and its receptors represent important therapeutic targets. The cellular actions of estrogen are mediated by the nuclear estrogen receptors ERα and ERβ as well as the 7-transmembrane spanning G protein-coupled estrogen receptor (GPER). We previously reported that estrogen activates the phosphoinositide 3-kinase (PI3Kinase) pathway via GPER, resulting in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production within the nucleus of breast cancer cells; however, the mechanisms and consequences of this activity remained unclear. MCF7 breast cancer cells were transfected with GFP-fused Forkhead box O3 (FOXO3) as a reporter to assess localization in response to estrogen stimulation. Inhibitors of PI3Kinases and EGFR were employed to determine the mechanisms of estrogen-mediated FOXO3a inactivation. Receptor knockdown with siRNA and the selective GPER agonist G-1 elucidated the estrogen receptor(s) responsible for estrogen-mediated FOXO3a inactivation. The effects of selective estrogen receptor modulators and downregulators (SERMs and SERDs) on FOXO3a in MCF7 cells were also determined. Cell survival (inhibition of apoptosis) was assessed by caspase activation. In the estrogen-responsive breast cancer cell line MCF7, FOXO3a inactivation occurs on a rapid time scale as a result of GPER, but not ERα, stimulation by estrogen, established by the GPER-selective agonist G-1 and knockdown of GPER and ERα. GPER-mediated inactivation of FOXO3a is effected by the p110α catalytic subunit of PI3Kinase as a result of transactivation of the EGFR. The SERMs tamoxifen and raloxifene, as well as the SERD ICI182,780, were active in mediating FOXO3a inactivation in a GPER-dependent manner. Additionally, estrogen-and G-1-mediated stimulation of MCF7 cells results in a decrease in caspase activation under proapoptotic conditions. Our results suggest that non-genomic signaling by GPER contributes

  19. Effects of phytoestrogens genistein and daidzein on progesterone and estrogen (estradiol) production of human term trophoblast cells in vitro.

    PubMed

    Richter, Dagmar Ulrike; Mylonas, Ioannis; Toth, Bettina; Scholz, Christoph; Briese, Volker; Friese, Klaus; Jeschke, Udo

    2009-01-01

    Phytoestrogens are a diverse group of nonsteroidal plant compounds that occur naturally in many plants. Because they possess a ring system similar to estrogens they are able to bind on estrogen receptors alpha and beta in humans. The effects of the phytoestrogens genistein and daidzein on the production of progesterone and estrogen in isolated human term trophoblast cells in vitro were tested in this study. Cytotrophoblast cells were isolated from human term placentas. Phytoestrogens genistein and daidzein were incubated in different concentrations with trophoblast cells. Untreated cells were used as controls. After 24 h aliquots were removed and tested for progesterone and estrogen production. The production of the steroid hormones progesterone and estrogen are influenced by phytoestrogens genistein and daidzein in human term trophoblast cells. A strong inhibition effect of both phytoestrogens tested in the production of progesterone was demonstrated. In addition, a significant stimulating effect on estrogen production by genistein and daidzein was observed. Results obtained with this study show that phytoestrogens (genistein and daidzein) sufficiently reduce progesterone production in human term trophoblast cells. Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that high doses of phytoestrogens at the feto-maternal interphase could play a negative role in maintenance of pregnancy. Stimulation of estrogen production by genistein and daidzein in trophoblast cells is probably due to estrogen receptor blocking effects of both phytoestrogens. Trophoblast cells seem to compensate blocking of its estrogen receptors by higher estrogen production.

  20. In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Prouillac, Caroline, E-mail: c.prouillac@vetagro-sup.fr; Koraichi, Farah; Videmann, Bernadette

    2012-03-15

    Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as amore » potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and βΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ► ZEN and metabolites have differential effect on trophoblast differentiation. ► ZEN and metabolites have differential effect on ABC transporter expression. ► ZEN and metabolites effects involved nuclear receptors interaction.« less

  1. The Effect of Estrogen Usage on Eccentric Exercise-Induced Damage in Rat Testes

    PubMed Central

    Can, Serpil; Selli, Jale; Buyuk, Basak; Aydin, Sergulen; Kocaaslan, Ramazan; Guvendi, Gulname Findik

    2015-01-01

    Background: Recent years, lots of scientific studies are focused on the possible mechanism of inflammatory response and oxidative stress which are the mechanism related with tissue damage and exercise fatigue. It is well-known that free oxygen radicals may be induced under invitro conditions as well as oxidative stress by exhaustive physical exercise. Objectives: The aim of this study was to investigate the effects of anabolic steroids in conjunction with exercise in the process of spermatogenesis in the testes, using histological and stereological methods. Materials and Methods: Thirty-six male Sprague Dawley rats were divided to six groups, including the control group, the eccentric exercise administered group, the estrogen applied group, the estrogen applied and dissected one hour after eccentric exercise group, the no estrogen applied and dissected 48 hours after eccentric exercise group and the estrogen applied and dissected 48 hours after eccentric exercise group. Eccentric exercise was performed on a motorized rodent treadmill and the estrogen applied groups received daily physiological doses by subcutaneous injections. Testicular tissues were examined using specific histopathological, immunohistochemical and stereological methods. Sections of the testes tissue were stained using the TUNEL method to identify apoptotic cells. Apoptosis was calculated as the percentage of positive cells, using stereological analysis. A statistical analysis of the data was carried out with one-way analysis of variance (ANOVA) for the data obtained from stereological analysis. Results: Conventional light microscopic results revealed that testes tissues of the eccentric exercise administered group and the estrogen supplemented group exhibited slight impairment. In groups that were both eccentrically exercised and estrogen supplemented, more deterioration was detected in testes tissues. Likewise, immunohistochemistry findings were also more prominent in the eccentrically exercised

  2. The effects of Cordyceps sinensis phytoestrogen on estrogen deficiency-induced osteoporosis in ovariectomized rats.

    PubMed

    Zhang, Da-wei; Wang, Zhen-lin; Qi, Wei; Zhao, Guang-yue

    2014-12-13

    Isoflavones are naturally occurring plant chemicals belonging to the "phytoestrogen" class. The aim of the present study was to examine the effects of isoflavones obtained from Cordyceps sinensis (CSIF) on development of estrogen deficiency-induced osteoporosis in ovariectomized rats. After the rats were treated orally with CSIF, serum alkaline phosphatase (ALP), tartarate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY), C-terminal crosslinked telopeptides of collagen type I (CTX), estradiol and interferonγ (IFN-γ) level were examined. At the same time, the urine calcium, plasma calcium, plasma phosphorus and the mass of uterus, thymus and body were also examined. The beneficial effects of CSIF on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, CTX level and IFN-γ level. At the same time, CSIF also increase the OC and estradiol level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary CSIF can prevent bone loss caused by estrogen deficiency. The significant estrogenic activity of CSIF demonstrated that CSIF has significant estrogenic effects in OVX rats.

  3. Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer.

    PubMed

    Maximov, Philipp Y; Abderrahman, Balkees; Fanning, Sean W; Sengupta, Surojeet; Fan, Ping; Curpan, Ramona F; Quintana Rincon, Daniela Maria; Greenland, Jeffery A; Rajan, Shyamala S; Greene, Geoffrey L; Jordan, V Craig

    2018-05-08

    Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment for breast cancer inevitably occurs, but unexpectedly low dose estrogen can cause regression of breast cancer and increase disease free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here we describe modulation of the estrogen receptor liganded with antiestrogens (endoxifen, 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE) EthoxyTPE (EtOXTPE) on estrogen-induced apoptosis in LTED breast cancer cells. Our results show that the angular TPE estrogen (EtOXTPE) is able to induce the ER-mediated apoptosis only at a later time compared to planar estradiol in these cells. Using RT-PCR, ChIP, Western blotting, molecular modelling and X-ray crystallography techniques we report novel conformations of the ER complex with an angular estrogen EtOXTPE and endoxifen. We propose that alteration of the conformation of the ER complexes, with changes in coactivator binding, governs estrogen-induced apoptosis through the PERK sensor system to trigger an Unfolded Protein Response (UPR). The American Society for Pharmacology and Experimental Therapeutics.

  4. Estrogenic involvement in social learning, social recognition and pathogen avoidance.

    PubMed

    Choleris, Elena; Clipperton-Allen, Amy E; Phan, Anna; Valsecchi, Paola; Kavaliers, Martin

    2012-04-01

    Sociality comes with specific cognitive skills that allow the proper processing of information about others (social recognition), as well as of information originating from others (social learning). Because sociality and social interactions can also facilitate the spread of infection among individuals the ability to recognize and avoid pathogen threat is also essential. We review here various studies primarily from the rodent literature supporting estrogenic involvement in the regulation of social recognition, social learning (socially acquired food preferences and mate choice copying) and the recognition and avoidance of infected and potentially infected individuals. We consider both genomic and rapid estrogenic effects involving estrogen receptors α and β, and G-protein coupled estrogen receptor 1, along with their interactions with neuropeptide systems in the processing of social stimuli and the regulation and expression of these various socially relevant behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Comparison of estrogen mixtures in vitro vs. in vivo

    EPA Science Inventory

    Numerous sources contribute to widespread contamination of drinking water sources with both natural and synthetic estrogens, which isa concern for potential ecological and human health effects. In vitro screening assays are valuable tools for identifying mechanisms of toxicity bu...

  6. Estrogens in Male Physiology.

    PubMed

    Cooke, Paul S; Nanjappa, Manjunatha K; Ko, CheMyong; Prins, Gail S; Hess, Rex A

    2017-07-01

    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. 17β-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. Copyright © 2017 the American Physiological Society.

  7. Metabolomics Approach to Investigate Estrogen Receptor-Dependent and Independent Effects of o,p'-DDT in the Uterus and Brain of Immature Mice.

    PubMed

    Wang, Dezhen; Zhu, Wentao; Wang, Yao; Yan, Jin; Teng, Miaomiao; Miao, Jiyan; Zhou, Zhiqiang

    2017-05-10

    Previous studies have demonstrated the endocrine disruption of o,p'-DDT. In this study, we used a 1 H NMR based metabolomics approach to investigate the estrogenic effects of o,p'-DDT (300 mg/kg) on the uterus and brain after 3 days of oral gavage administration, and ethynylestradiol (EE, 100 μg/kg) was used as a positive control. A supervised statistical analysis (PLS-DA) indicated that o,p'-DDT exerted both estrogenic receptor-(ER)-dependent and independent effects on the uterus but mainly ER-independent effects on the brain at metabolome levels, which was verified by coexposing with the antiestrogenic ICI 182,780. Four changed metabolites-glycine, choline, fumarate, and phenylalanine-were identified as ER-independent alterations in the uterus, while more metabolites, including γ-aminobutyrate, N-acetyl aspartate, and some amino acids, were disturbed based on the ER-independent mechanism in the brain. Together with biological end points, metabolomics is a promising approach to study potential estrogenic chemicals.

  8. Raw drone milk of honeybees elicits uterotrophic effect in rats: evidence for estrogenic activity.

    PubMed

    Seres, Adrienn B; Ducza, Eszter; Báthori, Mária; Hunyadi, Attila; Béni, Zoltán; Dékány, Miklós; Gáspár, Róbert

    2013-05-01

    Numerous honeybee products are used in medicine, but the literature furnishes no information concerning the effects of the drone milk (DM), although drone brood, which is similar to DM, was reported to elicit a hormone-like strengthening effect. In certain countries, DM is traditionally used to treat infertility and to promote vitality in both men and women. The aim of this study was to determine the putative estrogen hormone-like effect of raw DM in rats and to identify the effective compounds. Uterotrophic assays revealed that DM increased the relative weight of the immature rat uterus. This effect was confirmed by reverse transcription polymerase chain-reaction and Western blot methods, in which the mRNA and protein expression of the estrogen-dependent peptide complement component C3 was determined. Column chromatography and uterotrophic assays were used to fractionate and check bioactivity, respectively. The active compound after the last fractionation was identified by the nuclear magnetic resonance and mass spectrometry techniques as E-dec-2-enedioic acid, which is very similar to the fatty acids with estrogenic activity that were previously isolated from royal jelly. These results lead us to suppose that E-dec-2-enedioic acid is responsible for the estrogen-like effect of DM. This appears to be the first report on the pharmacological effects of DM and E-dec-2-enedioic acid in mammals.

  9. Estrogen enhances the bone regeneration potential of periodontal ligament stem cells derived from osteoporotic rats and seeded on nano-hydroxyapatite/collagen/poly(L-lactide).

    PubMed

    E, Ling-Ling; Xu, Wen-Huan; Feng, Lin; Liu, Yi; Cai, Dong-Qing; Wen, Ning; Zheng, Wen-Jie

    2016-06-01

    This study investigated the effects of estrogen on the bone regeneration potential of periodontal ligament stem cells (PDLSCs) derived from osteoporotic rats and seeded on a collagen-based composite scaffold [nano-hydroxyapatite/collagen/poly(L-lactide) (nHAC/PLA)]. For this purpose, 48 healthy 3‑month-old Sprague-Dawley female rats were divided into 2 groups as follows: the bilaterally ovariectomized (OVX) rats and sham‑operated rats. The PDLSCs were isolated at 3 months after surgery (by which time postmenopausal osteoporosis had developed). The effects of estrogen on the characteristics of these cells seeded in a culture plate and of the cells seeded on nHAC/PLA were then investigated. The PDLSC + nHAC/PLA constructs were implanted subcutaneously into the backs of severe combined immunodeficient (SCID) mice for 12 weeks in order to examine the role of estrogen in the bone formation ability of PDLSCs derived from osteoporotic rats. The results from methyl thiazolyl tetrazolium (MTT) assay revealed that the proliferation of the cells derived from the rats in the OVX group was significantly higher than that of the cells derived from the rats in the sham-operated group at the stage of logarithmic growth. The staining intensity of alkaline phosphatase (ALP) and the mineralization of the cells derived from the rats in the OVX group was significantly weaker than that of the cells from the rats in the sham-operated group. When the PDLSCs were seeded on nHAC/PLA, ALP activity, osteocalcin (OCN) secretion, mineral formation and the mRNA expression levels of ALP, OCN, estrogen receptor (ER)α and ERβ in the cells derived from the rats in the OVX group were markedly decreased. Treatment with 17β-estradiol (E2) significantly weakened the proliferative ability of the cells derived from the OVX group rats, and enhanced their osteogenic differentiation ability and the mRNA expression levels of ALP, OCN, ERα and ERβ. When the constructs were implanted

  10. Protective effects of estrogen against vascular calcification via estrogen receptor α-dependent growth arrest-specific gene 6 transactivation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nanao-Hamai, Michiko; Son, Bo-Kyung; Institute of Gerontology, The University of Tokyo, Tokyo

    Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest-specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor α (ERα) in response to E2. In human aortic smooth musclemore » cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERα-selective antagonist, and ERα siRNA, but not by PHTPP, an ERβ-selective antagonist, and ERβ siRNA, implicating an ERα-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERα. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2-BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERα. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERα-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women. - Highlights: • E2 inhibits Pi-induced calcification in vascular smooth muscles cells. • E2

  11. Phytoestrogens and Mycoestrogens Induce Signature Structure Dynamics Changes on Estrogen Receptor α

    PubMed Central

    Chen, Xueyan; Uzuner, Ugur; Li, Man; Shi, Weibing; Yuan, Joshua S.; Dai, Susie Y.

    2016-01-01

    Endocrine disrupters include a broad spectrum of chemicals such as industrial chemicals, natural estrogens and androgens, synthetic estrogens and androgens. Phytoestrogens are widely present in diet and food supplements; mycoestrogens are frequently found in grains. As human beings and animals are commonly exposed to phytoestrogens and mycoestrogens in diet and environment, it is important to understand the potential beneficial or hazardous effects of estrogenic compounds. Many bioassays have been established to study the binding of estrogenic compounds with estrogen receptor (ER) and provided rich data in the literature. However, limited assays can offer structure information with regard to the ligand/ER complex. Our current study surveys the global structure dynamics changes for ERα ligand binding domain (LBD) when phytoestrogens and mycoestrogens bind. The assay is based on the structure dynamics information probed by hydrogen deuterium exchange mass spectrometry and offers a unique viewpoint to elucidate the mechanism how phytoestrogens and mycoestrogens interact with estrogen receptor. The cluster analysis based on the hydrogen deuterium exchange (HDX) assay data reveals a unique pattern when phytoestrogens and mycoestrogens bind with ERα LBD compared to that of estradiol and synthetic estrogen modulators. Our study highlights that structure dynamics could play an important role in the structure function relationship when endocrine disrupters interact with estrogen receptors. PMID:27589781

  12. Estrogen-induced myelotoxicity in dogs: A review

    PubMed Central

    Sontas, Hasan B.; Dokuzeylu, Banu; Turna, Ozge; Ekici, Hayri

    2009-01-01

    Exogenous estrogens used for therapeutic purposes or endogenous estrogen sources such as functional Sertoli cell or ovarian granulosa cell tumors may cause bone marrow toxicity in dogs. The condition is characterized by hematologic abnormalities including thrombocytopenia, anemia, and leukocytosis or leukopenia. Despite intensive therapy with blood or platelet-rich transfusions, broad-spectrum antibiotics, steroids, and bone marrow stimulants, prognosis is unfavorable. Due to the the risk of stimulating the development of uterine diseases and the potential for inducing aplastic anemia, estrogen use in dogs is best avoided where possible. This paper describes the causes of estrogen-induced myelotoxicity, the clinical presentation of the patients, the diagnosis, and the treatment options in the dog. PMID:20046604

  13. Dietary choline requirements of women: effects of estrogen and genetic variation.

    PubMed

    Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph; Zeisel, Steven H

    2010-11-01

    Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. The objective was to determine whether the risk of low choline-related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546.

  14. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

    PubMed

    Johnson, Michael D; Kenney, Nicholas; Stoica, Adriana; Hilakivi-Clarke, Leena; Singh, Baljit; Chepko, Gloria; Clarke, Robert; Sholler, Peter F; Lirio, Apolonio A; Foss, Colby; Reiter, Ronald; Trock, Bruce; Paik, Soonmyoung; Martin, Mary Beth

    2003-08-01

    It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

  15. Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells.

    PubMed

    Sharan, Shruti; Nikhil, Kumar; Roy, Partha

    2013-06-01

    Endocrine disrupting chemicals are the natural/synthetic compounds which mimic or inhibit the actions of endogenous hormones. Organotin compounds, such as tributyltin (TBT) are typical environmental contaminants and suspected endocrine-disrupting chemical. The present study evaluates the estrogenic potential of this compound in vitro in ER (+) breast adenocarcinoma, MCF-7 cell line. Our data showed that tributyltin chloride (TBTCl) had agonistic activities for estrogen receptor-α (ER-α). Its estrogenic potential was checked using cell proliferation assay, aromatase assay, transactivation assay, and protein expression analysis. Low dose treatment of TBTCl had a proliferative effect on MCF-7 cells and resulted in up-regulation of aromatase enzyme activity and enhanced estradiol production in MCF-7 cells. Immunofluorescence staining showed translocation of ER-α from cytoplasm to nucleus and increased expression of ER-α, 3β-HSD and aromatase on treatment with increasing doses of TBTCl. Further, to decipher the probable signaling pathways involved in its action, the MCF-7 cells were transfected with different pathway dependent luciferase reporter plasmids (CRE, SRE, NF-κB and AP1). A significant increase in CRE and SRE and decrease in NF-κB regulated pathway were observed (p<0.05). Our results thus showed that the activation of SRE by TBTCl may be due to ligand dependent ER-α activation of the MAPK pathway and increased phosphorylation of ERK. In summary, the present data suggests that low dose of tributyltin genomically and non-genomically augmented estrogen dependent signaling by targeting various pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. In vitro assessment of thyroidal and estrogenic activities in poultry and broiler manure.

    PubMed

    Valdehita, A; Quesada-García, A; Delgado, M M; Martín, J V; García-González, M C; Fernández-Cruz, M L; Navas, J M

    2014-02-15

    Among the many chemicals found in avian manure, endocrine disruptors (EDs), of natural or anthropogenic origin, are of special environmental concern. Nowadays, an increasing amount of estrogens is being released into the environment via the use of manure to fertilize agricultural land. While most research in this field has focused on estrogenic phenomena, little is known about alterations related to other endocrine systems, such as the thyroidal one. Here we simultaneously assessed the potential estrogenic and thyroidal activity of poultry and broiler litter manure using in vitro approaches based on estrogen receptor (Er) and thyroid receptor (Tr) transactivation assays. In addition, leaching experiments were performed to assess whether the EDs present in the manure pass through a soil column and potentially reach the groundwater. Manure from four broiler and four poultry farms was collected in two sampling campaigns carried out in two seasons (fall and spring). Extracts from broiler and poultry manure exhibited strong thyroidal activity. Only poultry manure showed estrogenic activity, which is consistent with the low levels of estrogens expected in hatchlings. Leakage experiments were performed in columns with two kinds of arable soils: sandy and loamy. No estrogenicity or thyroidal activity was detectable in soils treated with the manure or in the corresponding leachates. These results indicate that substances with estrogenic or thyroidal activity were degraded in the soil under our experimental conditions. However, the long-term effects associated with the constant and intensive application of manure to agricultural land in some regions require further research. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity

    PubMed Central

    Teveroni, Emanuela; Sacconi, Sabrina; Calandra, Patrizia; Cascino, Isabella; Puma, Angela; Garibaldi, Matteo; Morosetti, Roberta; Ricci, Enzo; Trevisan, Carlo Pietro; Galluzzi, Giuliana; Pontecorvi, Alfredo; Deidda, Giancarlo

    2017-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is characterized by extreme variability in symptoms, with females being less severely affected than males and presenting a higher proportion of asymptomatic carriers. The sex-related factors involved in the disease are not known. Here, we have utilized myoblasts isolated from FSHD patients (FSHD myoblasts) to investigate the effect of estrogens on muscle properties. Our results demonstrated that estrogens counteract the differentiation impairment of FSHD myoblasts without affecting cell proliferation or survival. Estrogen effects are mediated by estrogen receptor β (ERβ), which reduces chromatin occupancy and transcriptional activity of double homeobox 4 (DUX4), a protein whose aberrant expression has been implicated in FSHD pathogenesis. During myoblast differentiation, we observed that the levels and activity of DUX4 increased progressively and were associated with its enhanced recruitment in the nucleus. ERβ interfered with this recruitment by relocalizing DUX4 in the cytoplasm. This work identifies estrogens as a potential disease modifier that underlie sex-related differences in FSHD by protecting against myoblast differentiation impairments in this disease. PMID:28263188

  18. The Estrogen Receptors: An Overview from Different Perspectives.

    PubMed

    Eyster, Kathleen M

    2016-01-01

    The estrogen receptors, ERα, ERβ, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the female reproductive tract and breast as one would expect, but also in tissues as diverse as bone, brain, liver, colon, skin, and salivary gland. The purpose of this discussion of the estrogen receptors is to provide a brief overview of the estrogen receptors and estrogen action from perspectives such as the historical, physiological, pharmacological, pathological, structural, and ligand perspectives.

  19. Estrogen Abolishes Latent Inhibition in Ovariectomized Female Rats

    ERIC Educational Resources Information Center

    Nofrey, Barbara S.; Ben-Shahar, Osnat M.; Brake, Wayne G.

    2008-01-01

    Estrogen is frequently prescribed as a method of birth control and as hormone replacement therapy for post-menopausal women with varied effects on cognition. Here the effects of estrogen on attention were examined using the latent inhibition (LI) behavioral paradigm. Ovariectomized (OVX) female rats were given either estrogen benzoate (EB, 10 or…

  20. Inhibitory effects of γ- and δ-tocopherols on estrogen-stimulated breast cancer in vitro and in vivo

    PubMed Central

    Bak, Min Ji; Gupta, Soumyasri Das; Wahler, Joseph; Lee, Hong Jin; Li, Xiaowei; Lee, Mao-Jung; Yang, Chung S; Suh, Nanjoo

    2017-01-01

    Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert anti-tumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of α-, γ- and δ-tocopherols as well as a natural γ-tocopherol rich mixture of tocopherols, γ-TmT, on estrogen-stimulated MCF-7 cells in vitro and in vivo. For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% α-, γ-, δ-tocopherol or γ-TmT for 5 weeks. Treatment with α-, γ-, δ-tocopherols and γ-TmT reduced tumor volumes by 29% (p<0.05), 45% (p<0.05), 41% (p<0.05) and 58% (p<0.01), as well as tumor weights by 20%, 37% (p<0.05), 39% (p<0.05) and 52% (p<0.05), respectively. γ- and δ-Tocopherols and γ-TmT inhibited the expression of cell proliferation-related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D and progesterone receptor in estrogen-stimulated MCF-7 cells in vitro. Further, γ- and δ-tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8-hydroxy-2’-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, γ-H2AX. Our results suggest that γ- and δ-tocopherols and the γ-tocopherol rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer. PMID:28096236

  1. Relaxant Effects of the Selective Estrogen Receptor Modulator, Bazedoxifene, and Estrogen Receptor Agonists in Isolated Rabbit Basilar Artery.

    PubMed

    Castelló-Ruiz, María; Salom, Juan B; Fernández-Musoles, Ricardo; Burguete, María C; López-Morales, Mikahela A; Arduini, Alessandro; Jover-Mengual, Teresa; Hervás, David; Torregrosa, Germán; Alborch, Enrique

    2016-10-01

    We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-β-estradiol, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) α agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-β-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERβ agonist) had no effect. Expression profile of genes encoding for ERα (ESR1), ERβ (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K channels, both a high-K medium and the Kv blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K channel blocker), glibenclamide (selective KATP blocker) or iberiotoxin (selective KCa blocker) were without effect. Bazedoxifene also inhibited both Ca- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ERα receptors; (2) increase of K conductance through Kv channels; and (3) inhibition of Ca entry through L-type Ca channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).

  2. Interactions between the cytomegalovirus promoter and the estrogen response element: implications for design of estrogen-responsive reporter plasmids.

    PubMed

    Derecka, K; Wang, C K; Flint, A P F

    2006-07-01

    We aimed to produce an estrogen-responsive reporter plasmid that would permit monitoring of estrogen receptor function in the uterus in vivo. The plasmid pBL-tk-CAT(+)ERE was induced by estrogen in bovine endometrial stromal cells. When the CAT gene was replaced by the secreted alkaline phosphatase SeAP, the resulting construct pBL-tk-SeAP(+)ERE remained estrogen responsive. However when the tk promoter was replaced by the cytomegalovirus (cmv) promoter, the resulting plasmid (pBL-cmv-SeAP(+)ERE) was not estrogen responsive. Inhibition of ERE function was not due to an effect in trans or due to lack of estrogen receptor. It was not due to an interaction between the cmv promoter and the SeAP gene. cmv promoter function was dependent on NF-kappaB, and mutagenesis in the NF-kappaB sites reduced basal reporter expression without imparting responsiveness to estrogen. A mutation in the TATA box also failed to impart estrogen responsiveness. Modeling of DNA accessibility indicated the ERE was inserted at a site accessible to transcription factors. We conclude that the cmv promoter inhibits ERE function in cis when the two sequences are located in the same construct, and that this effect does not involve an interaction between cmv and reporter gene, NF-kappaB sites or the TATA box, or DNA inaccessibility.

  3. Estrogens and Cognition: Friends or Foes?

    PubMed Central

    Korol, Donna L.; Pisani, Samantha L.

    2015-01-01

    Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. PMID:26149525

  4. Estrogens and progression of diabetic kidney damage.

    PubMed

    Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Elliot, Sharon J

    2011-01-01

    It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

  5. A Bayesian Network Model for Assessing Estrogen Fate and Transport in a Swine Waste Lagoon

    PubMed Central

    Lee, Boknam; Kullman, Seth W.; Yost, Erin; Meyer, Michael T.; Worley-Davis, Lynn; Reckhow, Kenneth H.

    2017-01-01

    Commercial swine waste lagoons are regarded as a major reservoir of natural estrogens, which have the potential to produce adverse physiological effects on exposed aquatic organisms and wildlife. However, there remains limited understanding of the complex mechanisms of physical, chemical, and biological processes that govern the fate and transport of natural estrogens within an anaerobic swine lagoon. To improve lagoon management and ultimately help control the offsite transport of these compounds from swine operations, a Bayesian network model was developed to predict estrogen fate and budget and compared against data collected from a commercial swine field site. In general, the model was able to predict the estrogen fate and budget in both the slurry and sludge stores within the swine lagoon. Sensitivity analysis within the model, demonstrated that the estrogen input loading from the associated barn facility was the most important factor in controlling estrogen concentrations within the lagoon slurry storage, while the settling rate was the most significant factor in the lagoon sludge storage. The degradation reactions were shown to be minor in both stores based on prediction of average total estrogen concentrations. Management scenario evaluations showed that the best possible management options to reduce estrogen levels in the lagoon are either to adjust the estrogen input loading from swine barn facilities or to effectively enhancing estrogen bonding with suspended solids through the use of organic polymers or inorganic coagulants. PMID:24798317

  6. Evaluation of Estrogenic Activity of Licorice Species in Comparison with Hops Used in Botanicals for Menopausal Symptoms

    PubMed Central

    Hajirahimkhan, Atieh; Simmler, Charlotte; Yuan, Yang; Anderson, Jeffrey R.; Chen, Shao-Nong; Nikolić, Dejan; Dietz, Birgit M.; Pauli, Guido F.; van Breemen, Richard B.; Bolton, Judy L.

    2013-01-01

    The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical

  7. [Equine estrogens vs. esterified estrogens in the climacteric and menopause. The controversy arrives in Mexico].

    PubMed

    Velasco-Murillo, V

    2001-01-01

    It exists controversies about if the effects and benefits of the esterified estrogens could be similar to those informed for equines, because its chemical composition and bioavailability are different. Esterified estrogens has not delta 8,9 dehydroestrone, and its absorption and level of maximum plasmatic concentrations are reached very fast. In United States of America and another countries, esterified estrogens has been marketed and using for treatment of climacteric syndrome and prevention of postmenopausal osteoporosis, based on the pharmacopoiea of that country, but the Food and Drug administration (FDA) has not yet authorized up today, a generic version of conjugated estrogens. In Instituto Mexicano del Seguro Social (IMSS) and another institutions of health sector in Mexico, starting in year 2000, it has been used esterified estrogens for medical treatment of climacteric and menopausal conditions. For this reason, in this paper we revised the most recent information about pharmacology, chemical composition, clinical use and costs of the conjugated estrogens with the purpose to guide the decisions to purchase this kind of drugs in Mexican heath institutions.

  8. Potential harmful effects of dietary supplements in sports medicine.

    PubMed

    Deldicque, Louise; Francaux, Marc

    2016-11-01

    The purpose of this article is to collect the most recent data regarding the safety of well-known or emerging dietary supplements used by athletes. From January 2014 to April 2016, about 30 articles have been published in the field. New data show that 90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable. About 50% of the supplements are contaminated by melamine, a source of nonprotein nitrogen. Additional data accumulate toward the safety of nitrate ingestion. In the last 2 years, the safety of emerging supplements such as higenamine, potentially interesting to lose weight, creatine nitrate and guanidinoacetic acid has been evaluated but still needs further investigation. The consumption of over-the-counter supplements is very popular in athletes. Although most supplements may be considered as safe when taking at the recommended doses, athletes should be aware of the potential risks linked to the consumption of supplements. In addition to the risks linked to overdosage and cross-effects when combining different supplements at the same time, inadvertent or deliberate contamination with stimulants, estrogenic compounds, diuretics or anabolic agents may occur.

  9. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors.

    PubMed

    Clegg, Deborah; Hevener, Andrea L; Moreau, Kerrie L; Morselli, Eugenia; Criollo, Alfredo; Van Pelt, Rachael E; Vieira-Potter, Victoria J

    2017-05-01

    With increased life expectancy, women will spend over three decades of life postmenopause. The menopausal transition increases susceptibility to metabolic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Thus, it is more important than ever to develop effective hormonal treatment strategies to protect aging women. Understanding the role of estrogens, and their biological actions mediated by estrogen receptors (ERs), in the regulation of cardiometabolic health is of paramount importance to discover novel targeted therapeutics. In this brief review, we provide a detailed overview of the literature, from basic science findings to human clinical trial evidence, supporting a protective role of estrogens and their receptors, specifically ERα, in maintenance of cardiometabolic health. In so doing, we provide a concise mechanistic discussion of some of the major tissue-specific roles of estrogens signaling through ERα. Taken together, evidence suggests that targeted, perhaps receptor-specific, hormonal therapies can and should be used to optimize the health of women as they transition through menopause, while reducing the undesired complications that have limited the efficacy and use of traditional hormone replacement interventions. Copyright © 2017 Endocrine Society.

  10. Immunosuppression Following Exposure to Exogenous Estrogens

    DTIC Science & Technology

    1983-08-01

    and laboratory animals aad has been associated with endo- metrial cancer, breast cancer, and vaginal adenocarcinoma (McLachlan, 1980). In mice, DES ... DES ), a nonsteroidal synthet- ic estrogen with potent estrogenic activity was examined. This compound has been employed as a therapeutic agent in...humans as well as a growth promotant in livestock (McMartin, 1978). There is mounting evidence, however, that DES is potentially carcinogenic in humans

  11. Activation of the G protein-coupled estrogen receptor, but not estrogen receptor α or β, rapidly enhances social learning.

    PubMed

    Ervin, Kelsy Sharice Jean; Mulvale, Erin; Gallagher, Nicola; Roussel, Véronique; Choleris, Elena

    2015-08-01

    Social learning is a highly adaptive process by which an animal acquires information from a conspecific. While estrogens are known to modulate learning and memory, much of this research focuses on individual learning. Estrogens have been shown to enhance social learning on a long-term time scale, likely via genomic mechanisms. Estrogens have also been shown to affect individual learning on a rapid time scale through cell-signaling cascades, rather than via genomic effects, suggesting they may also rapidly influence social learning. We therefore investigated the effects of 17β-estradiol and involvement of the estrogen receptors (ERs) using the ERα agonist propyl pyrazole triol, the ERβ agonist diarylpropionitrile, and the G protein-coupled ER 1 (GPER1) agonist G1 on the social transmission of food preferences (STFP) task, within a time scale that focused on the rapid effects of estrogens. General ER activation with 17β-estradiol resulted in a modest facilitation of social learning, with mice showing a preference up to 30min of testing. Specific activation of the GPER1 also rapidly enhanced social learning, with mice showing a socially learned preference up to 2h of testing. ERα activation instead shortened the expression of a socially learned food preference, while ERβ activation had little to no effects. Thus, rapid estrogenic modulation of social learning in the STFP may be the outcome of competing action at the three main receptors. Hence, estrogens' rapid effects on social learning likely depend on the specific ERs present in brain regions recruited during social learning. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Estrogen

    MedlinePlus

    ... life', the end of monthly menstrual periods). Some brands of estrogen are also used to treat vaginal ... prevent osteoporosis should consider a different treatment. Some brands of estrogen are also to relieve symptoms of ...

  13. Effects of FSH and 17beta-estradiol on the transactivation of estrogen-regulated promoters and cell proliferation in L cells.

    PubMed

    Pasapera, Ana María; Jiménez-Aguilera, María del Pilar; Chauchereau, Anne; Milgrom, Edwin; Olivares, Aleida; Uribe, Aída; Gutiérrez-Sagal, Rubén; Ulloa-Aguirre, Alfredo

    2005-03-01

    In the present study, we analyzed human follicle-stimulating hormone (FSH)-induced cell proliferation and transactivation of estrogen-sensitive reporter genes-in L cells stably expressing the human FSH receptor [L-(hFSHR(+)) cells]. In order to dissect the signaling pathways involved in this process, L-(hFSHR(+)) cells were transiently transfected with either the 3X-ERE-TAT-Luc or the ERE-VitA2-TK-CAT reporter genes and treated with FSH or PKA activators (cholera toxin, forskolin and 8-Br-cAMP) in the presence or absence of various kinase inhibitors. We found that FSH and all PKA activators, specifically induced transactivation of both reporter genes. Transactivation of estrogen-sensitive genes by FSH or PKA activators were blocked (approximately 90%) by H89 (PKA inhibitor) and LY294002 but not by Wortmannin (PI3-K inhibitors), 4-OH-tamoxifen, ICI182,780 or SB203580 (p38 MAPK inhibitor); PD98059 (ERK1/2 inhibitor) partially (approximately 30%) blocked the FSH-mediated effect. The combination of FSH and estradiol resulted in a synergistic effect on transactivation as well as on cell proliferation, and this enhancement was attenuated by antiestrogens. We additionally analyzed the participation of the coactivators SRC-1 and cAMP response element binding protein (CREB)-binding protein (CBP) in FSH-evoked estrogen receptor (ER)-dependent transactivation; we found that CBP but not SRC-1 potentiated FSH-induced transcriptional activation of both ER-sensitive reporters, being this effect stronger on the ERE-VitA2-TK-CAT than on the 3X-ERE-TAT-Luc reporter. Thus, in L-(hFSHR(+)) cells FSH induces transcriptional activation of estrogen-sensitive genes through an A-kinase-triggered signaling pathway, using also to a lesser extent the ERK1/2 and p38 pathways. PI3-K is not apparently involved in this FSH-mediated process since LY294002, but not Wortmannin, specifically binds ERs and completely blocks estrogen action. Presumably, CBP cooperates with the ER on genes that contain

  14. A recombinant estrogen receptor fragment-based homogeneous fluorescent assay for rapid detection of estrogens.

    PubMed

    Wang, Dan; Xie, Jiangbi; Zhu, Xiaocui; Li, Jinqiu; Zhao, Dongqin; Zhao, Meiping

    2014-05-15

    In this work, we demonstrate a novel estrogenic receptor fragment-based homogeneous fluorescent assay which enables rapid and sensitive detection of 17β-estradiol (E2) and other highly potent estrogens. A modified human estrogenic receptor fragment (N-His × 6-hER270-595-C-Strep tag II) has been constructed that contains amino acids 270-595 of wild-type human estrogenic receptor α (hER270-595) and two specific tags (6 × His and Strep tag II) fused to the N and C terminus, respectively. The designed receptor protein fragment could be easily produced by prokaryotic expression with high yield and high purity. The obtained protein exhibits high binding affinity to E2 and the two tags greatly facilitate the application of the recombinant protein. Taking advantage of the unique spectroscopic properties of coumestrol (CS), a fluorescent phytoestrogen, a CS/hER270-595-based fluorescent assay has been developed which can sensitively respond to E2 within 1.0 min with a linear working range from 0.1 to 20 ng/mL and a limit of detection of 0.1 ng/mL. The assay was successfully applied for rapid detection of E2 in the culture medium of rat hippocampal neurons. The method also holds great potential for high-throughput monitoring the variation of estrogen levels in complex biological fluids, which is crucial for investigation of the molecular basis of various estrogen-involved processes. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Removal of Estrogens and Estrogenicity through Drinking Water Treatment

    EPA Science Inventory

    Estrogenic compounds have been shown to be present in surface waters, leading to concerns over their possible presence in finished drining waters. In this work, two in vitro human cell line bioassays for estrogenicity were used to evaluate the removal of estrogens through conven...

  16. Fate and transport of selected estrogen compounds in Hawaii soils: effect of soil type and macropores.

    PubMed

    D'Alessio, Matteo; Vasudevan, Dharni; Lichwa, Joseph; Mohanty, Sanjay K; Ray, Chittaranjan

    2014-10-01

    The fate and transport of estrogen compounds in the environment is of increasing concern due to their potential impact on freshwater organisms, ecosystems and human health. The behavior of these compounds in batch experiments suggests low mobility, while field studies indicate the persistence of estrogen compounds in the soil with the possibility of migration to surface water as well as groundwater. To better understand the movement of these chemicals through soils, we examined their transport in three different Hawaiian soils and two aqueous matrices. The three different soils used were an Oxisol, a Mollisol and a cinder, characterized by different mineralogical properties and collected at depths of 60-90 cm and 210-240 cm. Two liquid matrices were used; deionized (DI) water containing calcium chloride (CaCl2), and recycled water collected from a wastewater treatment facility. The experiments were conducted in packed and structured columns. Non-equilibrium conditions were observed during the study, especially in the structured soil. This is believed to be primarily related to the presence of macropores in the soil. The presence of macropores resulted in reduced contact time between soil and estrogens, which facilitated their transport. We found that the organic carbon content and mineralogical composition of the soils had a profound effect on the transport of the estrogens. The mobility of estrone (E1) and 17β-estradiol (E2) was greater in cinder than in the other soils. In column experiments with recycled water, earlier breakthrough peaks and longer tails of estrogens were produced compared to those observed using DI water. The use of recycled water for agricultural purposes and the siting of septic tanks and cesspools should be critically reviewed in light of these findings, especially in areas where groundwater is the primary source of potable water, such as Hawaii. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Fate and transport of selected estrogen compounds in Hawaii soils: Effect of soil type and macropores

    NASA Astrophysics Data System (ADS)

    D'Alessio, Matteo; Vasudevan, Dharni; Lichwa, Joseph; Mohanty, Sanjay K.; Ray, Chittaranjan

    2014-10-01

    The fate and transport of estrogen compounds in the environment is of increasing concern due to their potential impact on freshwater organisms, ecosystems and human health. The behavior of these compounds in batch experiments suggests low mobility, while field studies indicate the persistence of estrogen compounds in the soil with the possibility of migration to surface water as well as groundwater. To better understand the movement of these chemicals through soils, we examined their transport in three different Hawaiian soils and two aqueous matrices. The three different soils used were an Oxisol, a Mollisol and a cinder, characterized by different mineralogical properties and collected at depths of 60-90 cm and 210-240 cm. Two liquid matrices were used; deionized (DI) water containing calcium chloride (CaCl2), and recycled water collected from a wastewater treatment facility. The experiments were conducted in packed and structured columns. Non-equilibrium conditions were observed during the study, especially in the structured soil. This is believed to be primarily related to the presence of macropores in the soil. The presence of macropores resulted in reduced contact time between soil and estrogens, which facilitated their transport. We found that the organic carbon content and mineralogical composition of the soils had a profound effect on the transport of the estrogens. The mobility of estrone (E1) and 17β-estradiol (E2) was greater in cinder than in the other soils. In column experiments with recycled water, earlier breakthrough peaks and longer tails of estrogens were produced compared to those observed using DI water. The use of recycled water for agricultural purposes and the siting of septic tanks and cesspools should be critically reviewed in light of these findings, especially in areas where groundwater is the primary source of potable water, such as Hawaii.

  18. Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure

    PubMed Central

    Horan, Tegan S.; Marre, Alyssa; Hassold, Terry; Lawson, Crystal; Hunt, Patricia A.

    2017-01-01

    The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure. PMID:28727826

  19. GPER1 mediates estrogen-induced neuroprotection against oxygen-glucose deprivation in the primary hippocampal neurons.

    PubMed

    Zhao, Tian-Zhi; Shi, Fei; Hu, Jun; He, Shi-Ming; Ding, Qian; Ma, Lian-Ting

    2016-07-22

    It is well-known that the neuroprotective effects of estrogen have potential in the prevention and amelioration of ischemic and degenerative neurological disorders, while the underlying mechanisms for estrogen actions are undefined. As an important mediator for the non-genomic functions of estrogen, GPER1 (G Protein-coupled Estrogen Receptor 1) has been suggested to involve in the beneficial roles of estrogen in neural cells. Here our studies on primary hippocampal neurons have focused on GPER1 in an in vitro model of ischemia using oxygen-glucose deprivation (OGD). GPER1 expression in the primary hippocampal neurons was stimulated by the OGD treatments. Both E2 (estradiol) and E2-BSA (membrane impermeable estradiol by covalent conjugation of bovine serum albumin) attenuated OGD-induced cell death in primary cultures of hippocampal neurons. Importantly, this membrane-mediated estrogen function requires GPER1 protein. Knocking down of GPER1 diminished, while overexpression of GPER1 potentiated, the protective roles of E2/E2-BSA following OGD. Additionally, the downstream mechanisms employed by membrane-associated estrogen signaling were found to include PI3K/Akt-dependent Ask1 inhibition in the primary hippocampal neurons. Overall, these research results could enhance our understanding of the neuroprotective actions for estrogen, and provide a new therapeutic target for improving stroke outcome and ameliorating degenerative neurological diseases. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions

    PubMed Central

    Bustos, Viviana; Nolan, Áine M.; Nijhuis, Anke; Harvey, Harry; Parker, Alexandra; Poulsom, Richard; McBryan, Jean; Thomas, Warren; Silver, Andrew; Harvey, Brian J.

    2017-01-01

    The estrogen receptor ERβ is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERβ expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17β-estradiol (E2) under hypoxic conditions after ERβ is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated (ATM), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERβ-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism. PMID:29137421

  1. GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions.

    PubMed

    Bustos, Viviana; Nolan, Áine M; Nijhuis, Anke; Harvey, Harry; Parker, Alexandra; Poulsom, Richard; McBryan, Jean; Thomas, Warren; Silver, Andrew; Harvey, Brian J

    2017-10-13

    The estrogen receptor ERβ is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERβ expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17β-estradiol (E2) under hypoxic conditions after ERβ is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated ( ATM ), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERβ-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism.

  2. Effects of ovariectomy and estrogen replacement therapy on laryngeal tissue: a histopathological experimental animal study.

    PubMed

    Tatlipinar, Arzu; Günes, Pembegül; Ozbeyli, Dilek; Cimen, Burak; Gökçeer, Tanju

    2011-12-01

    To determine the histopathological effect of estrogen deficiency and hormone replacement treatment on laryngeal tissue in ovariectomized rats. Animal study. The study was conducted at the animal experiment laboratory of Marmara University School of Medicine, Istanbul, Turkey. Six-month-old female Wistar albino rats were divided into the following 3 groups (n = 8 per group): sham-operated control, ovariectomized, and ovariectomized with estrogen replacement. Rats in the ovariectomized with estrogen replacement group received 17 β-estradiol valerate (200 µg/kg, subcutaneously) once a week. Animals were killed after 8 weeks of intervention. Significant changes were observed in the ovariectomized group when edema in lamina propria, inflammation in squamous, respiratory epithelia and lamina propria, pseudostratification, and cilia loss were assessed. Except cilia loss, there were no significant differences in the assessments between the sham-operated control and ovariectomized with estrogen replacement groups. On the basis of histopathological evaluations, it was shown that estrogen replacement helped to improve laryngeal changes due to experimentally induced menopause.

  3. Analysis of estrogenic activity in environmental waters in Rio de Janeiro state (Brazil) using the yeast estrogen screen.

    PubMed

    Dias, Amanda Cristina Vieira; Gomes, Frederico Wegenast; Bila, Daniele Maia; Sant'Anna, Geraldo Lippel; Dezotti, Marcia

    2015-10-01

    The estrogenicity of waters collected from an important hydrological system in Brazil (Paraiba do Sul and Guandu Rivers) was assessed using the yeast estrogen screen (YES) assay. Sampling was performed in rivers and at the outlets of conventional water treatment plants (WTP). The removal of estrogenic activity by ozonation and chlorination after conventional water treatment (clarification and sand filtration) was investigated employing samples of the Guandu River spiked with estrogens and bisphenol A (BPA). The results revealed a preoccupying incidence of estrogenic activity at levels higher than 1ngL(-1) along some points of the rivers. Another matter of concern was the number of samples from WTPs presenting estrogenicity surpassing 1ngL(-1). The oxidation techniques (ozonation and chlorination) were effective for the removal of estrogenic activity and the combination of both techniques led to good results using less amounts of oxidants. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Estrogen Levels Are Associated with Extinction Deficits in Women with Posttraumatic Stress Disorder

    PubMed Central

    Glover, Ebony M.; Jovanovic, Tanja; Mercer, Kristina B.; Kerley, Kimberly; Bradley, Bekh; Ressler, Kerry J.; Norrholm, Seth D.

    2013-01-01

    Background Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD. Methods We measured fear-potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E2) groups. Seventeen of 41 women (41.5%) in the low E2 group and 15 of 40 women (37.5%) met criteria for PTSD in the high E2 group. Results The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E2 groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E2 group. Conclusion This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD. PMID:22502987

  5. Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms.

    PubMed

    Doyle, Brian J; Frasor, Jonna; Bellows, Lauren E; Locklear, Tracie D; Perez, Alice; Gomez-Laurito, Jorge; Mahady, Gail B

    2009-01-01

    Outcomes from the Women's Health Initiative have demonstrated adverse effects associated with hormone therapy and have prioritized the need to develop new alternative treatments for the management of menopause and osteoporosis. To this end, we have been investigating natural herbal medicines used by Costa Rican women to manage menopausal symptoms. Seventeen plant species were collected and extracted in Costa Rica. To establish possible mechanisms of action and to determine their potential future use for menopause or osteoporosis, we investigated the estrogenic activities of the herbal extracts in an estrogen-reporter gene estrogen receptor (ER) beta-Chemically Activated Luciferase Expression assay in U2-OS cells and in reporter and endogenous gene assays in MCF-7 cells. Six of the plant extracts bound to the ERs. Four of the six extracts stimulated reporter gene expression in the ER-beta-Chemically Activated Luciferase Expression assay. All six extracts modulated expression of endogenous genes in MCF-7 cells, with four extracts acting as estrogen agonists and two extracts, Pimenta dioica and Smilax domingensis, acting as partial agonist/antagonists by enhancing estradiol-stimulated pS2 mRNA expression but reducing estradiol-stimulated PR and PTGES mRNA expression. Both P. dioica and S. domingensis induced a 2ERE-luciferase reporter gene in transient transfected MCF-7 cells, which was inhibited by the ER antagonist ICI 182,780. This work presents a plausible mechanism of action for many of the herbal medicines used by Costa Rican women to treat menopausal symptoms. However, it further suggests that studies of safety and efficacy are needed before these herbs should be used as alternative therapies to hormone therapy.

  6. Effects of birth trauma and estrogen on urethral elastic fibers and elastin expression.

    PubMed

    Lin, Guiting; Ning, Hongxiu; Wang, Guifang; Banie, Lia; Lue, Tom F; Lin, Ching-Shwun

    2010-10-01

    To investigate the effects of birth trauma and estrogen on urethral elastic fibers and elastin expression. Pregnant rats were subjected to sham operation (Delivery-only), DVDO (delivery, vaginal distension and ovariectomy), or DVDO + E₂ (estrogen). At 2, 4, 8, or 12 weeks, their urethras were harvested for elastic fiber staining and reverse transcription-polymerase chain reaction analysis. Urethral cells were treated with transforming growth factor- β1 (TGFβ1) and/or estrogen and analyzed for elastin mRNA expression. Urethral cells were also examined for the activities of Smad1- and Smad3/4-responsive elements in response to TGFβ1 and estrogen. At 8 weeks post-treatment, the urethras of DVDO rats had fewer and shorter elastic fibers when compared with Delivery-only rats, and those of DVDO + E₂ rats had fewer and shorter elastic fibers when compared with DVDO rats. Elastin mRNA was expressed at low levels in Delivery-only rats and at increasingly higher levels in DVDO rats at 2, 4, and 8 weeks but at sharply lower levels in DVDO + E₂ rats when compared with DVDO rats at 8 weeks. Urethral cells expressed increasingly higher levels of elastin mRNA in response to increasing concentrations of TGFβ1 up to 1 ng/mL. At this TGFβ1 concentration, urethral cells expressed significantly lower levels of elastin mRNA when treated with estrogen before or after TGFβ1 treatment. Both Smad1- and Smad3/4-responsive elements were activated by TGFβ1 and such activation was suppressed by estrogen. Birth trauma appears to activate urethral elastin expression via TGFβ1 signaling. Estrogen interferes with this signaling, resulting in improper assembly of elastic fibers. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Inhibitory Effects of γ- and δ-Tocopherols on Estrogen-Stimulated Breast Cancer In Vitro and In Vivo.

    PubMed

    Bak, Min Ji; Das Gupta, Soumyasri; Wahler, Joseph; Lee, Hong Jin; Li, Xiaowei; Lee, Mao-Jung; Yang, Chung S; Suh, Nanjoo

    2017-03-01

    Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress, and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert antitumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of α-, γ-, and δ-tocopherols as well as a natural γ-tocopherol-rich mixture of tocopherols, γ-TmT, on estrogen-stimulated MCF-7 cells in vitro and in vivo For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% α-, γ-, δ-tocopherol, or γ-TmT for 5 weeks. Treatment with α-, γ-, δ-tocopherols, and γ-TmT reduced tumor volumes by 29% ( P < 0.05), 45% ( P < 0.05), 41% ( P < 0.05), and 58% ( P < 0.01), as well as tumor weights by 20%, 37% ( P < 0.05), 39% ( P < 0.05), and 52% ( P < 0.05), respectively. γ- and δ-tocopherols and γ-TmT inhibited the expression of cell proliferation-related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D, and progesterone receptor in estrogen-stimulated MCF-7 cells in vitro Further, γ- and δ-tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8-hydroxy-2'-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, γ-H2AX. Our results suggest that γ- and δ-tocopherols and the γ-tocopherol-rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer. Cancer Prev Res; 10(3); 188-97. ©2017 AACR . ©2017 American Association for Cancer Research.

  8. Estrogenic activities of diuron metabolites in female Nile tilapia (Oreochromis niloticus).

    PubMed

    Pereira, Thiago Scremin Boscolo; Boscolo, Camila Nomura Pereira; Felício, Andreia Arantes; Batlouni, Sergio Ricardo; Schlenk, Daniel; de Almeida, Eduardo Alves

    2016-03-01

    Some endocrine disrupting chemicals (EDCs) can alter the estrogenic activities of the organism by directly interacting with estrogen receptors (ER) or indirectly through the hypothalamus-pituitary-gonadal axis. Recent studies in male Nile tilapia (Oreochromis niloticus) indicated that diuron may have anti-androgenic activity augmented by biotransformation. In this study, the effects of diuron and three of its metabolites were evaluated in female tilapia. Sexually mature female fish were exposed for 25 days to diuron, as well as to its metabolites 3,4-dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N-methylurea (DCPMU), at concentrations of 100 ng/L. Diuron metabolites caused increases in E2 plasma levels, gonadosomatic indices and in the percentage of final vitellogenic oocytes. Moreover, diuron and its metabolites caused a decrease in germinative cells. Significant differences in plasma concentrations of the estrogen precursor and gonadal regulator17α-hydroxyprogesterone (17α-OHP) were not observed. These results show that diuron metabolites had estrogenic effects potentially mediated through enhanced estradiol biosynthesis and accelerated the ovarian development of O. niloticus females. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Estrogens and Androgens in Skeletal Physiology and Pathophysiology

    PubMed Central

    Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk

    2016-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. PMID:27807202

  10. Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

    PubMed

    Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

    2017-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

  11. The Effects of Aerobic Exercise on Estrogen Metabolism in Healthy Premenopausal Women

    PubMed Central

    Smith, Alma J.; Phipps, William R.; Thomas, William; Schmitz, Kathryn H.; Kurzer, Mindy S.

    2013-01-01

    Background It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in estrogen metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal estrogen metabolism pertinent to breast cancer risk. Methods Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise 5 times a week for approximately 16 weeks (n = 212), or into a usual-lifestyle sedentary control group (n = 179). Urinary levels of estrogens (estrone [E1], estradiol, and estriol) and nine estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16α-hydroxyestrone (2-OHE1/16α-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated. Results The exercise intervention resulted in significant increases in aerobic fitness and lean body mass, and a significant decrease in percent body fat. For exercisers who completed the study (n = 165), 2-OHE1/16α-OHE1 increased significantly (P = 0.043), while E1 decreased significantly (P = 0.030) in control participants (n = 153). The change from baseline in 2-OHE1/16α-OHE1 was significantly different between groups (P = 0.045), even after adjustment for baseline values. Conclusions The exercise intervention resulted in a significant increase in the 2-OHE1/16α-OHE1 ratio, but no differences in other estrogen metabolites or ratios. Impact Our results suggest that changes in premenopausal estrogen metabolism may be a mechanism by which increased physical activity lowers breast cancer risk. PMID:23652373

  12. Dietary choline requirements of women: effects of estrogen and genetic variation123

    PubMed Central

    Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph

    2010-01-01

    Background: Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. Objective: The objective was to determine whether the risk of low choline–related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Design: Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. Results: A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Conclusions: Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546. PMID:20861172

  13. Removal of estrogens through water disinfection processes and formation of by-products.

    PubMed

    Pereira, Renata Oliveira; Postigo, Cristina; de Alda, Miren López; Daniel, Luiz Antonio; Barceló, Damià

    2011-02-01

    Estrogens constitute a recognized group of environmental emerging contaminants which have been proven to induce estrogenic effects in aquatic organisms exposed to them. Low removal efficiency in wastewater treatment plants results in the presence of this type of contaminants in surface waters and also even in finished drinking water. This manuscript reviews the environmental occurrence of natural (estrone, estradiol and estriol) and synthetic (ethynyl estradiol) estrogens in different water matrices (waste, surface, ground and drinking water), and their removal mainly via chemical oxidative processes. Oxidative treatments have been observed to be very efficient in eliminating estrogens present in water; however, disinfection by-products (DBPs) are generated during the process. Characterization of these DBPs is essential to assess the risk that drinking water may potentially pose to human health since these DBPs may also have endocrine disrupting properties. This manuscript reviews the DBPs generated during oxidative processes identified so far in the literature and the estrogenicity generated by the characterized DBPs and/or by the applied disinfection technology. Copyright © 2010 Elsevier Ltd. All rights reserved.

  14. Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture.

    PubMed

    Goetz, Laura G; Mamillapalli, Ramanaiah; Devlin, Maureen J; Robbins, Amy E; Majidi-Zolbin, Masoumeh; Taylor, Hugh S

    2017-11-01

    Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here, we investigate the long-term effects of XHT on bone health using a murine model. Female mice underwent ovariectomy at either 6 or 10 wk and began weekly testosterone or vehicle injections. Dual-energy X-ray absorptiometry (DXA) was performed (20 wk) to measure bone mineral density (BMD), and microcomputed tomography was performed to compare femoral cortical and trabecular bone architecture. The 6-wk testosterone group had comparable BMD with controls by DXA but reduced bone volume fraction, trabecular number, and cortical area fraction and increased trabecular separation by microcomputed tomography. Ten-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone with effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-wk ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, including bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, trabecular thickness, and connectivity density) to estrogen therapy and were superior compared with mice treated with testosterone only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments with potential future clinical implications for treating transgender youth or men with estrogen deficiency. Copyright © 2017 the American Physiological Society.

  15. Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons.

    PubMed

    Jayaraman, Anusha; Pike, Christian J

    2014-03-25

    Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Estrogen Degraders and Estrogen Degradation Pathway Identified in an Activated Sludge.

    PubMed

    Chen, Yi-Lung; Fu, Han-Yi; Lee, Tzong-Huei; Shih, Chao-Jen; Huang, Lina; Wang, Yu-Sheng; Ismail, Wael; Chiang, Yin-Ru

    2018-05-15

    The environmental release and fate of estrogens are becoming an increasing public concern. Bacterial degradation has been considered the main process for eliminating estrogens from wastewater treatment plants. Various bacterial isolates are reportedly capable of aerobic estrogen degradation, and several estrogen degradation pathways have been proposed in proteobacteria and actinobacteria. However, the ecophysiological relevance of estrogen-degrading bacteria in the environment is unclear. In this study, we investigated the estrogen degradation pathway and corresponding degraders in activated sludge collected from the Dihua Sewage Treatment Plant, Taipei, Taiwan. Cultivation-dependent and cultivation-independent methods were used to assess estrogen biodegradation in the collected activated sludge. Estrogen metabolite profile analysis revealed the production of pyridinestrone acid and two A/B-ring cleavage products in activated sludge incubated with estrone (1 mM), which are characteristic of the 4,5- seco pathway. PCR-based functional assays detected sequences closely related to alphaproteobacterial oecC , a key gene of the 4,5- seco pathway. Metagenomic analysis suggested that Novosphingobium spp. are major estrogen degraders in estrone-amended activated sludge. Novosphingobium sp. strain SLCC, an estrone-degrading alphaproteobacterium, was isolated from the examined activated sludge. The general physiology and metabolism of this strain were characterized. Pyridinestrone acid and the A/B-ring cleavage products were detected in estrone-grown strain SLCC cultures. The production of pyridinestrone acid was also observed during the aerobic incubation of strain SLCC with 3.7 nM (1 μg/liter) estrone. This concentration is close to that detected in many natural and engineered aquatic ecosystems. The presented data suggest the ecophysiological relevance of Novosphingobium spp. in activated sludge. IMPORTANCE Estrogens, which persistently contaminate surface water

  17. Brefeldin A is an estrogenic, Erk1/2-activating component in the extract of Agaricus blazei mycelia.

    PubMed

    Dong, Sijun; Furutani, Yoshiyuki; Kimura, Sadao; Zhu, Yun; Kawabata, Kazutaka; Furutani, Michiko; Nishikawa, Toshio; Tanaka, Takeshi; Masaki, Tomoh; Matsuoka, Rumiko; Kiyama, Ryoiti

    2013-01-09

    We purified an Erk1/2-activating component in Agaricus blazei and identified it as brefeldin A (BFA). The extract of A. blazei mycelia (ABE) previously showed an estrogenic gene-expression profile and positive effects in patients with cardiovascular symptoms. Here, we demonstrate that BFA has estrogenic activity in reporter gene assays and stimulates an estrogen-receptor pathway revealed by activation of Erk1/2, although BFA had no growth-stimulating activity in breast cancer MCF-7 cells. The presence of estrogenic activity without any explicit growth-stimulating effect is unique to BFA, and such components are termed here "silent estrogens". To test this hypothesis, we examined the target-gene transcription and signaling pathways induced by BFA. Furthermore, BFA was found in the mycelium but not fruiting body of A. blazei, suggesting the potential use of ABE for therapeutics and its supplementary use in traditional medicines and functional foods.

  18. Estrogen Receptors Modulation of Anxiety-Like Behavior.

    PubMed

    Borrow, A P; Handa, R J

    2017-01-01

    Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens' effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic-pituitary-adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems. © 2017 Elsevier Inc. All rights reserved.

  19. Modeling mixtures of environmental estrogens found in U.S. surface waters with an in vitro estrogen mediated transcriptionai activation assay (T47D-KBluc).

    EPA Science Inventory

    There is growing concern of exposure to fish, wildlife, and humans to water sources contaminated with estrogens and the potential impact on reproductive health. Environmental estrogens can come from various sources including concentrated animal feedlot operations (CAFO), municipa...

  20. Aerobic Exercise, Estrogens, and Breast Cancer Risk

    DTIC Science & Technology

    2011-11-01

    on endogenous sex hormone levels, menstrual cycle characteristics, and estrogen metabolism in sedentary, eumenorrheic, healthy premenopausal women...changes in menstrual cycle length, and 4) limited changes in estrogen metabolism. The resulting increases in urinary 2-hydroxyestrone levels and 2...effects of a 16-week, aerobic exercise intervention on endogenous sex hormone levels, menstrual cycle characteristics, and estrogen metabolism of young

  1. GPR30: A G protein-coupled receptor for estrogen.

    PubMed

    Prossnitz, Eric R; Arterburn, Jeffrey B; Sklar, Larry A

    2007-02-01

    Estrogen is a critical steroid in human physiology exerting its effect both at the transcriptional level as well as at the level of rapid intracellular signaling through second messengers. Many of estrogen's transcriptional effects have long been known to be mediated through classical nuclear steroid receptors but recent studies also demonstrate the existence of a 7-transmembrane G protein-coupled receptor, GPR30 that responds to estrogen with rapid cellular signaling. There is currently controversy over the ability of classical estrogen receptors to recapitulate GPR30-mediated signaling mechanisms and vice versa. This article will summarize recent literature and address the relationship between GPR30 and conventional estrogen receptor signaling.

  2. Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta.

    PubMed Central

    Vanacker, J M; Pettersson, K; Gustafsson, J A; Laudet, V

    1999-01-01

    The physiological activities of estrogens are thought to be mediated by specific nuclear receptors, ERalpha and ERbeta. However, certain tissues, such as the bone, that are highly responsive to estrogens only express a low level of these receptors. Starting from this apparent contradiction, we have evaluated the potentials of two related receptors ERRalpha and ERRbeta to intervene in estrogen signaling. ERalpha, ERRalpha and ERRbeta bind to and activate transcription through both the classical estrogen response element (ERE) and the SF-1 response element (SFRE). In contrast, ERbeta DNA-binding and transcriptional activity is restricted to the ERE. Accordingly, the osteopontin gene promoter is stimulated through SFRE sequences, by ERRalpha as well as by ERalpha, but not by ERbeta. Analysis of the cross-talk within the ER/ERR subgroup of nuclear receptors thus revealed common targets but also functional differences between the two ERs. PMID:10428965

  3. Estrogen Receptor Binding Affinity of Food Contact Material Components Estimated by QSAR.

    PubMed

    Sosnovcová, Jitka; Rucki, Marián; Bendová, Hana

    2016-09-01

    The presented work characterized components of food contact materials (FCM) with potential to bind to estrogen receptor (ER) and cause adverse effects in the human organism. The QSAR Toolbox, software application designed to identify and fill toxicological data gaps for chemical hazard assessment, was used. Estrogen receptors are much less of a lock-and-key interaction than highly specific ones. The ER is nonspecific enough to permit binding with a diverse array of chemical structures. There are three primary ER binding subpockets, each with different requirements for hydrogen bonding. More than 900 compounds approved as of FCM components were evaluated for their potential to bind on ER. All evaluated chemicals were subcategorized to five groups with respect to the binding potential to ER: very strong, strong, moderate, weak binder, and no binder to ER. In total 46 compounds were characterized as potential disturbers of estrogen receptor. Among the group of selected chemicals, compounds with high and even very high affinity to the ER binding subpockets were found. These compounds may act as gene activators and cause adverse effects in the organism, particularly during pregnancy and breast-feeding. It should be considered to carry out further in vitro or in vivo tests to confirm their potential to disturb the regulation of physiological processes in humans by abnormal ER signaling and subsequently remove these chemicals from the list of approved food contact materials. Copyright© by the National Institute of Public Health, Prague 2016

  4. Potential anabolic effects of androgens on bone.

    PubMed

    Kearns, Ann E; Khosla, Sundeep

    2004-04-01

    Sex steroid hormones are essential to normal skeletal growth and maintenance throughout life in both men and women. The importance of estrogens to bone health in women becomes obvious at menopause when estrogen deficiency occurs and results in accelerated bone loss. After menopause, estrogen deficiency results in drastic changes in the androgen-estrogen ratio. Thus, the relative importance of androgens after menopause may increase. Androgens also appear to be important for bone health in pre-menopausal women. Evidence from human, animal, and laboratory studies is leading to a better understanding of the effects of androgens on bone in women.

  5. Joint effects of heterogeneous estrogenic chemicals in the E-screen--exploring the applicability of concentration addition.

    PubMed

    Silva, Elisabete; Rajapakse, Nissanka; Scholze, Martin; Backhaus, Thomas; Ermler, Sibylle; Kortenkamp, Andreas

    2011-08-01

    In the last few years, significant advances have been made toward understanding the joint action of endocrine disrupting chemicals (EDCs). A number of studies have demonstrated that the combined effects of different types of EDCs (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by the model of concentration addition (CA). However, there is still limited information on the effects of mixtures of large numbers of chemicals with varied structural features, which are more representative of realistic human exposure scenarios. The work presented here aims at filling this gap. Using a breast cancer cell proliferation assay (E-Screen), we assessed the joint effects of five mixtures, containing between 3 and 16 estrogenic agents, including compounds as diverse as steroidal hormones (endogenous and synthetic), pesticides, cosmetic additives, and phytoestrogens. CA was employed to predict mixture effects, which were then compared with experimental outcomes. The effects of two of the mixtures tested were additive, being accurately predicted by CA. However, for the three other mixtures, CA slightly overestimated the experimental observations. In view of these results, we hypothesized that the deviations were due to increased metabolism of steroidal estrogens in the mixture setting. We investigated this by testing the impact of two such mixtures on the activation and expression of steroidal estrogen metabolizing enzymes, such as cytochrome P450 (CYP) 1A1, CYP 1B1, and CYP 3A4. Activation of CYP 1B1 and, consequently, a reduction in the levels of steroidal estrogens in the mixture could contribute to the shortfall from the additivity prediction that we observed.

  6. Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk.

    PubMed

    Hilakivi-Clarke, Leena; de Assis, Sonia; Warri, Anni

    2013-03-01

    Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

  7. Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk

    PubMed Central

    de Assis, Sonia; Warri, Anni

    2013-01-01

    Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations. PMID:23392570

  8. Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor α and β for improved detection of estrogenic/antiestrogenic chemicals

    PubMed Central

    Brennan, Jennifer C.; Bassal, Arzoo; He, Guochun; Denison, Michael S.

    2016-01-01

    Estrogenic endocrine disrupting chemicals are found in environmental and biological samples, commercial and consumer products, food, and numerous other sources. Given their ubiquitous nature and potential for adverse effects, there is a critical need for rapidly detecting these chemicals. We developed an estrogen-responsive recombinant human ovarian (BG1Luc4E2) cell line recently accepted by the USEPA and OECD as a bioanalytical method to detect estrogen receptor (ER) agonists/antagonists. Unfortunately, these cells appear to contain only one of the two known ER isoforms, ERα but not ERβ, and the differential ligand selectivity of these ERs indicates that the currently accepted screening method only detects a subset of total estrogenic chemicals. To improve the estrogen screening bioassay, BG1Luc4E2 cells were stably transfected with an ERβ expression plasmid and positive clones identified using ERβ-selective ligands (genistein and Br-ERβ-041). A highly responsive clone (BG1LucERβc9) was identified that exhibited greater sensitivity and responsiveness to ERβ-selective ligands than BG1Luc4E2 cells and qRT-PCR confirmed the presence of ERβ expression in these cells. Screening of pesticides and industrial chemicals identified chemicals that preferentially stimulated ERβ-dependent reporter gene expression. Together, these results not only demonstrate the utility of this dual ER recombinant cell line for detecting a broader range of estrogenic chemicals than the current BG1Luc4E2 cell line, but screening with both cell lines allows identification of ERα and ERβ-selective chemicals. PMID:26139245

  9. Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism.

    PubMed

    Bastianelli, Carlo; Farris, Manuela; Rosato, Elena; Brosens, Ivo; Benagiano, Giuseppe

    2017-03-01

    The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern.

  10. Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder.

    PubMed

    Glover, Ebony M; Jovanovic, Tanja; Mercer, Kristina B; Kerley, Kimberly; Bradley, Bekh; Ressler, Kerry J; Norrholm, Seth D

    2012-07-01

    Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD. We measured fear-potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E(2)) groups. Seventeen of 41 women (41.5%) in the low E(2) group and 15 of 40 women (37.5%) met criteria for PTSD in the high E(2) group. The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E(2) groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E(2) group. This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  11. Effect of acute transdermal estrogen administration on basal, mental stress and cold pressor-induced sympathetic responses in postmenopausal women.

    PubMed

    Sofowora, Gbemiga G; Singh, Iqbal; He, Huai B; Wood, Alastair J J; Stein, C Michael

    2005-06-01

    Administration of estrogen has vascular effects through poorly defined mechanisms that may include sympathetic withdrawal. To define the effects of acute estrogen administration on sympathetic responses, nineteen healthy postmenopausal women (age 54+/-2 years) were studied after application of a placebo or estrogen patch for 36 hours, in random order. A p-value, adjusted for multiple comparisons, of <0.017 was used to determine statistical significance. Heart rate, blood pressure, and norepinephrine spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Estrogen did not attenuate basal or stimulated hemodynamic responses significantly. The increase in mean arterial pressure after the Stroop test (5.9+/-1.2mm/ Hg on placebo vs 6.1+/-1.6mm/Hg on estrogen, p=0.9) and after the cold pressor test (12.6+/-2.4mm/Hg on placebo vs 13.0+/-2.2 mm/Hg on estrogen, p=0.8) did not differ. Basal, mental stress and cold pressor-stimulated norepinephrine spillover were not significantly affected by short-term estrogen administration. Norepinephrine spillover tended to be higher after estrogen (1296.2+/-238 ng/min) than placebo (832.5+/-129 ng/min) (p=0.02) at baseline and after the Stroop test (1881.1+/-330 ng/min vs 1014.6+/-249 ng/min) (p=0.02). Acute transdermal estrogen administration did not attenuate norepinephrine spillover or sympathetically mediated hemodynamic responses.

  12. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer.

    PubMed

    Filardo, Edward J

    2002-02-01

    The biological and biochemical effects of estrogen have been ascribed to its known receptors, which function as ligand-inducible transcription factors. However, estrogen also triggers rapid activation of classical second messengers (cAMP, calcium, and inositol triphosphate) and stimulation of intracellular signaling cascades mitogen-activated protein kinase (MAP K), PI3K and eNOS. These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins. We have shown that estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via the G-protein-coupled receptor (GPCR), GPR30, through the release of surface-bound proHB-EGF from estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling. GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the EGF-like effects of estrogen. This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review.

  13. Estrogen's Place in the Family of Synaptic Modulators.

    PubMed

    Kramár, Enikö A; Chen, Lulu Y; Rex, Christopher S; Gall, Christine M; Lynch, Gary

    2009-01-01

    Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2's actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of 'synaptic modulators' that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.

  14. Increasing women’s sexual desire: The comparative effectiveness of estrogens and androgens

    PubMed Central

    Cappelletti, Maurand; Wallen, Kim

    2016-01-01

    Both estradiol and testosterone have been implicated as the steroid critical for modulating women’s sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women’s sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women’s sexual desire; however, the mechanism by which supraphysiological testosterone increases women’s sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women’s sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women’s sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced. PMID:26589379

  15. Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities

    PubMed Central

    Campbell, Laura; Emmerson, Elaine; Davies, Faith; Gilliver, Stephen C.; Krust, Andre; Chambon, Pierre; Ashcroft, Gillian S.

    2010-01-01

    Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type–specific role of the two estrogen receptors, ERα and ERβ, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERα and ERβ in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERβ actually delayed wound healing. Moreover, healing in epidermal-specific ERβ null mice (K14-cre/ERβL2/L2) largely resembled that in global ERβ null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERβ, in marked contrast to most other tissues in the body where ERα is predominant. Surprisingly, agonists to both ERα and ERβ are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing. PMID:20733032

  16. G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

    PubMed Central

    Petrie, Whitney K.; Dennis, Megan K.; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R.

    2013-01-01

    Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth. PMID:24379833

  17. G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.

    PubMed

    Petrie, Whitney K; Dennis, Megan K; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B; Smith, Harriet O; Hathaway, Helen J; Prossnitz, Eric R

    2013-01-01

    Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the "ERα-selective" agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of "ER-targeted" therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.

  18. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to environmental water samples

    USGS Publications Warehouse

    Gorelick, Daniel A.; Iwanowicz, Luke R.; Hung, Alice L.; Blazer, Vicki; Halpern, Marnie E.

    2014-01-01

    Background: Environmental endocrine disruptors (EED) are exogenous chemicals that mimic endogenous hormones, such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ER) in the larval heart compared to the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit similar tissue-specific effects as BPA and genistein or why some compounds preferentially target receptors in the heart. Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of estrogen receptor genes by RNA in situ hybridization. Results: Selective patterns of ER activation were observed in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue-specificity in ER activation is due to differences in the expression of estrogen receptor subtypes. ERα is expressed in developing heart valves but not in the liver, whereas ERβ2 has the opposite profile. Accordingly, subtype-specific ER agonists activate the reporter in either the heart valves or the liver. Conclusion: The use of 5xERE:GFP transgenic zebrafish has revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero is associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

  19. Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity

    PubMed Central

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Ferretti, Max M.; Liu, Baomai; Baskin, Laurence S.; Cunha, Gerald R.

    2014-01-01

    The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200 ng/g/5μl in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development. PMID:25449353

  20. Effect of Age, Estrogen Status, and Late-Life GPER Activation on Cardiac Structure and Function in the Fischer344×Brown Norway Female Rat.

    PubMed

    Alencar, Allan K; da Silva, Jaqueline S; Lin, Marina; Silva, Ananssa M; Sun, Xuming; Ferrario, Carlos M; Cheng, Cheping; Sudo, Roberto T; Zapata-Sudo, Gisele; Wang, Hao; Groban, Leanne

    2017-02-01

    Age-associated changes in cardiac structure and function, together with estrogen loss, contribute to the progression of heart failure with preserved ejection fraction in older women. To investigate the effects of aging and estrogen loss on the development of its precursor, asymptomatic left ventricular diastolic dysfunction, echocardiograms were performed in 10 middle-aged (20 months) and 30 old-aged (30 months) female Fischer344×Brown-Norway rats, 4 and 8 weeks after ovariectomy (OVX) and sham procedures (gonads left intact). The cardioprotective potential of administering chronic G1, the selective agonist to the new G-protein-coupled estrogen receptor (GPER), was further evaluated in old rats (Old-OVX+G1) versus age-matched, vehicle-treated OVX and gonadal intact rats. Advanced age and estrogen loss led to decreases in myocardial relaxation and elevations in filling pressure, in part, due to reductions in phosphorylated phospholamban and increases in cardiac collagen deposition. Eight weeks of G-protein-coupled estrogen receptor activation in Old-OVX+G1 rats reversed the adverse effects of age and estrogen loss on myocardial relaxation through increases in sarcoplasmic reticulum Ca 2+ ATPase expression and reductions in interstitial fibrosis. These findings may explain the preponderance of heart failure with preserved ejection fraction in older postmenopausal women and provide a promising, late-life therapeutic target to reverse or halt the progression of left ventricular diastolic dysfunction. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Effects of atrazine on estrogen receptor α- and G protein-coupled receptor 30-mediated signaling and proliferation in cancer cells and cancer-associated fibroblasts.

    PubMed

    Albanito, Lidia; Lappano, Rosamaria; Madeo, Antonio; Chimento, Adele; Prossnitz, Eric R; Cappello, Anna Rita; Dolce, Vincenza; Abonante, Sergio; Pezzi, Vincenzo; Maggiolini, Marcello

    2015-05-01

    The pesticide atrazine does not bind to or activate the classical estrogen receptor (ER), but it up-regulates the aromatase activity in estrogen-sensitive tumor cells. The G protein estrogen receptor (GPR30/GPER) has been reported to be involved in certain biological responses to endogenous estrogens and environmental compounds exerting estrogen-like activity. We aimed to evaluate the potential of atrazine to trigger GPER-mediated signaling in cancer cells and cancer-associated fibroblasts (CAFs). Using gene reporter assays in diverse types of cancer cells, we found that atrazine did not transactivate endogenous ERα or chimeric proteins that encode the ERα and ERβ hormone binding domains. Conversely, atrazine was able to bind to GPER to induce ERK activation and the expression of estrogen target genes, which, interestingly, appeared to rely on both GPER and ERα expression. As a biological counterpart, atrazine stimulated the proliferation of ovarian cancer cells that depend on GPER and ERα, as evidenced by gene silencing experiments and the use of specific signaling inhibitors. Of note, through GPER, atrazine elicited ERK phosphorylation, gene expression, and migration in CAFs, thus extending its stimulatory role to these main players of the tumor microenvironment. Our results suggest a novel mechanism through which atrazine may exert relevant biological effects in cancer cells and CAFs. On the basis of our data, atrazine should be included among the environmental contaminants that may elicit estrogenic activity through GPER-mediated signaling.

  2. Comparison of in vitro estrogenic activity and estrogen concentrations in source and treated waters from 25 U.S. drinking water treatment plants.

    PubMed

    Conley, Justin M; Evans, Nicola; Mash, Heath; Rosenblum, Laura; Schenck, Kathleen; Glassmeyer, Susan; Furlong, Ed T; Kolpin, Dana W; Wilson, Vickie S

    2017-02-01

    In vitro bioassays have been successfully used to screen for estrogenic activity in wastewater and surface water, however, few have been applied to treated drinking water. Here, extracts of source and treated water samples were assayed for estrogenic activity using T47D-KBluc cells and analyzed by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS) for natural and synthetic estrogens (including estrone, 17β-estradiol, estriol, and ethinyl estradiol). None of the estrogens were detected above the LC-FTMS quantification limits in treated samples and only 5 source waters had quantifiable concentrations of estrone, whereas 3 treated samples and 16 source samples displayed in vitro estrogenicity. Estrone accounted for the majority of estrogenic activity in respective samples, however the remaining samples that displayed estrogenic activity had no quantitative detections of known estrogenic compounds by chemical analyses. Source water estrogenicity (max, 0.47ng 17β-estradiol equivalents (E2Eq) L -1 ) was below levels that have been linked to adverse effects in fish and other aquatic organisms. Treated water estrogenicity (max, 0.078ngE2EqL -1 ) was considerably below levels that are expected to be biologically relevant to human consumers. Overall, the advantage of using in vitro techniques in addition to analytical chemical determinations was displayed by the sensitivity of the T47D-KBluc bioassay, coupled with the ability to measure cumulative effects of mixtures, specifically when unknown chemicals may be present. Published by Elsevier B.V.

  3. Daidzein–Estrogen Interaction in the Rat Uterus and Its Effect on Human Breast Cancer Cell Growth

    PubMed Central

    Gaete, Leonardo; Bustamante, Rodrigo; Villena, Joan; Lemus, Igor; Gidekel, Manuel; Cabrera, Gustavo; Astorga, Paola

    2012-01-01

    Abstract Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17β (E2; subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 μg/mL) or E2 on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast. PMID:23216111

  4. Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer

    PubMed Central

    Stein, Rebecca A.; Chang, Ching-yi; Kazmin, Dmitri A.; Way, James; Schroeder, Thies; Wergin, Melanie; Dewhirst, Mark W.; McDonnell, Donald P.

    2009-01-01

    Expression of estrogen-related receptor alpha (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERα) and ERRα initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRα target genes, this study yielded the surprising result that most ERRα-regulated genes are unrelated to estrogen-signaling. The relatively small number of genes regulated by both ERα and ERRα led us to expand our study to the more aggressive and less clinically treatable ERα-negative class of breast cancers. In this setting we found that ERRα expression is required for the basal level of expression of many known and novel ERRα target genes. Introduction of an siRNA directed to ERRα into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRα expression in MDA-MB-231 cells had no impact on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRα in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer. PMID:18974123

  5. Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells

    USDA-ARS?s Scientific Manuscript database

    Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into an antiestrogenic ligand by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of dai...

  6. Nylon 6 electrospun nanofibers mat as effective sorbent for the removal of estrogens: kinetic and thermodynamic studies

    PubMed Central

    2014-01-01

    Nylon 6 electrospun nanofibers mat was prepared via electrospinning for the removal of three estrogens, namely, diethylstilbestrol (DES), dienestrol (DS), and hexestrol (HEX) from aqueous solution. Static adsorption as well as the dynamic adsorption was evaluated by means of batch and dynamic disk flow mode, respectively. The kinetic study indicated that the adsorption of the target compounds could be well fitted by the pseudo-second-order equation, suggesting the intra-particle/membrane diffusion process as the rate-limiting step of the adsorption process. The adsorption equilibrium data were all fitted well to the Freundlich isotherm models, with a maximum adsorption capacity values in the range of 97.71 to 208.95 mg/g, which can be compared to or moderately higher than other sorbents published in the literatures. The dynamic disk mode studies indicated that the mean removal yields of three model estrogens were over 95% with a notable smaller amount of adsorbent (4 mg). Thermodynamic study revealed that the adsorption process was exothermic and spontaneous in nature. Desorption results showed that the adsorption capacity can remain up to 80% after seven times usage. It was suggested that Nylon 6 electrospun nanofibers mat has great potential as a novel effective sorbent material for estrogens removal. PMID:25114645

  7. Influence of different estrogens on neuroplasticity and cognition in the hippocampus.

    PubMed

    Barha, Cindy K; Galea, Liisa A M

    2010-10-01

    Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning. Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Effects of estrogen on functional and neurological recovery after spinal cord injury: An experimental study with rats.

    PubMed

    Letaif, Olavo Biraghi; Cristante, Alexandre Fogaça; Barros Filho, Tarcísio Eloy Pessoa de; Ferreira, Ricardo; Santos, Gustavo Bispo dos; Rocha, Ivan Dias da; Marcon, Raphael Martus

    2015-10-01

    To evaluate the functional and histological effects of estrogen as a neuroprotective agent after a standard experimentally induced spinal cord lesion. In this experimental study, 20 male Wistar rats were divided into two groups: one group with rats undergoing spinal cord injury (SCI) at T10 and receiving estrogen therapy with 17-beta estradiol (4mg/kg) immediately following the injury and after the placement of skin sutures and a control group with rats only subjected to SCI. A moderate standard experimentally induced SCI was produced using a computerized device that dropped a weight on the rat's spine from a height of 12.5 mm. Functional recovery was verified with the Basso, Beattie and Bresnahan scale on the 2nd, 7th, 14th, 21st, 28th, 35th and 42nd days after injury and by quantifying the motor-evoked potential on the 42nd day after injury. Histopathological evaluation of the SCI area was performed after euthanasia on the 42nd day. The experimental group showed a significantly greater functional improvement from the 28th to the 42nd day of observation compared to the control group. The experimental group showed statistically significant improvements in the motor-evoked potential compared with the control group. The results of pathological histomorphometry evaluations showed a better neurological recovery in the experimental group, with respect to the proportion and diameter of the quantified nerve fibers. Estrogen administration provided benefits in neurological and functional motor recovery in rats with SCI beginning at the 28th day after injury.

  9. Effects of estrogen on functional and neurological recovery after spinal cord injury: An experimental study with rats

    PubMed Central

    Letaif, Olavo Biraghi; Cristante, Alexandre Fogaça; de Barros Filho, Tarcísio Eloy Pessoa; Ferreira, Ricardo; dos Santos, Gustavo Bispo; da Rocha, Ivan Dias; Marcon, Raphael Martus

    2015-01-01

    OBJECTIVES: To evaluate the functional and histological effects of estrogen as a neuroprotective agent after a standard experimentally induced spinal cord lesion. METHODS: In this experimental study, 20 male Wistar rats were divided into two groups: one group with rats undergoing spinal cord injury (SCI) at T10 and receiving estrogen therapy with 17-beta estradiol (4mg/kg) immediately following the injury and after the placement of skin sutures and a control group with rats only subjected to SCI. A moderate standard experimentally induced SCI was produced using a computerized device that dropped a weight on the rat's spine from a height of 12.5 mm. Functional recovery was verified with the Basso, Beattie and Bresnahan scale on the 2nd, 7th, 14th, 21st, 28th, 35th and 42nd days after injury and by quantifying the motor-evoked potential on the 42nd day after injury. Histopathological evaluation of the SCI area was performed after euthanasia on the 42nd day. RESULTS: The experimental group showed a significantly greater functional improvement from the 28th to the 42nd day of observation compared to the control group. The experimental group showed statistically significant improvements in the motor-evoked potential compared with the control group. The results of pathological histomorphometry evaluations showed a better neurological recovery in the experimental group, with respect to the proportion and diameter of the quantified nerve fibers. CONCLUSIONS: Estrogen administration provided benefits in neurological and functional motor recovery in rats with SCI beginning at the 28th day after injury. PMID:26598084

  10. Nonylphenol and estrogenic activity in aquatic environmental samples

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tanghe, T.; Devriese, G.; Verstraete, W.

    1999-03-01

    The authors surveyed a series of surface waters and sewage treatment plants in Flanders (north of Belgium) for the presence of estrogenic activity and a xeno-estrogenic compound para-nonylphenol (NP), respectively. The surface waters of rural origin, used for drinking water production were free of significant levels of estrogenic activity and NP. Domestic sewage, after proper treatment, appeared to be no major source of this chemical. Yet, in some industrial effluents and surface waters of highly industrialized regions, NP and/or estrogenic activity was prominent, that is, <1 to 122 {micro}g NP/L and 11 to 42 {micro}g NP/L, respectively. This is becausemore » of the ongoing use of NP polyethoxylates in industry. The response of the recombinant yeast estrogen assay to the environmental samples tested was not consistent with the detected concentrations of NP. Standard addition of a natural estrogen, 17{beta}-estradiol, generated no or a reduced response compared to the standard curve concentration. Application of humic acids to standard series of NP and 17{beta}-estradiol resulted in a dose-dependent decrease of the estrogenic response. It appears that this bioassay is subject to considerable interferences due to the complexity of environmental samples. Parallel implementation of extensive chemical screening for xenobiotics and use of the bioassay are needed for adequate assessment of the potential estrogenic hazard to avoid false negative evaluations.« less

  11. Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis.

    PubMed

    Cintron, Dahima; Rodriguez-Gutierrez, Rene; Serrano, Valentina; Latortue-Albino, Paula; Erwin, Patricia J; Murad, Mohammad Hassan

    2017-02-01

    Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aimed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. A comprehensive search of four databases was performed from inception through January 2016. Randomized clinical trials and observational cohort studies studying the effect of estrogen replacement therapy in patients with Turner syndrome under the age of 40 were included. Independently and in duplicate reviewers selected studies, extracted data and assessed risk of bias. Subgroup analyses were based on route of administration and type of estrogen formulation. Twenty-five studies at moderate to high risk of bias (12 randomized trials, 13 cohort studies) with 771 patients were included. Using random-effects models, estrogen replacement therapy showed an increase in bone mineral density [weighted mean change from baseline 0.09 g/cm2 (0.04-0.14)] that differed by type of estrogen but not route of administration. Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [weighted mean difference 9.33 mg/dl (4.82-13.85)] with no significant effect on other lipid fractions. The current evidence suggests possible benefit of estrogen replacement therapy on bone mineral density and high density lipoprotein cholesterol. Whether this improvement translates into changes in patient important outcomes (cardiovascular events or fractures) remains uncertain. Larger randomized clinical trials with direct comparisons on patient important outcomes are necessary.

  12. The G protein-coupled estrogen receptor GPER in health and disease

    PubMed Central

    Prossnitz, Eric R.; Barton, Matthias

    2012-01-01

    Estrogens mediate profound effects throughout the body, and regulate physiological and pathological processes in both women and men. The decreased incidence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, however, several manmade and plant-derived molecules also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1, (GPER, formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in cell experiments and preclinical studies, and the use of GPER-knockout mice, many more potential roles for GPER are currently being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer. GPER is emerging as a novel therapeutic target and prognostic indicator for these diseases. PMID:21844907

  13. The G-protein-coupled estrogen receptor GPER in health and disease.

    PubMed

    Prossnitz, Eric R; Barton, Matthias

    2011-08-16

    Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, several man-made and plant-derived molecules, such as bisphenol A and genistein, also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1 (GPER; formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in vitro and in preclinical studies and with the use of Gper knockout mice, many more potential roles for GPER are being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer, for which GPER is emerging as a novel therapeutic target and prognostic indicator.

  14. Estrogenic and anti-estrogenic influences in cultured brown trout hepatocytes: Focus on the expression of some estrogen and peroxisomal related genes and linked phenotypic anchors.

    PubMed

    Madureira, Tânia Vieira; Malhão, Fernanda; Pinheiro, Ivone; Lopes, Célia; Ferreira, Nádia; Urbatzka, Ralph; Castro, L Filipe C; Rocha, Eduardo

    2015-12-01

    Estrogens, estrogenic mimics and anti-estrogenic compounds are known to target estrogen receptors (ER) that can modulate other nuclear receptor signaling pathways, such as those controlled by the peroxisome proliferator-activated receptor (PPAR), and alter organelle (inc. peroxisome) morphodynamics. By using primary isolated brown trout (Salmo trutta f. fario) hepatocytes after 72 and 96h of exposure we evaluated some effects in selected molecular targets and in peroxisomal morphological features caused by: (1) an ER agonist (ethinylestradiol-EE2) at 1, 10 and 50μM; (2) an ER antagonist (ICI 182,780) at 10 and 50μM; and (3) mixtures of both (Mix I-10μM EE2 and 50μM ICI; Mix II-1μM EE2 and 10μM ICI and Mix III-1μM EE2 and 50μM ICI). The mRNA levels of the estrogenic targets (ERα, ERβ-1 and vitellogenin A-VtgA) and the peroxisome structure/function related genes (catalase, urate oxidase-Uox, 17β-hydroxysteroid dehydrogenase 4-17β-HSD4, peroxin 11α-Pex11α and PPARα) were analyzed by real-time polymerase chain reaction (RT-PCR). Stereology combined with catalase immunofluorescence revealed a significant reduction in peroxisome volume densities at 50μM of EE2 exposure. Concomitantly, at the same concentration, electron microscopy showed smaller peroxisome profiles, exacerbated proliferation of rough endoplasmic reticulum, and a generalized cytoplasmic vacuolization of hepatocytes. Catalase and Uox mRNA levels decreased in all estrogenic stimuli conditions. VtgA and ERα mRNA increased after all EE2 treatments, while ERβ-1 had an inverse pattern. The EE2 action was reversed by ICI 182,780 in a concentration-dependent manner, for VtgA, ERα and Uox. Overall, our data show the great value of primary brown trout hepatocytes to study the effects of estrogenic/anti-estrogenic inputs in peroxisome kinetics and in ER and PPARα signaling, backing the still open hypothesis of crosstalk interactions between these pathways and calling for more mechanistic

  15. Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor α and β for improved detection of estrogenic/antiestrogenic chemicals.

    PubMed

    Brennan, Jennifer C; Bassal, Arzoo; He, Guochun; Denison, Michael S

    2016-01-01

    Estrogenic endocrine-disrupting chemicals are found in environmental and biological samples, commercial and consumer products, food, and numerous other sources. Given their ubiquitous nature and potential for adverse effects, a critical need exists for rapidly detecting these chemicals. The authors developed an estrogen-responsive recombinant human ovarian (BG1Luc4E2) cell line recently accepted by the US Environmental Protection Agency (USEPA) and Organisation for Economic Co-operation and Development (OECD) as a bioanalytical method to detect estrogen receptor (ER) agonists/antagonists. Unfortunately, these cells appear to contain only 1 of the 2 known ER isoforms, ERα but not ERβ, and the differential ligand selectivity of these ERs indicates that the currently accepted screening method only detects a subset of total estrogenic chemicals. To improve the estrogen screening bioassay, BG1Luc4E2 cells were stably transfected with an ERβ expression plasmid and positive clones identified using ERβ-selective ligands (genistein and Br-ERβ-041). A highly responsive clone (BG1LucERβc9) was identified that exhibited greater sensitivity and responsiveness to ERβ-selective ligands than BG1Luc4E2 cells, and quantitative reverse-transcription polymerase chain reaction confirmed the presence of ERβ expression in these cells. Screening of pesticides and industrial chemicals identified chemicals that preferentially stimulated ERβ-dependent reporter gene expression. Together, these results not only demonstrate the utility of this dual-ER recombinant cell line for detecting a broader range of estrogenic chemicals than the current BG1Luc4E2 cell line, but screening with both cell lines allows identification of ERα- and ERβ-selective chemicals. © 2015 SETAC.

  16. Ethanol-extracted Cameroonian propolis exerts estrogenic effects and alleviates hot flushes in ovariectomized Wistar rats.

    PubMed

    Zingue, Stéphane; Nde, Chantal Beatrice Magne; Michel, Thomas; Ndinteh, Derek Tantoh; Tchatchou, Jules; Adamou, Moïse; Fernandez, Xavier; Fohouo, Fernand-Nestor Tchuenguem; Clyne, Colin; Njamen, Dieudonné

    2017-01-21

    Since the biological properties of propolis depend to the plants that can be found in a specific region, propolis from unexplored regions attracts the attention of scientists. Ethanolic extract of Cameroonian propolis (EEP) is used to treat various ailments including gynecological problems and amenorrhea. Since there were no scientific data to support the above claims, the present study was therefore undertaken to assess estrogenic properties of Cameroonian propolis. To achieve our goal, the ability of EEP to induce MCF-7 cells proliferation in E-screen assay as well as to activate estrogen receptors α (ERα) and β (ERβ) in cell-based reporter gene assays using human embryonic kidney cells (HEK293T) transfected with ERs was tested. Further, a 3-day uterotrophic assay was performed and the ability of EEP to alleviate hot flushes in ovariectomized adult rats was evaluated. In vitro, EEP showed an antiestrogenic activity in both HEK293T ER-α and ER-β cells. In vivo, EEP induced a significant increase in a bell shape dose response manner of the uterine wet weight, the total protein levels in the uterus, the uterine and vaginal epithelium height and acini border cells of mammary gland with the presence of abundant eosinophil secretions. Moreover, EEP induced a significant decrease in the total number, average duration as well as frequency of hot flushes after 3 days of treatment in rat (equivalent to a month in woman). The dose of 150 mg/kg exhibited the most potent estrogenic effects among all the tested doses. The UPLC-HRMS analysis showed the presence of caffeic acid derivatives and trirtepernoids in EEP, which are well known endowed with estrogenic properties. These results suggest that Ethanolic extract of Cameroonian propolis has estrogen-like effects in vivo and may alleviate some menopausal problems such as vaginal dryness and hot flushes. Ethanol-extracted Cameroobian propolis exhibited in vitro and in vivo estrogen-like effects. This extract may contain

  17. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens

    USGS Publications Warehouse

    Iwanowicz, Luke R.; Stafford, James L.; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W.; Blazer, Vicki

    2014-01-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines.

  18. Ethanolic extract of dandelion (Taraxacum mongolicum) induces estrogenic activity in MCF-7 cells and immature rats.

    PubMed

    Oh, Seung Min; Kim, Ha Ryong; Park, Yong Joo; Lee, Yong Hwa; Chung, Kyu Hyuck

    2015-11-01

    Plants of the genus Taraxacum, commonly known as dandelions, are used to treat breast cancer in traditional folk medicine. However, their use has mainly been based on empirical findings without sufficient scientific evidence. Therefore, we hypothesized that dandelions would behave as a Selective estrogen receptor modulator (SERM) and be effective as hormone replacement therapy (HRT) in the postmenopausal women. In the present study, in vitro assay systems, including cell proliferation assay, reporter gene assay, and RT-PCR to evaluate the mRNA expression of estrogen-related genes (pS2 and progesterone receptor, PR), were performed in human breast cancer cells. Dandelion ethanol extract (DEE) significantly increased cell proliferation and estrogen response element (ERE)-driven luciferase activity. DEE significantly induced the expression of estrogen related genes such as pS2 and PR, which was inhibited by tamoxifen at 1 μmol·L(-1). These results indicated that DEE could induce estrogenic activities mediated by a classical estrogen receptor pathway. In addition, immature rat uterotrophic assay was carried out to identify estrogenic activity of DEE in vivo. The lowest concentration of DEE slightly increased the uterine wet weight, but there was no significant effect with the highest concentration of DEE. The results demonstrate the potential estrogenic activities of DEE, providing scientific evidence supporting their use in traditional medicine. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  19. Effects of tibolone on sulfatase pathway of estrogens metabolism and on growth of MCF-7 human breast tumors implanted in ovariectomized nude mice.

    PubMed

    Desreux, Joëlle; Kloosterboer, Helenius; Noël, Agnès; Frankenne, Francis; Lemaire, Madeleine; Putman, Monique; Foidart, Jean-Michel

    2007-01-01

    The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17beta-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

  20. Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels

    PubMed Central

    Sribnick, Eric A.; Del Re, Angelo M.; Ray, Swapan K.; Woodward, John J.; Banik, Naren L.

    2009-01-01

    Estrogen-mediated neuroprotection is observed in neurodegenerative disease and neurotrauama models; however, determining a mechanism for these effects has been difficult. We propose that estrogen may limit cell death in the nervous system tissue by inhibiting increases in intracellular free Ca2+. Here, we present data using VSC 4.1 cell line, a ventral spinal motoneuron and neuroblastoma hybrid cell line. Treatment with 1 mM glutamate for 24 h induced apoptosis. When cells were pre-treated with 100 nM 17β-estradiol (estrogen) for 1 h and then co-treated with glutamate, apoptotic death was significantly attenuated. Estrogen also prevented glutamate-mediated changes in resting membrane potential and membrane capacitance. Treatment with either 17α-estradiol or cell impermeable estrogen did not mimic the findings seen with estrogen. Glutamate treatment significantly increased both intracellular free Ca2+ and the activities of downstream proteases such as calpain and caspase-3. Estrogen attenuated both the increases in intracellular free Ca2+ and protease activities. In order to determine the pathway responsible for estrogen-mediated inhibition of these increases in intracellular free Ca2+, cells were treated with several Ca2+ entry inhibitors, but only the L-type Ca2+ channel blocker nifedipine demonstrated cytoprotective effects comparable to estrogen. To expand these findings, cells were treated with the L-type Ca2+ channel agonist FPL 64176, which increased both cell death and intracellular free Ca2+, and estrogen inhibited both effects. From these observations, we conclude that estrogen limits glutamate-induced cell death in VSC 4.1 cells through effects on L-type Ca2+ channels, inhibiting Ca2+ influx as well as activation of the pro-apoptotic proteases calpain and caspase-3. PMID:19389388

  1. Estrogen synthesis and signaling pathways during ageing: from periphery to brain

    PubMed Central

    Cui, Jie; Shen, Yong; Li, Rena

    2012-01-01

    Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissue as liver, heart, muscle, bone and brain. The tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. Here, we will focus on tissue and cell-specific estrogen synthesis and estrogen receptor signaling. This review will include three parts: (I) tissue and cell-specific estrogen synthesis and metabolism, (II) tissue and cell-specific distribution of estrogen receptors and signaling and (III) tissue-specific estrogen function and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease and Parkinson disease. This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases. PMID:23348042

  2. Using Fenton Oxidation to Simultaneously Remove Different Estrogens from Cow Manure

    PubMed Central

    Sun, Minxia; Xu, Defu; Ji, Yuefei; Liu, Juan; Ling, Wanting; Li, Shunyao; Chen, Mindong

    2016-01-01

    The presence of estrogens in livestock excrement has raised concerns about their potential negative influence on animals and the overall food cycle. This is the first investigation to simultaneously remove estrogens, including estriol (E3), bisphenol A (BPA), diethylstilbestrol (DES), estradiol (E2), and ethinyl estradiol (EE2), from cow manure using a Fenton oxidation technique. Based on the residual concentrations and removal efficiency of estrogens, the Fenton oxidation reaction conditions were optimized as follows: a H2O2 dosage of 2.56 mmol/g, a Fe(II) to H2O2 molar ratio of 0.125 M/M, a solid to water mass ratio of 2 g/mL, an initial pH of 3, and a reaction time of 24 h. Under these conditions, the simultaneous removal efficiencies of E3, BPA, DES, E2, and EE2, with initial concentrations in cow manure of 97.40, 96.54, 100.22, 95.01, and 72.49 mg/kg, were 84.9%, 99.5%, 99.1%, 97.8%, and 84.5%, respectively. We clarified the possible Fenton oxidation reaction mechanisms that governed the degradation of estrogens. We concluded that Fenton oxidation technique could be effective for efficient removal of estrogens in livestock excrement. Results are of great importance for cow manure reuse in agricultural management, and can be used to reduce the threat of environmental estrogens to human health and ecological safety. PMID:27649223

  3. Estrogen regulates spatially distinct cardiac mitochondrial subpopulations.

    PubMed

    Ribeiro Junior, Rogério Faustino; Rodrigues, Paula Lopes; Morra, Elis Aguiar; Ronconi, Karoline Sousa; Do Val Lima, Patrícia Ribeiro; Porto, Marcella Leite; Simões, Maylla Ronacher; Vassallo, Dalton Valentim; Figueiredo, Suely Gomes; Stefanon, Ivanita

    2017-07-01

    Increased susceptibility to permeability transition pore (mPTP) is a significant concern to decreased cardiac performance in postmenopausal females. The goal of this study was to assess the effects of estrogen deficiency on the two spatially distinct mitochondrial subpopulations from left ventricle: subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IFM) based on: morphology, membrane potential, oxidative phosphorylation, mPTP and reactive oxygen species production. Female rats (8weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with placebo (OVX), estrogen replacement (OVX+E2) and Sham for 60days. The yield for IFM was found higher in the OVX group and lower in the SSM. SSM internal complexity and size were higher in the OVX group, although membrane potential was not different. The maximal rate of mitochondrial respiration, states 3 and 4, using glutamate+malate as substrate, were higher in IFM and SSM from the OVX group. The respiratory control ratio (RCR - state3/state 4), was not different in both SSM and IFM with glutamate+malate. The ADP:O ratio was found lower in IFM and SSM from OVX compared to Sham. When pyruvate was used, state 3 was found unchanged in both IFM and SSM, state 4 was greater in IFM from OVX rats compared to Sham and the ADP/O ratio was decreased. The RCR was unchanged in both subpopulations. The IFM from OVX rats presented a lower Ca 2+ retention capacity compared to Sham, however, the SSM remained unchanged. Hydrogen peroxide formation was found increased in the IFM from OVX animals with glutamate+malate and rotenone+succinate as substrates. The SSM showed increased ROS production only with rotenone+succinate. Western blot analyzes showed decreased levels of PGC-1α and NRF-1 in the OVX group. Estrogen replacement was able to restore most of the alterations induced by ovariectomy. In conclusion, our data shows that estrogen deficiency has distinct effects on the two

  4. Removal of steroid estrogens from wastewater using granular activated carbon: comparison between virgin and reactivated carbon.

    PubMed

    Rowsell, Victoria Francesca; Pang, Dawn Sok Cheng; Tsafou, Foteini; Voulvoulis, Nikolaos

    2009-04-01

    This research was set up in response to new European legislation to identify cost-effective treatment for removal of steroid estrogens from effluent. This study aimed to compare estrogen removal of two types of granular activated carbon: virgin (F400) and reactivated (C401) carbon. Rapid, small-scale column tests were conducted with a total bed volume of 24.9 cm3 over three columns, and analysis was carried out using high-performance liquid chromatography. Results demonstrated that C401 performed more efficiently with greater than or equal to 81% estrogen removal in wastewater compared to F400 which produced greater than or equal to 65% estrogen removal. Estrogen removal can be affected by competitive adsorption from natural organic matter present in wastewater. In addition, the physical properties of each carbon had the potential to influence adsorption differently, thus resulting in the observed varied adsorption capability of the two carbons.

  5. A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements.

    PubMed

    Powers, Chelsea N; Setzer, William N

    2015-01-01

    The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERβ (a total of 27 different protein crystal structures). The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men's herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds. This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.

  6. Developmental estrogen exposures and disruptions to maternal behavior and brain: Effects of ethinyl estradiol, a common positive control.

    PubMed

    Catanese, Mary C; Vandenberg, Laura N

    2017-11-07

    Due of its structural similarity to the endogenous estrogen 17β-estradiol (E2), the synthetic estrogen 17α-ethinyl estradiol (EE2) is widely used to study the effects of estrogenic substances on sensitive organs at multiple stages of development. Here, we investigated the effects of EE2 on maternal behavior and the maternal brain in females exposed during gestation and the perinatal period. We assessed several components of maternal behavior including nesting behavior and pup retrieval; characterized the expression of estrogen receptor (ER)α in the medial preoptic area (MPOA), a brain region critical for the display of maternal behavior; and measured expression of tyrosine hydroxylase, a marker for dopaminergic cells, in the ventral tegmental area (VTA), a brain region important in maternal motivation. We found that developmental exposure to EE2 induces subtle effects on several aspects of maternal behavior including time building the nest and time spent engaged in self-care. Developmental exposure to EE2 also altered ERα expression in the central MPOA during both early and late lactation and led to significantly reduced tyrosine hydroxylase immunoreactivity in the VTA. Our results demonstrate both dose- and postpartum stage-related effects of developmental exposure to EE2 on behavior and brain that manifest later in adulthood, during the maternal period. These findings provide further evidence for effects of exposure to exogenous estrogenic compounds during the critical periods of fetal and perinatal development. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells

    PubMed Central

    2010-01-01

    Background Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens. Methods We studied the effects of low concentrations of endogenous estrogens (estradiol, estriol, and estrone) at 10 pM (representing pre-development levels), and 1 nM (representing higher cycle-dependent and pregnancy levels) in combinations with the same levels of xenoestrogens in GH3/B6/F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio-immunoassay. Extracellular-regulated kinase (1 and 2) phospho-activations and the levels of three estrogen receptors in the cell membrane (ERα, ERβ, and GPER) were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized (respectively). Results All xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation (phosphorylation) of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses. Conclusions Responses mediated by endogenous estrogens representing different life stages are vulnerable to very

  8. Egg wash wastewater: estrogenic risk or environmental asset?

    PubMed

    Shappell, Nancy W

    2013-07-01

    Commercial production of eggs and egg products requires the washing of eggs to remove urinary-fecal material and broken egg residue. In the case of one Ohio farming facility, 1.6 million birds produce 1.4 million eggs per day, using approximately 50 mL of wash water/egg or approximately 70,000 L per day. The aqueous waste stream was evaluated for estrogenicity to determine if potential for endocrine disruption would result from agricultural application of such wastewater. Samples collected the Fall (October) of 2010 included: water from 2 egg washers operating in series, inlet pipe to the treatment lagoon, a lagoon composite, and products used within the facility in the cleaning of equipment and treatment of the waste. In February 2011, the treatment lagoon was fitted with an extensive aeration system and subsequent sample sets were collected on 3 consecutive days in May and November. Samples were extracted by solid phase extraction and assayed for estrogenic activity using the in vitro E-Screen assay. Raw untreated wastewater from the egg washers contained 17β-estradiol equivalents (E2 Eqs) ranging from 9 to 18 ng/L, pipe grab samples entering into the treatment lagoon ranged from <0.14 to 4.4 ng/L (variability related to time of emptying of egg wash tanks), whereas treatment lagoon water contained 0.3 to 4.0 ng/L E2 Eq. Addition of an aeration system to the treatment lagoon eliminated surface "frothing," reduced noxious odor emission, and E2 Eqs were lower than the pre-aeration concentrations (4 ng/L [n = 1, no statistical comparison possible] vs 0.3 to 1.4 ng/L in 2011). Because of matrix effects, estrogens were not quantifiable by LC-MS2 in even egg washwater extracts, at concentrations in which internal deuterated estrogen standards were quantifiable. Estrone and E2 parent ions were detected in egg washwater samples only, and confirmatory ion fragments were detected in only one of these samples. Estrogenicity of the wastewater from the treatment lagoon was

  9. The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

    PubMed Central

    Menazza, Sara; Murphy, Elizabeth

    2016-01-01

    Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to two nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue specific co-activators and co-repressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as GPER to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long term effects. The kinase signaling pathways can also mediate transcriptional changes, and can synergize with the estrogen receptor to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER-membrane signaling mechanisms. PMID:26838792

  10. Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.

    PubMed

    Jameera Begam, A; Jubie, S; Nanjan, M J

    2017-04-01

    Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. The role of estrogens for male bone health.

    PubMed

    Ohlsson, Claes; Vandenput, Liesbeth

    2009-06-01

    Sex steroids are important for the growth and maintenance of both the female and the male skeleton. However, the relative contribution of androgens versus estrogens in the regulation of the male skeleton is unclear. Experiments using mice with inactivated sex steroid receptors demonstrated that both activation of the estrogen receptor (ER)alpha and activation of the androgen receptor result in a stimulatory effect on both the cortical and trabecular bone mass in males. ERbeta is of no importance for the skeleton in male mice while it modulates the ERalpha-action on bone in female mice. Previous in vitro studies suggest that the membrane G protein-coupled receptor GPR30 also might be a functional ER. Our in vivo analyses of GPR30-inactivated mice revealed no function of GPR30 for estrogen-mediated effects on bone mass but it is required for normal regulation of the growth plate and estrogen-mediated insulin-secretion. Recent clinical evidence suggests that a threshold exists for estrogen effects on bone in men: rates of bone loss and fracture risk seem to be the highest in men with estradiol levels below this threshold. Taken together, even though these findings do not exclude an important role for testosterone in male skeletal homeostasis, it is now well-established that estrogens are important regulators of bone health in men.

  12. Potential estrogenic effects of wastewaters on gene expression in Pimephales promelas and fish assemblages in streams of southeastern New York

    USGS Publications Warehouse

    Baldigo, Barry P.; George, Scott D.; Phillips, Patrick J.; Hemming, Joceyln D. C.; Denslow, Nancy D.; Kroll, Kevin J.

    2015-01-01

    Direct linkages between endocrine-disrupting compounds (EDCs) from municipal and industrial wastewaters and impacts on wild fish assemblages are rare. The levels of plasma vitellogenin (Vtg) and Vtg messenger ribonucleic acid (mRNA) in male fathead minnows (Pimephales promelas) exposed to wastewater effluents and dilutions of 17α-ethinylestradiol (EE2), estrogen activity, and fish assemblages in 10 receiving streams were assessed to improve understanding of important interrelations. Results from 4-d laboratory assays indicate that EE2, plasma Vtg concentration, and Vtg gene expression in fathead minnows, and 17β-estradiol equivalents (E2Eq values) were highly related to each other (R2 = 0.98–1.00). Concentrations of E2Eq in most effluents did not exceed 2.0 ng/L, which was possibly a short-term exposure threshold for Vtg gene expression in male fathead minnows. Plasma Vtg in fathead minnows only increased significantly (up to 1136 μg/mL) in 2 wastewater effluents. Fish assemblages were generally unaffected at 8 of 10 study sites, yet the density and biomass of 79% to 89% of species populations were reduced (63–68% were reduced significantly) in the downstream reach of 1 receiving stream. These results, and moderate to high E2Eq concentrations (up to 16.1 ng/L) observed in effluents during a companion study, suggest that estrogenic wastewaters can potentially affect individual fish, their populations, and entire fish communities in comparable systems across New York, USA. 

  13. Triclosan exposure modulates estrogen-dependent responses in the rat uterotrophic assay.

    EPA Science Inventory

    Our previous studies in the juvenile rat indicated that the biocide triclosan may alter steroid hormone levels. Here, we hypothesize that triclosan possesses estrogenic activity. In the first study, we evaluated the potential estrogenicity of triclosan using the immature rat uter...

  14. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens.

    PubMed

    Iwanowicz, Luke R; Stafford, James L; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W; Blazer, Vicki S

    2014-09-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines. Published by Elsevier Ltd.

  15. Leptin influences estrogen metabolism and accelerates prostate cell proliferation.

    PubMed

    Habib, Christine N; Al-Abd, Ahmed M; Tolba, Mai F; Khalifa, Amani E; Khedr, Alaa; Mosli, Hisham A; Abdel-Naim, Ashraf B

    2015-01-15

    The present study was designed to investigate the effect of leptin on estrogen metabolism in prostatic cells. Malignant (PC-3) and benign (BPH-1) human prostate cells were treated with 17-β-hydroxyestradiol (1 μM) alone or in combination with leptin (0.4, 4, 40 ng/ml) for 72 h. Cell proliferation assay, immunocytochemical staining of estrogen receptor (ER), liquid chromatography-tandem mass spectrometry method (LC-MS) and semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) were used. Cell proliferation assay demonstrated that leptin caused significant growth potentiation in both cells. Immunocytochemical staining showed that leptin significantly increased the expression of ER-α and decreased that of ER-β in PC-3 cells. LC-MS method revealed that leptin increased the concentration 4-hydroxyestrone and/or decreased that of 2-methoxyestradiol, 4-methoxyestradiol and 2-methoxyestrone. Interestingly, RT-PCR showed that leptin significantly up-regulated the expression of aromatase and cytochrome P450 1B1 (CYP1B1) enzymes; however down-regulated the expression of catechol-o-methyltransferase (COMT) enzyme. These data indicate that leptin-induced proliferative effect in prostate cells might be partly attributed to estrogen metabolism. Thus, leptin might be a novel target for therapeutic intervention in prostatic disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Estrogenic activity of constituents of underarm deodorants determined by E-Screen assay.

    PubMed

    Lange, Claudia; Kuch, Bertram; Metzger, Jörg W

    2014-08-01

    The purpose of this study was to ascertain whether different kinds of underarm deodorants commercially available in Germany might contain substances with estrogenic potential which after use enter the aquatic environment via wastewater. Twenty five deodorants produced by ten different manufacturers in the form of sprays, roll-ons and sticks were investigated using an in vitro-test system (E-Screen assay) for the determination of estrogenic activity based on the human breast cancer cell line MCF-7. Seven out of ten spray deodorant samples showed a quantifiable estrogenic activity. In the case of the sticks and roll-ons it was only one out of six and one out of nine, respectively. The 17β-estradiol equivalent concentrations (EEQs) of the samples ranged from 0.1 ng g(-1) to 9 ng g(-1) deodorant. Spray deodorant samples showed the highest activities in the E-Screen assay compared to the stick and roll-on deodorants. In order to identify substances possibly contributing to the observed biological activity the samples were additionally analyzed by GC/MS. The obtained results of this non-target screening led to the selection of 62 single substances present in the deodorants which for their part were analyzed by E-Screen assay. Eight of these single substances, all of them fragrances, showed estrogenic effects with estradiol equivalence factors (EEFs) similar to parabens, a group of 4-hydroxybenzoic acid esters commonly used as preservatives in personal care products, which are known to have a slight estrogenic effect. Thus, these fragrances are obviously responsible to a substantial degree for the observed estrogenic activity of the deodorants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Evaluation of a recombinant yeast cell estrogen screening assay.

    PubMed Central

    Coldham, N G; Dave, M; Sivapathasundaram, S; McDonnell, D P; Connor, C; Sauer, M J

    1997-01-01

    A wide range of chemicals with diverse structures derived from plant and environmental origins are reported to have hormonal activity. The potential for appreciable exposure of humans to such substances prompts the need to develop sensitive screening methods to quantitate and evaluate the risk to the public. Yeast cells transformed with plasmids encoding the human estrogen receptor and an estrogen responsive promoter linked to a reporter gene were evaluated for screening compounds for estrogenic activity. Relative sensitivity to estrogens was evaluated by reference to 17 beta-estradiol (E2) calibration curves derived using the recombinant yeast cells, MCF-7 human breast cancer cells, and a prepubertal mouse uterotrophic bioassay. The recombinant yeast cell bioassay (RCBA) was approximately two and five orders of magnitude more sensitive to E2 than MCF-7 cells and the uterotrophic assay, respectively. The estrogenic potency of 53 chemicals, including steroid hormones, synthetic estrogens, environmental pollutants, and phytoestrogens, was measured using the RCBA. Potency values produced with the RCBA relative to E2 (100) included estrone (9.6), diethylstilbestrol (74.3), tamoxifen (0.0047), alpha-zearalanol (1.3), equol (0.085), 4-nonylphenol (0.005), and butylbenzyl phathalate (0.0004), which were similar to literature values but generally higher than those produced by the uterotrophic assay. Exquisite sensitivity, absence of test compound biotransformation, ease of use, and the possibility of measuring antiestrogenic activity are important attributes that argue for the suitability of the RCBA in screening for potential xenoestrogens to evaluate risk to humans, wildlife, and the environment. Images Figure 1. Figure 2. Figure 3. Figure 4. PMID:9294720

  18. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

    PubMed

    Lichtenfels, Martina; Dornelles, Arethuza da Silva; Petry, Fernanda Dos Santos; Blank, Martina; de Farias, Caroline Brunetto; Roesler, Rafael; Schwartsmann, Gilberto

    2017-11-01

    Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

  19. Environmental estrogen(s) induced swimming behavioural alterations in adult zebrafish (Danio rerio).

    PubMed

    Goundadkar, Basavaraj B; Katti, Pancharatna

    2017-09-01

    The present study is an attempt to investigate the effects of long-term (75days) exposure to environmental estrogens (EE) on the swimming behaviour of zebrafish (Danio rerio). Adult zebrafish were exposed semi-statically to media containing commonly detected estrogenic water contaminants (EE2, DES and BPA) at a concentration (5ng/L) much lower than environmentally recorded levels. Time spent in swimming, surface preference, patterns and path of swimming were recorded (6mins) for each fish using two video cameras on day 15, 30 60 and 75. Video clips were analysed using a software program. Results indicate that chronic exposure to EE leads to increased body weight and size of females, reduced (P<0.05) swimming time, delay in latency, increased (P<0.05) immobility, erratic movements and freezing episodes. We conclude that estrogenic contamination of natural aquatic systems induces alterations in locomotor behaviour and associated physiological disturbances in inhabitant fish fauna. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Effect of subacute exposure to lead and estrogen on immature pre-weaning rat leukocytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Villagra, R.; Tchernitchin, N.N.; Tchernitchin, A.N.

    1997-02-01

    Lead is an environmental pollutant known to cause damage to human health, affecting specially the central nervous system, reproductive organs, the immune system and kidney. From the perspective or reproduction, lead affects both men and women. Reported effects in women include infertility, miscarriage, pre-eclampsia, pregnancy hypertension and premature delivery. In experimental animals, lead affects female reproductive organs through different mechanisms. The heavy metal may interact at the enzyme level. It may interfere with the action of reproductive hormones at the target organ, modifying the activity of estrogen receptors in the pregnant uterus and inhibiting responses where estrogens play a role.more » Lead may induce imprinting mechanism, causing persistent changes in uterine estrogen receptors and ovary LH receptors following perinatal exposure. Finally, it may interfere at the level of hypothalamus-pituitary, decreasing pituitary response to growth hormone releasing factor, affecting levels of FSH and LH and increasing blood levels of glucocorticoids, which modify the action of estrogens in the uterus. This study examines the mechanisms of lead-induced interference with female reproductive and immune functions. 33 refs., 2 figs., 2 tabs.« less

  1. Aging, Estrogens, and Episodic Memory in Women

    PubMed Central

    Henderson, Victor W.

    2009-01-01

    Objective To review the relation in midlife and beyond between estrogen exposures and episodic memory in women. Background Episodic memory performance declines with usual aging, and impairments in episodic memory often portend the development of Alzheimer's disease. In the laboratory, estradiol influences hippocampal function and animal learning. However, it is controversial whether estrogens affect memory after a woman's reproductive years. Method Focused literature review, including a summary of a systematic search of clinical trials of estrogens in which outcomes included an objective measure of episodic memory. Results The natural menopause transition is not associated with objective changes in episodic memory. Strong clinical trial evidence indicates that initiating estrogen-containing hormone therapy after about age 60 years does not benefit episodic memory. Clinical trial findings in middle-age women before age 60 are limited by smaller sample sizes and shorter treatment durations, but these also do not indicate substantial memory effects. Limited short-term evidence, however, suggests that estrogens may improve verbal memory after surgical menopause. Although hormone therapy initiation in old age increases dementia risk, observational studies raise the question of an early critical window during which midlife estrogen therapy reduces late-life Alzheimer's disease. However, almost no data address whether midlife estrogen therapy affects episodic memory in old age. Conclusions Episodic memory is not substantially impacted by the natural menopause transition or improved by use of estrogen-containing hormone therapy after age 60. Further research is needed to determine whether outcomes differ after surgical menopause or whether episodic memory later in life is modified by midlife estrogenic exposures. PMID:19996872

  2. Estrogen Receptors Modulation of Anxiety-Like Behavior

    PubMed Central

    Borrow, A.P.; Handa, R.J.

    2018-01-01

    Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens’ effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic–pituitary–adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems. PMID:28061972

  3. Estrogen stimulated migration and invasion of estrogen receptor-negative breast cancer cells involves an ezrin-dependent crosstalk between G protein-coupled receptor 30 and estrogen receptor beta signaling.

    PubMed

    Zhou, Kewen; Sun, Peng; Zhang, Yaxing; You, Xinchao; Li, Ping; Wang, Tinghuai

    2016-07-01

    Estrogen mediates important cellular activities in estrogen receptor negative (ER-) breast cancer cells via membrane associated G protein-coupled receptor 30 (GPR30). However, the biological role and mechanism of estrogen action on cell motility and invasion in this aggressive kind of tumors remains poorly understood. We showed here that treatment with 17β-estradiol (E2) in ER-negative cancer cells resulted in ezrin-dependent cytoskeleton rearrangement and elicited a stimulatory effect on cell migration and invasion. Mechanistically, E2 induced ezrin activation was mediated by distinct mechanisms in different cell contexts. In SK-BR-3 cells with a high GPR30/ERβ ratio, silencing of GPR30 was able to abolish E2 induced ERK1/2, AKT phosphorylation and ezrin activation, whereas in MDA-MB-231 cells with low GPR30/ERβ ratio, E2 stimulated ezrin activation was mediated by the ERβ/PI3K/AKT signaling pathway. Importantly, we showed that activation of GPR30 signaling significantly prevents ERβ activation induced ezrin phosphorylation, cell migration and invasion, indicating an antagonist effect between GPR30 and ERβ signaling in MDA-MB-231 cells. These findings highlight the important interplay between different estrogen receptors in estrogen induced cell motility and invasiveness in ER-negative breast cancer cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Appropriate 'housekeeping' genes for use in expression profiling the effects of environmental estrogens in fish

    PubMed Central

    Filby, Amy L; Tyler, Charles R

    2007-01-01

    Background Attempts to develop a mechanistic understanding of the effects of environmental estrogens on fish are increasingly conducted at the level of gene expression. Appropriate application of real-time PCR in such studies requires the use of a stably expressed 'housekeeping' gene as an internal control to normalize for differences in the amount of starting template between samples. Results We sought to identify appropriate genes for use as internal controls in experimental treatments with estrogen by analyzing the expression of eight functionally distinct 'housekeeping' genes (18S ribosomal RNA [18S rRNA], ribosomal protein l8 [rpl8], elongation factor 1 alpha [ef1a], glucose-6-phosphate dehydrogenase [g6pd], beta actin [bactin], glyceraldehyde-3-phosphate dehydrogenase [gapdh], hypoxanthine phosphoribosyltransferase 1 [hprt1], and tata box binding protein [tbp]) following exposure to the environmental estrogen, 17α-ethinylestradiol (EE2), in the fathead minnow (Pimephales promelas). Exposure to 10 ng/L EE2 for 21 days down-regulated the expression of ef1a, g6pd, bactin and gapdh in the liver, and bactin and gapdh in the gonad. Some of these effects were gender-specific, with bactin in the liver and gapdh in the gonad down-regulated by EE2 in males only. Furthermore, when ef1a, g6pd, bactin or gapdh were used for normalization, the hepatic expression of two genes of interest, vitellogenin (vtg) and cytochrome P450 1A (cyp1a) following exposure to EE2 was overestimated. Conclusion Based on the data presented, we recommend 18S rRNA, rpl8, hprt1 and/or tbp, but not ef1a, g6pd, bactin and/or gapdh, as likely appropriate internal controls in real-time PCR studies of estrogens effects in fish. Our studies show that pre-validation of control genes considering the scope and nature of the experiments to be performed, including both gender and tissue type, is critical for accurate assessments of the effects of environmental estrogens on gene expression in fish. PMID

  5. Rapid effects of dorsal hippocampal G-protein coupled estrogen receptor on learning in female mice.

    PubMed

    Lymer, Jennifer; Robinson, Alana; Winters, Boyer D; Choleris, Elena

    2017-03-01

    Through rapid mechanisms of action, estrogens affect learning and memory processes. It has been shown that 17β-estradiol and an Estrogen Receptor (ER) α agonist enhances performance in social recognition, object recognition, and object placement tasks when administered systemically or infused in the dorsal hippocampus. In contrast, systemic and dorsal hippocampal ERβ activation only promote spatial learning. In addition, 17β-estradiol, the ERα and the G-protein coupled estrogen receptor (GPER) agonists increase dendritic spine density in the CA1 hippocampus. Recently, we have shown that selective systemic activation of the GPER also rapidly facilitated social recognition, object recognition, and object placement learning in female mice. Whether activation the GPER specifically in the dorsal hippocampus can also rapidly improve learning and memory prior to acquisition is unknown. Here, we investigated the rapid effects of infusion of the GPER agonist, G-1 (dose: 50nM, 100nM, 200nM), in the dorsal hippocampus on social recognition, object recognition, and object placement learning tasks in home cage. These paradigms were completed within 40min, which is within the range of rapid estrogenic effects. Dorsal hippocampal administration of G-1 improved social (doses: 50nM, 200nM G-1) and object (dose: 200nM G-1) recognition with no effect on object placement. Additionally, when spatial cues were minimized by testing in a Y-apparatus, G-1 administration promoted social (doses: 100nM, 200nM G-1) and object (doses: 50nM, 100nM, 200nM G-1) recognition. Therefore, like ERα, the GPER in the hippocampus appears to be sufficient for the rapid facilitation of social and object recognition in female mice, but not for the rapid facilitation of object placement learning. Thus, the GPER in the dorsal hippocampus is involved in estrogenic mediation of learning and memory and these effects likely occur through rapid signalling mechanisms. Copyright © 2016 Elsevier Ltd. All rights

  6. Melatonin affects the dynamic steady-state equilibrium of estrogen sulfates in human umbilical vein endothelial cells by regulating the balance between estrogen sulfatase and sulfotransferase.

    PubMed

    González, Alicia; Martínez-Campa, Carlos; Alonso-González, Carolina; Cos, Samuel

    2015-12-01

    Melatonin is known to reduce the growth of endocrine-responsive breast cancers by interacting with estrogen signaling pathways. Estrogens play an important role in breast cancer, but also in various types of tissues, including vascular tissue. Estrogen sulfatase (STS) converts inactive estrogen sulfates into active estrogens, whereas estrogen sulfotransferase (EST) sulfonates estrogens to estrogen sulfates. Therefore, STS and EST are considered to be involved in the regulation of local estrogen levels in hormone‑dependent tumors and in non-pathologic tissues, such as those of the vascular system. Estrogens have a major impact on the vasculature, influencing vascular function, the expression of adhesion proteins, angiogenesis and the inflammatory state. In this study, we investigated the status of STS and EST in human umbilical vein endothelial cells (HUVECs) and the modulatory effects of melatonin. Both STS and EST were highly expressed in the HUVECs. The enzymatic activity correlated with the expression levels in these cells. Our findings also demonstrated that melatonin, at physiological concentrations, modulated the synthesis and transformation of biologically active estrogens in HUVECs through the inhibition of STS activity and expression, and the stimulation of EST activity and expression. Since melatonin decreased the STS levels and increased the EST levels, it modified the dynamic steady‑state equilibrium of estrogen sulfates by increasing the inactive estrogen levels and decreasing the active estrogen levels. Therefore, melatonin may modulate the known different biological actions of estrogens in endothelial cells, as well as in estrogen-dependent tumors and non-pathologic tissues.

  7. Rapid Actions of Xenoestrogens Disrupt Normal Estrogenic Signaling

    PubMed Central

    Watson, Cheryl S.; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A.

    2014-01-01

    Some chemicals used in consumer products or manufacturing (eg. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (eg. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα ) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, Bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities. PMID:24269739

  8. Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein-Coupled Estrogen Receptor.

    PubMed

    Gros, Robert; Hussain, Yasin; Chorazyczewski, Jozef; Pickering, J Geoffrey; Ding, Qingming; Feldman, Ross D

    2016-11-01

    Estrogens are important regulators of cardiovascular function. Some of estrogen's cardiovascular effects are mediated by a G-protein-coupled receptor mechanism, namely, G-protein-coupled estrogen receptor (GPER). Estradiol-mediated regulation of vascular cell programmed cell death reflects the balance of the opposing actions of GPER versus estrogen receptor α (ERα). However, the significance of these opposing actions on the regulation of vascular smooth muscle cell proliferation or migration in vitro is unclear, and the significance in vivo is unknown. To determine the effects of GPER activation in vitro, we studied rat aortic vascular smooth muscle cells maintained in primary culture. GPER was reintroduced using adenoviral gene transfer. Both estradiol and G1, a GPER agonist, inhibited both proliferation and cell migration effects that were blocked by the GPER antagonist, G15. To determine the importance of the GPER-ERα balance in regulating vascular remodeling in a rat model of carotid ligation, we studied the effects of upregulation of GPER expression versus downregulation of ERα. Reintroduction of GPER significantly attenuated the extent of medial hypertrophy and attenuated the extent of CD45 labeling. Downregulation of ERα expression comparably attenuated the extent of medial hypertrophy and inflammation after carotid ligation. These studies demonstrate that the balance between GPER and ERα regulates vascular remodeling. Receptor-specific modulation of estrogen's effects may be an important new approach in modifying vascular remodeling in both acute settings like vascular injury and perhaps in longer term regulation like in hypertension. © 2016 American Heart Association, Inc.

  9. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

    PubMed

    Xu, Xiaohong; Gu, Ting; Shen, Qiaoqiao

    2015-03-01

    Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen. © 2014 International Society for Neurochemistry.

  10. Estrogens and women's health: interrelation of coronary heart disease, breast cancer and osteoporosis.

    PubMed

    Kuller, L H; Matthews, K A; Meilahn, E N

    2000-11-30

    The determinants of blood levels of estrogen, estrogen metabolites, and relation to receptors and post-transitional effects are the likely primary cause of breast cancer. Very high risk women for breast cancer can now be identified by measuring bone mineral density and hormone levels. These high risk women have rates of breast cancer similar to risk of myocardial infarction. They are candidates for SERM therapies to reduce risk of breast cancer. The completion of the Women's Health Initiative and other such trials will likely provide a definite association of risk and benefit of both estrogen alone and estrogen-progesterone therapy, coronary heart disease, osteoporotic fracture, and breast cancer. The potential intervention of hormone replacement therapy, obesity, or weight gain and increased atherogenic lipoproteinemia may be of concern and confound the results of clinical trials. Estrogens, clearly, are important in the risk of bone loss and osteoporotic fracture. Obesity is the primary determinant of postmenopausal estrogen levels and reduced risk of fracture. Weight reduction may increase rates of bone loss and fracture. Clinical trials that evaluate weight loss should monitor effects on bone. The beneficial addition of increased physical activity, higher dose of calcium or vitamin D, or use of bone reabsorption drugs in coordination with weight loss should be evaluated. Any therapy that raises blood estrogen or metabolite activity and decreases bone loss may increase risk of breast cancer. Future clinical trials must evaluate multiple endpoints such as CHD, osteoporosis, and breast cancer within the study. The use of surrogate markers such as bone mineral density, coronary calcium, carotid intimal medial thickness and plaque, endothelial function, breast density, hormone levels and metabolites could enhance the evaluation of risk factors, genetic-environmental intervention, and new therapies.

  11. DEVELOPMENT OF A QUANTITATIVE ASSAY FOR VITELLOGENIN TO MONITOR ESTROGEN-LIKE ENVIRONMENTAL CONTAMINANTS

    EPA Science Inventory

    Many environmental contaminants have the potential to disrupt endocrine systems of wildlife and humans resulting in impairment of reproductive and other systems. A subset of these contaminants may initiate these effects by binding to the estrogen receptor. In oviparous vertebrate...

  12. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to environmental water samples.

    PubMed

    Gorelick, Daniel A; Iwanowicz, Luke R; Hung, Alice L; Blazer, Vicki S; Halpern, Marnie E

    2014-04-01

    Environmental endocrine disruptors (EEDs) are exogenous chemicals that mimic endogenous hormones such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ERs) in the larval heart compared with the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit tissue-specific effects similar to those of BPA and genistein, or why some compounds preferentially target receptors in the heart. We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of ER genes by RNA in situ hybridization. We observed selective patterns of ER activation in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue specificity in ER activation was due to differences in the expression of ER subtypes. ERα was expressed in developing heart valves but not in the liver, whereas ERβ2 had the opposite profile. Accordingly, subtype-specific ER agonists activated the reporter in either the heart valves or the liver. The use of 5xERE:GFP transgenic zebrafish revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero was associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

  13. N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth.

    PubMed

    Cao, Wenqing; Ma, ZhiFan; Rasenick, Mark M; Yeh, ShuYan; Yu, JiangZhou

    2012-01-01

    Although evidence has shown the regulating effect of n-3 poly-unsaturated fatty acid (n-3 PUFA) on cell signaling transduction, it remains unknown whether n-3 PUFA treatment modulates estrogen signaling. The current study showed that docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) shifted the pro-survival and proliferative effect of estrogen to a pro-apoptotic effect in human breast cancer (BCa) MCF-7 and T47D cells. 17 β-estradiol (E2) enhanced the inhibitory effect of n-3 PUFAs on BCa cell growth. The IC50 of DHA or EPA in MCF-7 cells decreased when combined with E2 (10 nM) treatment (from 173 µM for DHA only to 113 µM for DHA+E2, and from 187 µm for EPA only to 130 µm for EPA+E2). E2 also augmented apoptosis in n-3 PUFA-treated BCa cells. In contrast, in cells treated with stearic acid (SA, C18:0) as well as cells not treated with fatty acid, E2 promoted breast cancer cell growth. Classical (nuclear) estrogen receptors may not be involved in the pro-apoptotic effects of E2 on the n-3 PUFA-treated BCa cells because ERα agonist failed to elicit, and ERα knockdown failed to block E2 pro-apoptotic effects. Subsequent studies reveal that G protein coupled estrogen receptor 1 (GPER1) may mediate the pro-apoptotic effect of estrogen. N-3 PUFA treatment initiated the pro-apoptotic signaling of estrogen by increasing GPER1-cAMP-PKA signaling response, and blunting EGFR, Erk 1/2, and AKT activity. These findings may not only provide the evidence to link n-3 PUFAs biologic effects and the pro-apoptotic signaling of estrogen in breast cancer cells, but also shed new insight into the potential application of n-3 PUFAs in BCa treatment.

  14. Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.

    PubMed

    Ono, Hiroko; Nakamura, Atsushi; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Shinohara, Shunji

    2016-02-15

    Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Electrochemical estrogen screen method based on the electrochemical behavior of MCF-7 cells.

    PubMed

    Li, Jinlian; Song, Jia; Bi, Sheng; Zhou, Shi; Cui, Jiwen; Liu, Jiguang; Wu, Dongmei

    2016-08-05

    It was an urgent task to develop quick, cheap and accurate estrogen screen method for evaluating the estrogen effect of the booming chemicals. In this study, the voltammetric behavior between the estrogen-free and normal fragmented MCF-7 cell suspensions were compared, and the electrochemical signal (about 0.68V attributed by xanthine and guanine) of the estrogen-free fragmented MCF-7 cell suspension was obviously lower than that of the normal one. The electrochemistry detection of ex-secretion purines showed that the ability of ex-secretion purines of cells sharp decreased due to the removing of endogenous estrogen. The results indicated that the electrochemical signal of MCF-7 cells was related to the level of intracellular estrogen. When the level of intracellular estrogen was down-regulated, the concentrations of the xanthine and hypoxanthine decreased, which led to the electrochemical signal of MCF-7 cells fall. Based on the electrochemical signal, the electrochemical estrogen screen method was established. The estrogen effect of estradiol, nonylphenol and bisphenol A was evaluated with the electrochemical method, and the result was accordant with that of MTT assay. The electrochemical estrogen screen method was simple, quickly, cheap, objective, and it exploits a new way for the evaluation of estrogenic effects of chemicals. Copyright © 2016. Published by Elsevier B.V.

  16. Brain Sex Matters: estrogen in cognition and Alzheimer’s disease

    PubMed Central

    Li, Rena; Cui, Jie; Shen, Yong

    2014-01-01

    Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and the brain. During the past decade, increasing evidence suggests that brain estrogen can not only be synthesized by neurons, but also by astrocytes. Brain estrogen also works locally at the site of synthesis in paracrine and/or intracrine fashion to maintain important tissue-specific functions. Here, we will focus on the biology of brain estrogen and its impact on cognitive function and Alzheimer’s disease. This comprehensive review provides new insights into brain estrogens by presenting a better understanding of the tissue-specific estrogen effects and their roles in healthy ageing and cognitive function. PMID:24418360

  17. Hyperestrogenemia and presence of estrogen receptors associated with an epithelial ovarian tumor of low malignant potential.

    PubMed

    Ben-Hur, H; Dgani, R; Insler, V; Lifschitz-Mercer, B; Blickstein, I; Mor, G; Kohen, F; Shani, A; Biran, H

    1996-01-01

    An 80-year-old woman presented with breast congestion, tenderness and pain. Mammography was normal. Circulating estradiol was markedly elevated, while LH and FSH were low. Pelvic examination and imaging revealed an ovarian mass which was extirpated during total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed an ovarian mucinous cystadenocarcinoma of low malignant potential, stage 1. The tumor was positively stained for estrogen receptors. Estradiol levels returned to normal post-operatively, with a corresponding adjustment of LH/FSH. Possible autocrine steroid production is discussed.

  18. Impact of Estrogens and Estrogen Receptor Alpha (ESR1) in Brain Lipid Metabolism.

    PubMed

    Morselli, Eugenia; de Souza Santos, Roberta; Gao, Su; Ávalos, Yenniffer; Criollo, Alfredo; Palmer, Biff F; Clegg, Deborah J

    2018-03-06

    Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system.

  19. Development of Novel Peptide Inhibitors of the Estrogen Receptor

    DTIC Science & Technology

    1997-10-01

    plasmids used for the transfection experiments described below included pERE-TK- CAT , an estrogen responsive chloramphenicol acetylase reporter plasmid...The inhibitory potential of expressed fragments of ER were assessed by measuring the activity of chloramphenicol acetyltransferase ( CAT ) enzyme...with an ER expression plasmid (pCMV-ER) and an estrogen-responsive reporter plasmid (pERE-TK- CAT ) in order to look for inhibition of an ER mediated

  20. Screening for estrogenic and antiestrogenic activities of plants growing in Egypt and Thailand

    PubMed Central

    El-Halawany, Ali M.; El Dine, Riham Salah; Chung, Mi Hwa; Nishihara, Tsutomu; Hattori, Masao

    2011-01-01

    Background: There is a growing demand for the discovery of new phytoestrogens to be used as a safe and effective hormonal replacement therapy. Materials and Methods: The methanol extracts of 40 plants from the Egyptian and Thailand folk medicines were screened for their estrogen agonist and antagonist activities. The estrogenic and antiestrogenic effects of the tested extracts were carried out using the yeast two-hybrid assay system expressing ERα and ERβ. In addition, all the extracts were subjected to a naringinase treatment and retested for their estrogenic activity. Results: The methanol extracts of Derris reticulata and Dracaena lourieri showed the most potent estrogenic activity on both estrogen-receptor subtypes, while, the methanol extracts of Butea monosperma, Erythrina fusca, and Dalbergia candenatensis revealed significant estrogenic activity on ERβ only. Nigella sativa, Sophora japonica, Artabotrys harmandii, and Clitorea hanceana showed estrogenic effect only after naringinase treatment. The most potent antiestrogenic effect was revealed by Aframomum melegueta, Dalbergia candenatensis, Dracena loureiri, and Mansonia gagei. PMID:21772754

  1. Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial.

    PubMed

    Schmitz, Kathryn H; Williams, Nancy I; Kontos, Despina; Domchek, Susan; Morales, Knashawn H; Hwang, Wei-Ting; Grant, Lorita L; DiGiovanni, Laura; Salvatore, Domenick; Fenderson, Desire'; Schnall, Mitchell; Galantino, Mary Lou; Stopfer, Jill; Kurzer, Mindy S; Wu, Shandong; Adelman, Jessica; Brown, Justin C; Good, Jerene

    2015-11-01

    Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise <75 min/week. Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.

  2. Erythrina excelsa exhibits estrogenic effects in vivo and in vitro and is cytotoxic on breast and colon cancer cell lines.

    PubMed

    Tchoukouegno Ngueu, Sadrine; Tchoumtchoua, Job; Njamen, Dieudonné; Halabalaki, Maria; Laudenbach-Leschowski, Ute; Diel, Patrick

    2016-01-01

    Eythrina excelsa Baker (Fabaceae) is a medicinal plant used to treat various ailments including those of the female genital tract. The objective of this study is to investigate the estrogenic and cytotoxic effects of the ethanol extract of the stem bark of E. excelsa. Erythrina excelsa was evaluated in vitro using the yeast estrogen screen (YES). The extract was then tested in a 3-day uterotrophic assay on ovariectomised Wistar rats at doses of 50 and 100 mg/kg BW/d. Cytotoxic effects were assessed on breast (MCF-7) and colon (HT-29) cancer cell lines using the MTT cell viability assay. Additionally, a LC-PDA-ESI (+)-HRMS and HRMS/MS method was developed and applied for the identification of representative secondary metabolites scaffolds in the extract. In the YES, the extract stimulated the transactivation of the estrogen receptor in a dose-dependent manner with an EC50 value of 1.8 μg/mL. In rats, E. excelsa increased uterine wet weight, uterine epithelial height, and the mRNA expression of estrogen-responsive genes in the uterus and liver at 50 whereas at 100 mg/kg BW/d anti-estrogenic effects were observed. In the MTT-assay, a dose-dependent decrease of the viability of both cell lines was observed with EC50 values of 13.6 μg/mL (MCF-7) and 27.7 μg/mL (HT-29). The phytochemical analysis revealed that the extract is rich in isoflavonoids, mainly prenylated and pyran-derivatives thereof. Erythrina excelsa is rich in prenylated and pyran-substituted isoflavonoids, exhibits estrogenic/anti-estrogenic and cytotoxic effects and warrant sufficient interest for deeper investigations.

  3. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. Conclusion Given the established role for IL-6 in ERα-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer. PMID:26893580

  4. Estrogenic effect of leachates and soil extracts from lysimeters spiked with sewage sludge and reference endocrine disrupters.

    PubMed

    Dizer, Halim; Fischer, Birgit; Sepulveda, Isabel; Loffredo, Elisabetta; Senesi, Nicola; Santana, Fernando; Hansen, Peter-D

    2002-01-01

    Several experiments were conducted to evaluate the behavior and performance of some potential endocrine disrupters (ECDs). Two in vitro screening assays, one based on MCF7-cell proliferation (E-screen test) and the other on estrogenic receptor activity [enzyme-linked receptor assay (ELRA)], were used for the tests, which were done in lysimeters 80 cm in diameter with depth of 30 cm (shallow) or 90 cm (deep). A sandy soil was used to fill in all lysimeters, which were spiked on the surface with either: (a) a sewage sludge (SS) at a dose equivalent to 20 tons ha-1; (b) a mixture of reference ECDs, comprising 17 alpha- and 17 beta-estradiol (E2), nonylphenol, octylphenol, and bisphenol A at doses 100 times higher than the maximum concentrations respectively found in the applied SS; or (c) a mixture of ECDs and SS. After percolation of the lysimeters with rain and/or artificial water, five leachates were sampled from each lysimeter during a period of 210 days. Immediately after the lysimeter percolation experiments, four and six soil fractions were dissected from, respectively, the 30-cm and 90-cm lysimeters and extracted by water. Both the leachate and soil extract samples were analyzed for their estrogenicity using the assays indicated above. The E-screen assay was highly sensitive only for some leachate and extract samples but gave no response for most leachates and soil extracts. The results of the ELRA assay suggests a significantly higher estrogenicity of leachate samples from shallow lysimeters compared with that of leachates from deep lysimeters. In contrast, the estrogenic effect measured for soil extracts of shallow lysimeters was lower than that measured for soil extracts of deep lysimeters. The results of the E-screen assay suggests the occurrence of a fast mobilization of applied ECDs and a moderate retardation effect of native ECDs contained in applied SS in the sandy soil used in the lysimeters. In lysimeters spiked with a mixture of SS and ECDs, the

  5. Exogenous Estrogen as Mediator of Racial Differences in Bioactive Insulin-Like Growth Factor-I Levels Among Postmenopausal Women

    PubMed Central

    Vitolins, Mara Z.; Paskett, Electra D.; Chang, Shine

    2015-01-01

    Background. The role of exogenous estrogen use in racial differences in insulin-like growth factor-I (IGF-I) levels which affect cancer risk is unclear. We investigated whether the relationship between race and circulating bioactive IGF-I proteins was mediated by exogenous estrogen and the extent to which exogenous estrogen influenced the race–IGF-I relationship in postmenopausal women. Methods. This cross-sectional study included 636 white and 133 African American postmenopausal women enrolled in an ancillary study of the Women’s Health Initiative Observational Study. To assess exogenous estrogen use (nonusers [n = 262] vs users [n = 507]) as a mediator of the race–IGF-I relationship, we used the Baron–Kenny method and an estimation of the proportional change in the odd ratios for IGF-I levels on race plus a bootstrapping test for the significance of the mediation effect. Results. Compared with white women, African American women were more likely to have high IGF-I levels and less likely to use exogenous estrogen. After accounting for race, estrogen nonusers had higher IGF-I levels than estrogen users did. Among oral contraceptive ever users, exogenous estrogen had a strong mediation effect (67%; p = .018) in the race–IGF-I relationship. In the women with a history of hypertension, exogenous estrogen explained racial differences in IGF-I levels to a modest degree (23%; p = .029). Conclusions. Exogenous estrogen use has a potentially important role in disparities in IGF-I bioactivity between postmenopausal African American and white women. A history of oral contraceptive use and hypertension may be part of the interconnected hormonal pathways related to racial differences in IGF-I levels. PMID:25238773

  6. Breast density and parenchymal texture measures as potential risk factors for estrogen-receptor positive breast cancer

    NASA Astrophysics Data System (ADS)

    Keller, Brad M.; Chen, Jinbo; Conant, Emily F.; Kontos, Despina

    2014-03-01

    Accurate assessment of a woman's risk to develop specific subtypes of breast cancer is critical for appropriate utilization of chemopreventative measures, such as with tamoxifen in preventing estrogen-receptor positive breast cancer. In this context, we investigate quantitative measures of breast density and parenchymal texture, measures of glandular tissue content and tissue structure, as risk factors for estrogen-receptor positive (ER+) breast cancer. Mediolateral oblique (MLO) view digital mammograms of the contralateral breast from 106 women with unilateral invasive breast cancer were retrospectively analyzed. Breast density and parenchymal texture were analyzed via fully-automated software. Logistic regression with feature selection and was performed to predict ER+ versus ER- cancer status. A combined model considering all imaging measures extracted was compared to baseline models consisting of density-alone and texture-alone features. Area under the curve (AUC) of the receiver operating characteristic (ROC) and Delong's test were used to compare the models' discriminatory capacity for receptor status. The density-alone model had a discriminatory capacity of 0.62 AUC (p=0.05). The texture-alone model had a higher discriminatory capacity of 0.70 AUC (p=0.001), which was not significantly different compared to the density-alone model (p=0.37). In contrast the combined density-texture logistic regression model had a discriminatory capacity of 0.82 AUC (p<0.001), which was statistically significantly higher than both the density-alone (p<0.001) and texture-alone regression models (p=0.04). The combination of breast density and texture measures may have the potential to identify women specifically at risk for estrogen-receptor positive breast cancer and could be useful in triaging women into appropriate risk-reduction strategies.

  7. Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2.

    PubMed

    Brufani, Mario; Rizzi, Nicoletta; Meda, Clara; Filocamo, Luigi; Ceccacci, Francesca; D'Aiuto, Virginia; Bartoli, Gabriele; Bella, Angela La; Migneco, Luisa M; Bettolo, Rinaldo Marini; Leonelli, Francesca; Ciana, Paolo; Maggi, Adriana

    2017-05-31

    Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17β-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17β-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

  8. GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight.

    PubMed

    Vogel, Heike; Wolf, Stefanie; Rabasa, Cristina; Rodriguez-Pacheco, Francisca; Babaei, Carina S; Stöber, Franziska; Goldschmidt, Jürgen; DiMarchi, Richard D; Finan, Brian; Tschöp, Matthias H; Dickson, Suzanne L; Schürmann, Annette; Skibicka, Karolina P

    2016-11-01

    The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  9. Estrogen regulation of chicken riboflavin carrier protein gene is mediated by ERE half sites without direct binding of estrogen receptor.

    PubMed

    Bahadur, Urvashi; Ganjam, Goutham K; Vasudevan, Nandini; Kondaiah, Paturu

    2005-02-28

    Estrogen is an important steroid hormone that mediates most of its effects on regulation of gene expression by binding to intracellular receptors. The consensus estrogen response element (ERE) is a 13bp palindromic inverted repeat with a three nucleotide spacer. However, several reports suggest that many estrogen target genes are regulated by diverse elements, such as imperfect EREs and ERE half sites (ERE 1/2), which are either the proximal or the distal half of the palindrome. To gain more insight into ERE half site-mediated gene regulation, we used a region from the estrogen-regulated chicken riboflavin carrier protein (RCP) gene promoter that contains ERE half sites. Using moxestrol, an analogue of estrogen and transient transfection of deletion and mutation containing RCP promoter/reporter constructs in chicken hepatoma (LMH2A) cells, we identified an estrogen response unit (ERU) composed of two consensus ERE 1/2 sites and one non-consensus ERE 1/2 site. Mutation of any of these sites within this ERU abolishes moxestrol response. Further, the ERU is able to confer moxestrol responsiveness to a heterologous promoter. Interestingly, RCP promoter is regulated by moxestrol in estrogen responsive human MCF-7 cells, but not in other cell lines such as NIH3T3 and HepG2 despite estrogen receptor-alpha (ER-alpha) co transfection. Electrophoretic mobility shift assays (EMSAs) with promoter regions encompassing the half sites and nuclear extracts from LMH2A cells show the presence of a moxestrol-induced complex that is abolished by a polyclonal anti-ERalpha antibody. Surprisingly, estrogen receptor cannot bind to these promoter elements in isolation. Thus, there appears to be a definite requirement for some other factor(s) in addition to estrogen receptor, for the generation of a suitable response of this promoter to estrogen. Our studies therefore suggest a novel mechanism of gene regulation by estrogen, involving ERE half sites without direct binding of ER to the

  10. Estrogen Metabolites Are Not Associated With Colorectal Cancer Risk In Postmenopausal Women

    PubMed Central

    Falk, Roni T.; Dallal, Cher M.; Lacey, James V.; Bauer, Douglas C.; Buist, Diana SM; Cauley, Jane A.; Hue, Trisha F.; LaCroix, Andrea; Tice, Jeffrey A.; Pfeiffer, Ruth M.; Xu, Xia; Veenstra, Timothy D.; Brinton, Louise A.

    2015-01-01

    Background A potential protective role for estrogen in colon carcinogenesis has been suggested based on exogenous hormone use, but it is unclear from previous studies whether endogenous estrogens are related to colorectal cancer (CRC) risk. These few prior studies focused on parent estrogens; none evaluated effects of estrogen metabolism in postmenopausal women. Methods We followed 15,595 women (ages 55–80) enrolled in B~FIT (Breast and Bone Follow-up to the Fracture Intervention Trial (FIT)) who donated blood between 1992 and 1993 for cancer through December 2004. A panel of 15 estrogen metabolites (EM), including estradiol and estrone, were measured in serum from 187 CRC cases and a subcohort of 501 women not using exogenous hormones at blood draw. We examined EM individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 position), and by ratios of the groupings using Cox proportional hazards regression models. Results No significant associations were seen for estrone (HRQ4 v Q1=1.15, 95% CI=0.69–1.93, ptrend=0.54), estradiol (HRQ4 v Q1= 0.98, 95% CI=0.58–1.64, ptrend>0.99) or total EM (the sum of all EM; HRQ4 v Q1=1.35. 95% CI=0.81–2.24, ptrend=0.33). Most metabolites in the 2-, 4- or 16-pathway were unrelated to risk, although a borderline trend in risk was associated with high levels of 17-epiestriol. Conclusion Circulating estrogens and their metabolites were generally unrelated to CRC risk in postmenopausal women. Impact Additional studies are needed to understand how exogenous estrogen may prevent CRC PMID:26104910

  11. Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma

    PubMed Central

    Sareddy, Gangadhara R.; Li, Xiaonan; Liu, Jinyou; Viswanadhapalli, Suryavathi; Garcia, Lauren; Gruslova, Aleksandra; Cavazos, David; Garcia, Mike; Strom, Anders M.; Gustafsson, Jan-Ake; Tekmal, Rajeshwar Rao; Brenner, Andrew; Vadlamudi, Ratna K.

    2016-01-01

    Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM. PMID:27126081

  12. Hepatic gene expression patterns following trauma-hemorrhage: effect of posttreatment with estrogen.

    PubMed

    Yu, Huang-Ping; Pang, See-Tong; Chaudry, Irshad H

    2013-01-01

    The aim of this study was to examine the role of estrogen on hepatic gene expression profiles at an early time point following trauma-hemorrhage in rats. Groups of injured and sham controls receiving estrogen or vehicle were killed 2 h after injury and resuscitation, and liver tissue was harvested. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. A large number of genes were differentially expressed at the 2-h time point in injured animals with or without estrogen treatment. The upregulation or downregulation of a cohort of 14 of these genes was validated by reverse transcription-polymerase chain reaction. This large-scale microarray analysis shows that at the 2-h time point, there is marked alteration in hepatic gene expression following trauma-hemorrhage. However, estrogen treatment attenuated these changes in injured animals. Pathway analysis demonstrated predominant changes in the expression of genes involved in metabolism, immunity, and apoptosis. Upregulation of low-density lipoprotein receptor, protein phosphatase 1, regulatory subunit 3C, ring-finger protein 11, pyroglutamyl-peptidase I, bactericidal/permeability-increasing protein, integrin, αD, BCL2-like 11, leukemia inhibitory factor receptor, ATPase, Cu transporting, α polypeptide, and Mk1 protein was found in estrogen-treated trauma-hemorrhaged animals. Thus, estrogen produces hepatoprotection following trauma-hemorrhage likely via antiapoptosis and improving/restoring metabolism and immunity pathways.

  13. (Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meeuwen, J.A. van; Korthagen, N.; Jong, P.C. de

    In the public opinion, phytochemicals (PCs) present in the human diet are often considered beneficial (e.g. by preventing breast cancer). Two possible mechanisms that could modulate tumor growth are via interaction with the estrogen receptor (ER) and inhibition of aromatase (CYP19). Multiple in vitro studies confirmed that these compounds act estrogenic, thus potentially induce tumor growth, as well as aromatase inhibitory, thus potentially reduce tumor growth. It is thought that in the in vivo situation breast epithelial (tumor) cells communicate with surrounding connective tissue by means of cytokines, prostaglandins and estradiol forming a complex feedback mechanism. Recently our laboratory developedmore » an in vitro co-culture model of healthy mammary fibroblasts and MCF-7 cells that (at least partly) simulated this feedback mechanism (M. Heneweer et al., TAAP vol. 202(1): 50-58, 2005). In the present study biochanin A, chrysin, naringenin, apigenin, genistein and quercetin were studied for their estrogenic properties (cell proliferation, pS2 mRNA) and aromatase inhibition in MCF-7 breast tumor cells, healthy mammary fibroblasts and their co-culture. The proliferative potency of these compounds in the MCF-7 cells derived from their EC{sub 50}s decreased in the following order: estadiol (4*10{sup -3} nM) > biochanin A (9 nM) > genistein (32 nM) > testosterone (46 nM) > naringenin (287 nM) > apigenin (440 nM) > chrysin (4 {mu}M). The potency to inhibit aromatase derived from their IC{sub 50}s decreased in the following order: chrysin (1.5 {mu}M) > naringenin (2.2 {mu}M) > genistein (3.6 {mu}M) > apigenin (4.1 {mu}M) > biochanin A (25 {mu}M) > quercetin (30 {mu}M). The results of these studies show that these PCs can induce cell proliferation or inhibit aromatase in the same concentration range (1-10 {mu}M). Results from co-cultures did not elucidate the dominant effect of these compounds. MCF-7 cell proliferation occurs at concentrations that are not uncommon

  14. Estrogen biology: new insights into GPER function and clinical opportunities.

    PubMed

    Prossnitz, Eric R; Barton, Matthias

    2014-05-25

    Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen's rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and the activity of clinically used drugs, such as SERMs and SERDs, in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. A preliminary risk assessment of potential exposure to naturally occurring estrogens from Beijing (China) market milk products.

    PubMed

    Chen, Chen; Mi, Xiaoxia; Yuan, Yuwei; Chen, Gang; Ren, Li; Wang, Kaiqiang; Zhu, Dan; Qian, Yongzhong

    2014-09-01

    This study was conducted to determine the occurrence of the natural steroid hormones estrone (E1), 17α-estradiol (αE2), 17β-estradiol (βE2) and estriol (E3) in 38 commercial milk samples obtained from markets in Beijing, China. Liquid Chromatography coupled with tandem mass spectrometry (LC-MS/MS) was employed to determine estrogens levels. The concentrations of E1, αE2, βE2 and E3 in different milk products varied from 0-146.12 ng/L, 0-70.12 ng/L, 0-31.85 ng/L to 0-2.18 ng/L, respectively. We compared exposures to estrogens through milk consumption with acceptable daily intakes (ADIs) and threshold for toxicological concern (TTC) to determine whether estrogen intakes from milk consumption are larger or smaller than the toxicity-based benchmarks. The combined margin of safety MOS (MOST) for total estrogens are about 72-99, 118-161, 539-1104, for 2-4, 4-7 year-old residential children, and adults, respectively. The lowest MOST for children of 2-4 years old result from comparing total of estrogens with the lowest TTC value (0.15 μg/person/day) (MOS=3.5). The MOS values suggest that the individual and total estrogens that may present in milk are not causing a health risk for the local residents, including young children. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Transgenic Zebrafish Reveal Tissue-Specific Differences in Estrogen Signaling in Response to Environmental Water Samples

    PubMed Central

    Iwanowicz, Luke R.; Hung, Alice L.; Blazer, Vicki S.; Halpern, Marnie E.

    2014-01-01

    Background: Environmental endocrine disruptors (EEDs) are exogenous chemicals that mimic endogenous hormones such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ERs) in the larval heart compared with the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit tissue-specific effects similar to those of BPA and genistein, or why some compounds preferentially target receptors in the heart. Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of ER genes by RNA in situ hybridization. Results: We observed selective patterns of ER activation in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue specificity in ER activation was due to differences in the expression of ER subtypes. ERα was expressed in developing heart valves but not in the liver, whereas ERβ2 had the opposite profile. Accordingly, subtype-specific ER agonists activated the reporter in either the heart valves or the liver. Conclusion: The use of 5xERE:GFP transgenic zebrafish revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero was associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves. Citation: Gorelick DA, Iwanowicz LR, Hung AL, Blazer VS, Halpern ME. 2014. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to

  17. A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis.

    PubMed

    Filardo, Edward J

    2018-02-01

    Mechanisms of carcinogenesis by estrogen center on its mitogenic and genotoxic potential on tumor target cells. These models suggest that estrogen receptor (ER) signaling promotes expansion of the transformed population and that subsequent accumulation of somatic mutations that drive cancer progression occur via metabolic activation of cathecol estrogens or by epigenetic mechanisms. Recent findings that GPER is linked to obesity, vascular pathology and immunosuppression, key events in the development of metabolic syndrome and intra-tissular estrogen synthesis, provides an alternate view of estrogen-induced carcinogenesis. Consistent with this concept, GPER is directly associated with clinicopathological indices that predict cancer progression and poor survival in breast and gynecological cancers. Moreover, GPER manifests cell biological responses and a microenvironment conducive for tumor development and cancer progression, regulating cellular responses associated with glandular homeostasis and survival, invading surrounding tissue and attracting a vascular supply. Thus, the cellular actions attributed to GPER fit well with the known molecular mechanisms of G-protein coupled receptors, GPCRs, namely, their ability to transactivate integrins and EGF receptors and alter the interaction between glandular epithelia and their extracellular environment, affecting epithelial-to-mesenchymal transition (EMT) and allowing for tumor cell survival and dissemination. This perspective reviews the molecular and cellular responses manifested by GPER and evaluates its contribution to female reproductive cancers as diseases that progress as a result of dysregulated glandular homeostasis resulting in chronic inflammation and metastasis. This review is organized in sections as follows: I) a brief synopsis of the current state of knowledge regarding estrogen-induced carcinogenesis, II) a review of evidence from clinical and animal-based studies that support a role for GPER in cancer

  18. Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

    EPA Science Inventory

    Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in “BPA-free” products. We have compared estrogeni...

  19. Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells.

    PubMed

    Jiang, Cheng; Guo, Junming; Wang, Zhe; Xiao, Bingxiu; Lee, Hyo-Jung; Lee, Eun-Ok; Kim, Sung-Hoon; Lu, Junxuan

    2007-01-01

    Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Attenuating ER activities by natural products is a promising strategy to decrease breast cancer risk. We recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) have potent novel antiandrogen receptor signaling activities. Because the ER and the androgen receptor belong to the steroid receptor superfamily, we examined whether these compounds affected ER expression and signaling in breast cancer cells. We treated estrogen-dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells with decursin and DA, and examined cell growth, apoptosis, and ERalpha and ERbeta expression in both cell lines - and, in particular, estrogen-stimulated signaling in the MCF-7 cells. We compared these compounds with decursinol to determine their structure-activity relationship. Decursin and DA exerted growth inhibitory effects on MCF-7 cells through G1 arrest and caspase-mediated apoptosis. These compounds decreased ERalpha in MCF-7 cells at both mRNA and protein levels, and suppressed estrogen-stimulated genes. Decursin and the pure antiestrogen Faslodex exerted an additive growth inhibitory effect on MCF-7 cells. In MDA MB-231 cells, these compounds induced cell-cycle arrests in the G1 and G2 phases as well as inducing apoptosis, accompanied by an increased expression of ERbeta. In contrast, decursinol, which lacks the side chain of decursin and DA, did not have these cellular and molecular activities at comparable concentrations. The side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities. These data provide mechanistic rationales for validating the chemopreventive and therapeutic efficacy of decursin and its derivatives in preclinical animal models of breast cancer.

  20. Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells

    PubMed Central

    Jiang, Cheng; Guo, Junming; Wang, Zhe; Xiao, Bingxiu; Lee, Hyo-Jung; Lee, Eun-Ok; Kim, Sung-Hoon; Lu, Junxuan

    2007-01-01

    Introduction Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Attenuating ER activities by natural products is a promising strategy to decrease breast cancer risk. We recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) have potent novel antiandrogen receptor signaling activities. Because the ER and the androgen receptor belong to the steroid receptor superfamily, we examined whether these compounds affected ER expression and signaling in breast cancer cells. Methods We treated estrogen-dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells with decursin and DA, and examined cell growth, apoptosis, and ERα and ERβ expression in both cell lines – and, in particular, estrogen-stimulated signaling in the MCF-7 cells. We compared these compounds with decursinol to determine their structure-activity relationship. Results Decursin and DA exerted growth inhibitory effects on MCF-7 cells through G1 arrest and caspase-mediated apoptosis. These compounds decreased ERα in MCF-7 cells at both mRNA and protein levels, and suppressed estrogen-stimulated genes. Decursin and the pure antiestrogen Faslodex™ exerted an additive growth inhibitory effect on MCF-7 cells. In MDA MB-231 cells, these compounds induced cell-cycle arrests in the G1 and G2 phases as well as inducing apoptosis, accompanied by an increased expression of ERβ. In contrast, decursinol, which lacks the side chain of decursin and DA, did not have these cellular and molecular activities at comparable concentrations. Conclusion The side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities. These data provide mechanistic rationales for validating the chemopreventive and therapeutic efficacy of decursin and its derivatives in preclinical animal models of breast cancer. PMID:17986353

  1. Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents.

    PubMed

    Mesnage, Robin; Phedonos, Alexia; Biserni, Martina; Arno, Matthew; Balu, Sucharitha; Corton, J Christopher; Ugarte, Ricardo; Antoniou, Michael N

    2017-10-01

    The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. We evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (≥10,000 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα predicts a weak and unstable interaction (-4.10 kcal mol -1 ) compared to estradiol (-25.79 kcal mol -1 ), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Our study reveals that glyphosate, but not other components present in GBHs, can activate ERα in vitro, albeit at relatively high concentrations. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

    PubMed Central

    Gaudin, Françoise; Machelon, Véronique; Brigitte, Madly; Jacquard, Carine; Pillon, Arnaud; Balaguer, Patrick; Balabanian, Karl; Lazennec, Gwendal

    2012-01-01

    Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients. PMID:22970307

  3. Black tea and D. candidum extracts play estrogenic activity via estrogen receptor α-dependent signaling pathway

    PubMed Central

    Wang, Yongsen; Sun, Jing; Zhang, Kun; Hu, Xin; Sun, Yuchu; Sheng, Jun; Fu, Xueqi

    2018-01-01

    In recent years, phytoestrogens have been shown as useful selective estrogen receptor modulators. The estrogen-like effects of black tea (BT) and D. candidum (DC), as well as the combination of the two herbs, have remained largely elusive. This study aims to investigate the phytoestrogenic effect of BT and DC extract, and the possible mechanism. The effects on T47D (ER+ cell line) proliferation were evaluated by using MTT assay. The S phase proportion of ER+ cells was determined by using flow cytometry. The estrogen antagonist ICI 182,780 was applied to block the ER function. The activation of ER-mediated PI3K/AKT and ERK signal pathways were observed by using western blot. Expression of ERα and PGR, as well as PS2 and Cyclin D1 were detected by using western blot and real-time quantitative PCR. Firstly, our results found that BT and DC extracts promoted cell proliferation in ER-positive cells, and this effect was ER-dependent. Besides, BT and DC extracts increased the S-phase cell number. Next, PI3K, AKT and ERK pathways below ER were activated by phytoestrogen treatment, and this activation was blocked by the ER antagonist. Moreover, prolonged BT and DC treatments increased the expression of ESR1 and PGR. Consistently, the mRNA levels of not only ESR1 and PGR but also estrogen-dependent effectors ps2 and cyclin D1, were increased by phytoestrogens and blocked by ICI 182,780. Taken Together, BT and DC extracts have phytoestrogenic effects, and this may provide new ideas and experimental basis for the development and application of phytoestrogens. PMID:29422998

  4. Effect of estrogen on molecular and functional characteristics of the rodent vaginal muscularis

    PubMed Central

    Basha, Maureen E.; Chang, Shaohua; Burrows, Lara J.; Lassmann, Jenny; Wein, Alan J.; Moreland, Robert S.; Chacko, Samuel K.

    2013-01-01

    Introduction Vaginal atrophy is a consequence of menopause however little is known concerning the effect of a decrease in systemic estrogen on vaginal smooth muscle structure and function. As the incidence of pelvic floor disorders increases with age, it is important to determine if estrogen regulates the molecular composition and contractility of the vaginal muscularis. Aim The goal of this study was to determine the effect of estrogen on molecular and functional characteristics of the vaginal muscularis utilizing a rodent model of surgical menopause. Methods 3–4 month old Sprague Dawley rats underwent sham laparotomy (Sham, n=18) or ovariectomy (Ovx, n=39). Two weeks following surgery, animals received a subcutaneous osmotic pump containing vehicle (Sham, Ovx) or 17- β estradiol (Ovx). Animals were euthanized one week later and the proximal vagina was collected for analysis of contractile protein expression and in vitro studies of contractility. Measurements were analyzed using a one-way ANOVA followed by Tukey's post hoc analysis (α= 0.05). Main Outcome Measures Protein and mRNA transcript expression levels of contractile proteins, in vitro measurements of vaginal contractility Results Ovariectomy decreased the expression of carboxyl-terminal myosin heavy chain isoform SM1 and h-caldesmon and reduced the amplitude of contraction of the vaginal muscularis in response to KCl. Estradiol replacement reversed these changes. No differences were detected in the % vaginal muscularis, mRNA transcript expression of amino terminal MHC isoforms, l-caldesmon expression and maximal velocity of shortening. Conclusion Systemic estrogen replacement restores functional and molecular characteristics of the vaginal muscularis of ovariectomized rats. Our results indicate that menopause is associated with changes in the vaginal muscularis, which may contribute to the increased incidence of pelvic floor disorders with age. PMID:23438289

  5. Amygdala subnuclei resting-state functional connectivity sex and estrogen differences.

    PubMed

    Engman, Jonas; Linnman, Clas; Van Dijk, Koene R A; Milad, Mohammed R

    2016-01-01

    The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. The Molecular, Cellular and Clinical Consequences of Targeting the Estrogen Receptor Following Estrogen Deprivation Therapy

    PubMed Central

    Fan, Ping; Maximov, Philipp Y.; Curpan, Ramona F.; Abderrahman, Balkees; Jordan, V. Craig

    2015-01-01

    During the past twenty years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed “morning after pill”, was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite “antiestrogen” resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER Modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women’s health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long-term Hormone Replacement Therapy (HRT). A new synthetic progestin with estrogen-like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells. PMID:26052034

  7. Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis.

    PubMed

    Elliot, S J; Berho, M; Korach, K; Doublier, S; Lupia, E; Striker, G E; Karl, M

    2007-08-01

    Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes alpha- or -beta were deleted (alpha- or betaER knockout (KO)) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female betaERKO and male alphaERKO mice had no glomerular dysfunction at 9 months of age; however, alphaERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in alphaERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-beta1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner.

  8. Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens.

    PubMed

    Newbold, R R; Liehr, J G

    2000-01-15

    Catechol estrogens may mediate estrogen-induced carcinogenesis because 4-hydroxyestradiol induces DNA damage and renal tumors in hamsters, and this metabolite is formed in the kidney and estrogen target tissues by a specific estrogen 4-hydroxylase. We examined the carcinogenic potential of catechol estrogen in an experimental model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal exposure to diethylstilbestrol. Outbred female CD-1 mice were treated with 2- or 4-hydroxyestradiol, 17beta-estradiol, or 17alpha-ethinyl estradiol on days 1-5 of neonatal life (2 microg/pup/day) and sacrificed at 12 or 18 months of age. Mice treated with 17beta-estradiol or 17a-ethinyl estradiol had a total uterine tumor incidence of 7% or 43%, respectively. 2-Hydroxyestradiol induced tumors in 12% of the mice, but 4-hydroxyestradiol was the most carcinogenic estrogen, with a 66% incidence of uterine adenocarcinoma. Both 2- and 4-hydroxylated catechols were estrogenic and increased uterine wet weights in these neonates. These data demonstrate that both 2- and 4-hydroxyestradiol are carcinogenic metabolites. The high tumor incidence induced by 4-hydroxyestradiol supports the postulated role of this metabolite in hormone-associated cancers.

  9. Prediction of Estrogen Runoff and Transport Driven by Rainfalls from Swine Spray Fields

    NASA Astrophysics Data System (ADS)

    Lee, B.; Reckhow, K. H.; Kullman, S. W.

    2010-12-01

    Animal waste-borne steroidal hormones, which are referred to as natural steroidal estrogens, are recognized pollutants to surface water systems. Steroidal estrogens exhibit strong potency, even at very low concentrations, as endocrine disrupting chemicals on aquatic organisms. In North Carolina, the swine concentrated animal feeding operations (CAFOs) have been a major source for the release of estrogens to watersheds. Release is a direct result of the land application of the generated waste as an organic fertilizer. However, data regarding the estrogen loss and transport through the surface runoff and soil erosion to the water bodies after the spray-fields application has been up till now very limited. We have developed a decision support tool that can help predict and ultimately manage the potential mobilization and transport of estrogens from CAFOs, through the processes of surface runoff transport and sediment loss, into adjacent water bodies. Our decision support tool was built using a dynamic Bayesian Network (DBN) framework. The developed DBN model integrates the processes of a sediment loss and a surface runoff by using the modified universal soil loss equation (MUSLE) and the SCS-CN curve runoff models. Estrogen mobility is assessed as a function of rainfall intensity and land use management with consideration to the temporal distribution of both. The DBN is used to model the estrogen concentration in the runoff process, to determine the degree of off-site movement of estrogens, and to verify the potential environmental significance of the estrogen inputs into the stream. We believe that our modeling framework is particularly useful for use in field situations where estrogen runoff data are not available or are scarce. The DBN model also provides a means to handle the uncertainties of mathematical sediment and runoff models as a dynamic probability model.

  10. Binding of Estrogenic Compounds to Recombinant Estrogen Receptor-α: Application to Environmental Analysis

    PubMed Central

    Pillon, Arnaud; Boussioux, Anne-Marie; Escande, Aurélie; Aït-Aïssa, Sélim; Gomez, Elena; Fenet, Hélène; Ruff, Marc; Moras, Dino; Vignon, Françoise; Duchesne, Marie-Josèphe; Casellas, Claude; Nicolas, Jean-Claude; Balaguer, Patrick

    2005-01-01

    Estrogenic activity in environmental samples could be mediated through a wide variety of compounds and by various mechanisms. High-affinity compounds for estrogen receptors (ERs), such as natural or synthetic estrogens, as well as low-affinity compounds such as alkylphenols, phthalates, and polychlorinated biphenyls are present in water and sediment samples. Furthermore, compounds such as polycyclic aromatic hydrocarbons, which do not bind ERs, modulate estrogen activity by means of the aryl hydrocarbon receptor (AhR). In order to characterize compounds that mediate estrogenic activity in river water and sediment samples, we developed a tool based on the ER-αligand-binding domain, which permitted us to estimate contaminating estrogenic compound affinities. We designed a simple transactivation assay in which compounds of high affinity were captured by limited amounts of recombinant ER-αand whose capture led to a selective inhibition of transactivation. This approach allowed us to bring to light that water samples contain estrogenic compounds that display a high affinity for ERs but are present at low concentrations. In sediment samples, on the contrary, we showed that estrogenic compounds possess a low affinity and are present at high concentration. Finally, we used immobilized recombinant ER-αto separate ligands for ER and AhR that are present in river sediments. Immobilized ER-α, which does not retain dioxin-like compounds, enabled us to isolate and concentrate ER ligands to facilitate their further analysis. PMID:15743715

  11. Selective estrogen receptor modulators and risk for coronary heart disease.

    PubMed

    Cano, A; Hermenegildo, C; Oviedo, P; Tarín, J J

    2007-04-01

    Coronary heart disease (CHD) is the leading cause of death in women in most countries. Atherosclerosis is the main biological process determining CHD. Clinical data support the notion that CHD is sensitive to estrogens, but debate exists concerning the effects of the hormone on atherosclerosis and its complications. Selective estrogen receptor modulators (SERMs) are compounds capable of binding the estrogen receptor to induce a functional profile distinct from estrogens. The possibility that SERMs may shift the estrogenic balance on cardiovascular risk towards a more beneficial profile has generated interest in recent years. There is considerable information on the effects of SERMs on distinct areas that are crucial in atherogenesis. The complexity derived from the diversity of variables affecting their mechanism of action plus the differences between compounds make it difficult to delineate one uniform trend for SERMs. The present picture, nonetheless, is one where SERMs seem less powerful than estrogens in atherosclerosis protection, but more gentle with advanced forms of the disease. The recent publication of the Raloxifene Use for The Heart (RUTH) study has confirmed a neutral effect for raloxifene. Prothrombotic states may favor occlusive thrombi at sites occupied by atheromatous plaques. Platelet activation has received attention as an important determinant of arterial thrombogenesis. Although still sparse, available evidence globally suggests neutral or beneficial effects for SERMs.

  12. Discovery of estrogen receptor α modulators from natural compounds in Si-Wu-Tang series decoctions using estrogen-responsive MCF-7 breast cancer cells.

    PubMed

    Liu, Li; Ma, Hongyue; Tang, Yuping; Chen, Wenxing; Lu, Yin; Guo, Jianming; Duan, Jin-Ao

    2012-01-01

    The binding between the estrogen receptor α (ER-α) and a variety of compounds in traditional Chinese formulae, Si-Wu-Tang (SWT) series decoctions, was studied using a stably-transfected human breast cancer cell line (MVLN). In 38 compounds tested from SWT series decoctions, the estrogen-like activity of 22 compounds was above 60% in 20 μg mL(-1). Furthermore, theoretical affinity of these compounds was certificated using the functional virtual screen of ER-α modulators by FlexX-Pharm. The accuracy of functional virtual screening of ER-α modulators could reach to 77.27%. The results showed that some compounds, such as organic acids and flavones in SWT series decoctions could be used as selective estrogen receptor modulators (SERMs) and could be selected for further development as potential agents for estrogen related diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions.

    PubMed

    Hanson, Alicia M; Perera, K L Iresha Sampathi; Kim, Jaekyoon; Pandey, Rajesh K; Sweeney, Noreena; Lu, Xingyun; Imhoff, Andrea; Mackinnon, Alexander Craig; Wargolet, Adam J; Van Hart, Rochelle M; Frick, Karyn M; Donaldson, William A; Sem, Daniel S

    2018-06-14

    Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC 50 s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.

  14. Effects of Preoperative Local Estrogen in Postmenopausal Women With Prolapse: A Randomized Trial

    PubMed Central

    Good, Meadow M.; Roshanravan, Shayzreen M.; Shi, Haolin; Schaffer, Joseph I.; Singh, Ravinder J.; Word, R. Ann

    2014-01-01

    Context: Pelvic organ prolapse (POP) increases in prevalence with age; recurrence after surgical repair is common. Objective: The objective of the study was to determine the effects of local estrogen treatment on connective tissue synthesis and breakdown in the vaginal wall of postmenopausal women planning surgical repair of POP. Design: This was a randomized trial. Setting: The study was conducted at an academic tertiary medical center. Patients or Other Participants: Postmenopausal women with a uterus and symptomatic anterior and/or apical prolapse at stage 2 or greater participated in the study. Intervention: Estrogen (Premarin) or placebo cream for 6 weeks preoperatively was the intervention. Main Outcome Measures: Full-thickness anterior apical vaginal wall biopsies were obtained at the time of hysterectomy and analyzed for mucosa and muscularis thickness, connective tissue synthesis, and degradation. Serum levels of estrone and 17β-estradiol were analyzed at baseline and the day of surgery using highly sensitive liquid chromatography-tandem mass spectrometry. Results: Fifteen women per group (n = 30 total) were randomized; 13 per group underwent surgery. Among drug-adherent participants (n = 8 estrogen, n = 13 placebo), epithelial and muscularis thickness was increased 1.8- and 2.7-fold (P = .002 and P =.088, respectively) by estrogen. Collagen types 1α1 and 1α2 mRNA increased 6.0- and 1.8-fold in the vaginal muscularis (P < .05 for both); collagen type Ia protein increased 9-fold in the muscularis (P = .012), whereas collagen III was not changed significantly. MMP-12 (human macrophage elastase) mRNA was suppressed in the vaginal mucosa from estrogen-treated participants (P = .011), and matrix metalloprotease-9 activity was decreased 6-fold in the mucosa and 4-fold in the muscularis (P = .02). Consistent with menopausal norms, serum estrone and 17β-estradiol were low and did not differ among the two groups. Conclusions: Vaginal estrogen application for 6

  15. Neuro-estrogens rapidly regulate sexual motivation but not performance

    PubMed Central

    Seredynski, Aurore L.; Balthazart, Jacques; Christophe, Virginie J.; Ball, Gregory F.; Cornil, Charlotte A.

    2013-01-01

    Estrogens exert pleiotropic effects on reproductive traits, which include differentiation and activation of reproductive behaviors and the control of the secretion of gonadotropins. Estrogens also profoundly affect non-reproductive traits such as cognition and neuroprotection. These effects are usually attributed to nuclear receptor binding and subsequent regulation of target gene transcription. Estrogens also affect neuronal activity and cell-signaling pathways via faster, membrane-initiated events. How these two types of actions that operate in distinct time scales interact in the control of complex behavioral responses is poorly understood. Here, we show that the central administration of estradiol rapidly increases the expression of sexual motivation, as assessed by several measures of sexual motivation produced in response to the visual presentation of a female but not sexual performance in male Japanese quail. This effect is mimicked by membrane-impermeable analogs of estradiol, indicating that it is initiated at the cell membrane. Conversely, blocking the action of estrogens or their synthesis by a single intracereboventricular injection of estrogen receptor antagonists or aromatase inhibitors respectively decreases sexual motivation within minutes without affecting performance. The same steroid has thus evolved complementary mechanisms to regulate different behavioral components (motivation vs. performance) in distinct temporal domains (long- vs. short-term) so that diverse reproductive activities can be properly coordinated to improve reproductive fitness. Given the pleiotropic effects exerted by estrogens, other responses controlled by these steroids might also depend on a slow genomic regulation of neuronal plasticity underlying behavioral activation and an acute control of motivation to engage in behavior. PMID:23283331

  16. Estrogen receptor modulatory effects of germinated brown rice bioactives in the uterus of rats through the regulation of estrogen-induced genes

    PubMed Central

    Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi Bint; Saeed, Mohammed Ibrahim; Imam, Mustapha Umar; Ishaka, Aminu

    2013-01-01

    -β reactivity at the glandular epithelium, while the group treated with EST showed immunoreactivity at the glandular, luminal, and stromal epithelium. Conclusion GBR phenolics moderately regulate the expression of ER-β, HSP70, and IL-4 receptor genes, and gave a positive immunoreaction to ER-β antigen in the uterus. ASG regulates the expression of CaBP9k and IL-4 receptor genes, and ORZ regulates the expression of the CaBP9k gene, while GABA at 100 mg/kg regulates the expression of the HSP70 gene. GBR and its bioactives might have an effect on estrogen-regulated genes in the uterus of rats. PMID:24324328

  17. G-Protein-Coupled Estrogen Receptor Antagonist G15 Decreases Estrogen-Induced Development of Non-Small Cell Lung Cancer.

    PubMed

    Liu, Changyu; Liao, Yongde; Fan, Sheng; Fu, Xiangning; Xiong, Jing; Zhou, Sheng; Zou, Man; Wang, Jianmiao

    2017-08-25

    G-protein-coupled estrogen receptor (GPER) was found to promote Non-small cell lung cancer (NSCLC) by estrogen, indicating the potential necessity of inhibiting GPER by selective antagonist. This study was performed to elucidate the function of GPER selective inhibitor G15 in NSCLC development. Cytoplasmic GPER (cGPER) and nuclear GPER (nGPER) were detected by immunohistochemical analysis in NSCLC samples. The relation of GPER and estrogen receptor β (ERβ) expression and correlation between GPER, ERβ and clinical factors were analyzed. The effects of activating GPER and function of G15 were analyzed in proliferation of A549, H1793 cell lines and development of urethane-induced adenocarcinoma. Overexpression of cGPER and nGPER was detected in 80.49% (120/150) and 52.00% (78/150) of the NSCLC samples. High expression of GPER related with higher stages, poorer differentiation and high expression of ERβ. Protein level of GPER in A549 and H1793 cell lines increased by treatment of E2, G1 (GPER agonist) or Ful (fulvestrant, ERβ antagonist), and decreased by G15. Administration with G15 reversed the E2- or G1-induced cell growth by inhibiting GPER. In urethane-induced adenocarcinoma mice, number of tumor nodules and tumor index increased in E2 or G1 group and decreased by treatment of G15. These findings deomonstrate that using of G15 to block GPER signaling may be considered as a new therapeutic target in NSCLC.

  18. U-Shape Suppressive Effect of Phenol Red on the Epileptiform Burst Activity via Activation of Estrogen Receptors in Primary Hippocampal Culture

    PubMed Central

    Liu, Xu; Chen, Ben; Chen, Lulan; Ren, Wan-Ting; Liu, Juan; Wang, Guoxiang; Fan, Wei; Wang, Xin; Wang, Yun

    2013-01-01

    Phenol red is widely used in cell culture as a pH indicator. Recently, it also has been reported to have estrogen-like bioactivity and be capable of promoting cell proliferation in different cell lines. However, the effect of phenol red on primary neuronal culture has never been investigated. By using patch clamp technique, we demonstrated that hippocampal pyramidal neurons cultured in neurobasal medium containing no phenol red had large depolarization-associated epileptiform bursting activities, which were rarely seen in neurons cultured in phenol red-containing medium. Further experiment data indicate that the suppressive effect of the phenol red on the abnormal epileptiform burst neuronal activities was U-shape dose related, with the most effective concentration at 28 µM. In addition, this concentration related inhibitory effect of phenol red on the epileptiform neuronal discharges was mimicked by 17-β-estradiol, an estrogen receptor agonist, and inhibited by ICI-182,780, an estrogen receptor antagonist. Our results suggest that estrogen receptor activation by phenol red in the culture medium prevents formation of abnormal, epileptiform burst activity. These studies highlight the importance of phenol red as estrogen receptor stimulator and cautions of careful use of phenol red in cell culture media. PMID:23560076

  19. Editor's Highlight: Transcriptome Profiling Reveals Bisphenol A Alternatives Activate Estrogen Receptor Alpha in Human Breast Cancer Cells.

    PubMed

    Mesnage, Robin; Phedonos, Alexia; Arno, Matthew; Balu, Sucharitha; Corton, J Christopher; Antoniou, Michael N

    2017-08-01

    Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in "BPA-free" products. We have compared estrogenic activity of BPA with 6 bisphenol analogues [bisphenol S (BPS); bisphenol F (BPF); bisphenol AP (BPAP); bisphenol AF (BPAF); bisphenol Z (BPZ); bisphenol B (BPB)] in 3 human breast cancer cell lines. Estrogenicity was assessed (10-11-10-4 M) by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element-mediated transcription in a luciferase assay. BPAF was the most potent bisphenol, followed by BPB > BPZ ∼ BPA > BPF ∼ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs. Data mining of ToxCast high-throughput screening assays confirm our results but also show divergence in the sensitivities of the assays. Gene expression profiles were determined in MCF-7 cells by microarray analysis. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by Illumina-based RNA sequencing. In conclusion, BPA alternatives are not necessarily less estrogenic than BPA in human breast cancer cells. BPAF, BPB, and BPZ were more estrogenic than BPA. These findings point to the importance of better understanding the risk of adverse effects from exposure to BPA alternatives, including hormone-dependent breast cancer. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

  20. Effects of Environmental Estrogens on Apoptosis in Normal and Cancerous Breast Epithelial Cells

    DTIC Science & Technology

    2001-03-01

    breast cancer in population which consume diets rich in these flavonoid phytoestrogens has prompted us to further examine the effects of these...chemicals on apoptosis. Initial studies revealed certain flavonoid phytochemicals possessed potent antiestrogenic effects (Appendix documents #4,5...of specific aim 1 to include examination of the flavonoid phytochemical environmental estrogens. Examination of Bcl-2 expression and effects on

  1. Roles of α- and β-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle.

    PubMed

    Sánchez-Andrade, G; Kendrick, K M

    2011-01-01

    Establishing clear effects of gender and natural hormonal changes during female ovarian cycles on cognitive function has often proved difficult. Here we have investigated such effects on the formation and long-term (24 h) maintenance of social recognition memory in mice together with the respective involvement of α- and β-estrogen receptors using α- and β-estrogen receptor knockout mice and wildtype controls. Results in wildtype animals showed that while females successfully formed a memory in the context of a habituation/dishabituation paradigm at all stages of their ovarian cycle, only when learning occurred during proestrus (when estrogen levels are highest) was it retained after 24 h. In α-receptor knockout mice (which showed no ovarian cycles) both formation and maintenance of this social recognition memory were impaired, whereas β-receptor knockouts showed no significant deficits and exhibited the same proestrus-dependent retention of memory at 24 h. To investigate possible sex differences, male α- and β-estrogen receptor knockout mice were also tested and showed similar effects to females excepting that α-receptor knockouts had normal memory formation and only exhibited a 24 h retention deficit. This indicates a greater dependence in females on α-receptor expression for memory formation in this task. Since non-specific motivational and attentional aspects of the task were unaffected, our findings suggest a general α-receptor dependent facilitation of memory formation by estrogen as well as an enhanced long-term retention during proestrus. Results are discussed in terms of the differential roles of the two estrogen receptors, the neural substrates involved and putative interactions with oxytocin. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Effect of the combination of methyltestosterone and esterified estrogens compared with esterified estrogens alone on apolipoprotein CIII and other apolipoproteins in very low density, low density, and high density lipoproteins in surgically postmenopausal women.

    PubMed

    Chiuve, Stephanie E; Martin, Lisa A; Campos, Hannia; Sacks, Frank M

    2004-05-01

    Androgens are known to lower plasma triglycerides, an independent risk factor for coronary heart disease (CHD). Triglycerides are carried in plasma on very low density (VLDL) and low density (LDL) lipoprotein particles. Apolipoprotein CIII (apoCIII), a strong predictor of CHD, impairs the metabolism of VLDL and LDL, contributing to increased triglycerides. The objective of this study was to assess the effect of oral methyltestosterone (2.5 mg/d), added to esterified estrogens (1.25 mg/d), on concentrations of apolipoproteins and lipoproteins, specifically those containing apoCIII, compared with esterified estrogens alone in surgically postmenopausal women. The women in the methyltestosterone plus esterified estrogen group had significant decreases in total triglycerides, apoCI, apoCII, apoCIII, apoE, and high density lipoprotein (HDL) cholesterol compared with those in the esterified estrogen group. The decreases in apoCIII concentrations occurred in VLDL (62%; P = 0.02), LDL (35%; P = 0.001), and HDL (17%; P < 0.0001). There were also decreases in cholesterol and triglycerides concentrations of apoCIII containing LDL, and apoCI concentration of apoCIII containing VLDL. There was no effect on VLDL and LDL particles that did not contain apoCIII or on apoB concentrations. In conclusion, methyltestosterone, when administered to surgically postmenopausal women taking esterified estrogen, has a selective effect to reduce the apoCIII concentration in VLDL and LDL, a predictor of CHD. Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII.

  3. Exogenous estrogen as mediator of racial differences in bioactive insulin-like growth factor-I levels among postmenopausal women.

    PubMed

    Jung, Su Yon; Vitolins, Mara Z; Paskett, Electra D; Chang, Shine

    2015-04-01

    The role of exogenous estrogen use in racial differences in insulin-like growth factor-I (IGF-I) levels which affect cancer risk is unclear. We investigated whether the relationship between race and circulating bioactive IGF-I proteins was mediated by exogenous estrogen and the extent to which exogenous estrogen influenced the race-IGF-I relationship in postmenopausal women. This cross-sectional study included 636 white and 133 African American postmenopausal women enrolled in an ancillary study of the Women's Health Initiative Observational Study. To assess exogenous estrogen use (nonusers [n = 262] vs users [n = 507]) as a mediator of the race-IGF-I relationship, we used the Baron-Kenny method and an estimation of the proportional change in the odd ratios for IGF-I levels on race plus a bootstrapping test for the significance of the mediation effect. Compared with white women, African American women were more likely to have high IGF-I levels and less likely to use exogenous estrogen. After accounting for race, estrogen nonusers had higher IGF-I levels than estrogen users did. Among oral contraceptive ever users, exogenous estrogen had a strong mediation effect (67%; p = .018) in the race-IGF-I relationship. In the women with a history of hypertension, exogenous estrogen explained racial differences in IGF-I levels to a modest degree (23%; p = .029). Exogenous estrogen use has a potentially important role in disparities in IGF-I bioactivity between postmenopausal African American and white women. A history of oral contraceptive use and hypertension may be part of the interconnected hormonal pathways related to racial differences in IGF-I levels. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Putnik, Milica, E-mail: milica.putnik@ki.se; Zhao, Chunyan, E-mail: chunyan.zhao@ki.se; Gustafsson, Jan-Ake, E-mail: jan-ake.gustafsson@ki.se

    Highlights: Black-Right-Pointing-Pointer Estrogen signaling and demethylation can both control gene expression in breast cancers. Black-Right-Pointing-Pointer Cross-talk between these mechanisms is investigated in human MCF-7 breast cancer cells. Black-Right-Pointing-Pointer 137 genes are influenced by both 17{beta}-estradiol and demethylating agent 5-aza-2 Prime -deoxycytidine. Black-Right-Pointing-Pointer A set of genes is identified as targets of both estrogen signaling and demethylation. Black-Right-Pointing-Pointer There is no direct molecular interplay of mediators of estrogen and epigenetic signaling. -- Abstract: Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between thesemore » two pathways by identifying their common target genes and exploring underlying molecular mechanisms in human MCF-7 breast cancer cells. Gene expression profiling revealed that the expression of approximately 140 genes was influenced by both 17{beta}-estradiol (E2) and a demethylating agent 5-aza-2 Prime -deoxycytidine (DAC). Gene ontology (GO) analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis. Based on previously reported association with breast cancer, estrogen signaling and/or DNA methylation, CpG island prediction and GO analysis, we selected six genes (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2) for further analysis. Tamoxifen reverses the effect of E2 on the expression of all selected genes, suggesting that they are direct targets of estrogen receptor. Furthermore, DAC treatment reactivates the expression of all selected genes in a dose-dependent manner. Promoter CpG island methylation status analysis revealed that only the promoters of BTG3 and FHL2 genes are methylated, with DAC inducing demethylation, suggesting DNA methylation directs

  5. COMPARISON OF FATHEAD MINNOW AND HUMAN ESTROGEN RECEPTOR BINDING TO ENDOCRINE DISRUPTING COMPOUNDS

    EPA Science Inventory

    Environmental estrogens have the potential to disrupt endocrine function in a myriad of species. However, in vitro assays designed to detect and characterize endocrine disrupting chemicals (EDCs) typically utilize mammalian estrogen receptors. Our overall objective is to charac...

  6. [The effects of herb lithospermum extract on MCF-7 cell and estrogen and progestogen levels in mice].

    PubMed

    Wang, Wei; Li, Ping-ping

    2003-11-01

    To study the effects of lithospermum extract on MCF-7 cell and estrogen and progestogen levels in mice. Cell growth curve and Western Blotting were used to do animal experiment. Lithospermum extract could inhibit the growth of MCF-7 cell. It could also inhibit the expression of ER and increase the expression of PR with large dose. After the mice were bred with Lithospermum, their serum estrogen and progestogen levels reduced, their uterus weight index decresed and uterus ER and PR levels increased. It could also improve the hyperplasia of uterus caused by tamoxifen. Lithospermum extract can inhibit the growth of MCF-7 cell and inhibit the level of estrogen and progestogen in mice.

  7. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

    PubMed

    Bonkhoff, Helmut

    2018-01-01

    The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

  8. Estrogenic Effects of Several BPA Analogs in the Developing Zebrafish Brain

    PubMed Central

    Cano-Nicolau, Joel; Vaillant, Colette; Pellegrini, Elisabeth; Charlier, Thierry D.; Kah, Olivier; Coumailleau, Pascal

    2016-01-01

    Important set of studies have demonstrated the endocrine disrupting activity of Bisphenol A (BPA). The present work aimed at defining estrogenic-like activity of several BPA structural analogs, including BPS, BPF, BPAF, and BPAP, on 4- or 7-day post-fertilization (dpf) zebrafish larva as an in vivo model. We measured the induction level of the estrogen-sensitive marker cyp19a1b gene (Aromatase B), expressed in the brain, using three different in situ/in vivo strategies: (1) Quantification of cyp19a1b transcripts using RT-qPCR in wild type 7-dpf larva brains exposed to bisphenols; (2) Detection and distribution of cyp19a1b transcripts using in situ hybridization on 7-dpf brain sections (hypothalamus); and (3) Quantification of the cyp19a1b promoter activity in live cyp19a1b-GFP transgenic zebrafish (EASZY assay) at 4-dpf larval stage. These three different experimental approaches demonstrated that BPS, BPF, or BPAF exposure, similarly to BPA, significantly activates the expression of the estrogenic marker in the brain of developing zebrafish. In vitro experiments using both reporter gene assay in a glial cell context and competitive ligand binding assays strongly suggested that up-regulation of cyp19a1b is largely mediated by the zebrafish estrogen nuclear receptor alpha (zfERα). Importantly, and in contrast to other tested bisphenol A analogs, the bisphenol AP (BPAP) did not show estrogenic activity in our model. PMID:27047331

  9. Detecting Estrogenic Ligands in Personal Care Products using a Yeast Estrogen Screen Optimized for the Undergraduate Teaching Laboratory.

    PubMed

    Edwards, Thea M; Morgan, Howard E; Balasca, Coralia; Chalasani, Naveen K; Yam, Lauren; Roark, Alison M

    2018-01-01

    The Yeast Estrogen Screen (YES) is used to detect estrogenic ligands in environmental samples and has been broadly applied in studies of endocrine disruption. Estrogenic ligands include both natural and manmade "Environmental Estrogens" (EEs) found in many consumer goods including Personal Care Products (PCPs), plastics, pesticides, and foods. EEs disrupt hormone signaling in humans and other animals, potentially reducing fertility and increasing disease risk. Despite the importance of EEs and other Endocrine Disrupting Chemicals (EDCs) to public health, endocrine disruption is not typically included in undergraduate curricula. This shortcoming is partly due to a lack of relevant laboratory activities that illustrate the principles involved while also being accessible to undergraduate students. This article presents an optimized YES for quantifying ligands in personal care products that bind estrogen receptors alpha (ERα) and/or beta (ERβ). The method incorporates one of the two colorimetric substrates (ortho-nitrophenyl-β-D-galactopyranoside (ONPG) or chlorophenol red-β-D-galactopyranoside (CPRG)) that are cleaved by β-galactosidase, a 6-day refrigerated incubation step to facilitate use in undergraduate laboratory courses, an automated application for LacZ calculations, and R code for the associated 4-parameter logistic regression analysis. The protocol has been designed to allow undergraduate students to develop and conduct experiments in which they screen products of their choosing for estrogen mimics. In the process, they learn about endocrine disruption, cell culture, receptor binding, enzyme activity, genetic engineering, statistics, and experimental design. Simultaneously, they also practice fundamental and broadly applicable laboratory skills, such as: calculating concentrations; making solutions; demonstrating sterile technique; serially diluting standards; constructing and interpolating standard curves; identifying variables and controls; collecting

  10. Detecting Estrogenic Ligands in Personal Care Products using a Yeast Estrogen Screen Optimized for the Undergraduate Teaching Laboratory

    PubMed Central

    Edwards, Thea M.; Morgan, Howard E.; Balasca, Coralia; Chalasani, Naveen K.; Yam, Lauren; Roark, Alison M.

    2018-01-01

    The Yeast Estrogen Screen (YES) is used to detect estrogenic ligands in environmental samples and has been broadly applied in studies of endocrine disruption. Estrogenic ligands include both natural and manmade "Environmental Estrogens" (EEs) found in many consumer goods including Personal Care Products (PCPs), plastics, pesticides, and foods. EEs disrupt hormone signaling in humans and other animals, potentially reducing fertility and increasing disease risk. Despite the importance of EEs and other Endocrine Disrupting Chemicals (EDCs) to public health, endocrine disruption is not typically included in undergraduate curricula. This shortcoming is partly due to a lack of relevant laboratory activities that illustrate the principles involved while also being accessible to undergraduate students. This article presents an optimized YES for quantifying ligands in personal care products that bind estrogen receptors alpha (ERα) and/or beta (ERβ). The method incorporates one of the two colorimetric substrates (ortho-nitrophenyl-β-D-galactopyranoside (ONPG) or chlorophenol red-β-D-galactopyranoside (CPRG)) that are cleaved by β-galactosidase, a 6-day refrigerated incubation step to facilitate use in undergraduate laboratory courses, an automated application for LacZ calculations, and R code for the associated 4-parameter logistic regression analysis. The protocol has been designed to allow undergraduate students to develop and conduct experiments in which they screen products of their choosing for estrogen mimics. In the process, they learn about endocrine disruption, cell culture, receptor binding, enzyme activity, genetic engineering, statistics, and experimental design. Simultaneously, they also practice fundamental and broadly applicable laboratory skills, such as: calculating concentrations; making solutions; demonstrating sterile technique; serially diluting standards; constructing and interpolating standard curves; identifying variables and controls; collecting

  11. Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.

    PubMed

    Farman, H H; Windahl, S H; Westberg, L; Isaksson, H; Egecioglu, E; Schele, E; Ryberg, H; Jansson, J O; Tuukkanen, J; Koskela, A; Xie, S K; Hahner, L; Zehr, J; Clegg, D J; Lagerquist, M K; Ohlsson, C

    2016-08-01

    Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.

  12. Environmental estrogens alter early development in Xenopus laevis.

    PubMed

    Bevan, Cassandra L; Porter, Donna M; Prasad, Anita; Howard, Marthe J; Henderson, Leslie P

    2003-04-01

    A growing number of environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. We exposed Xenopus laevis embryos at early gastrula to the commonly encountered environmental estrogens nonylphenol, octylphenol, and methoxychlor, the antiandrogen, p,p-DDE, or the synthetic androgen, 17 alpha-methyltestosterone at concentrations ranging from 10 nM to 10 microM and examined them at tailbud stages (approximately 48 hr of treatment). Exposure to the three environmental estrogens, as well as to the natural estrogen 17 beta-estradiol, increased mortality, induced morphologic deformations, increased apoptosis, and altered the deposition and differentiation of neural crest-derived melanocytes in tailbud stage embryos. Although neural crest-derived melanocytes were markedly altered in embryos treated with estrogenic toxicants, expression of the early neural crest maker Xslug, a factor that regulates both the induction and subsequent migration of neural crest cells, was not affected, suggesting that the disruption induced by these compounds with respect to melanocyte development may occur at later stages of their differentiation. Co-incubation of embryos with the pure antiestrogen ICI 182,780 blocked the ability of nonylphenol to induce abnormalities in body shape and in melanocyte differentiation but did not block the effects of methoxychlor. Our data indicate not only that acute exposure to these environmental estrogens induces deleterious effects on early vertebrate development but also that different environmental estrogens may alter the fate of a specific cell type via different mechanisms. Finally, our data suggest that the differentiation of neural crest-derived melanocytes may be particularly sensitive to the disruptive actions of these ubiquitous chemical contaminants.

  13. Estrogen receptor mRNA in mineralized tissues of rainbow trout: calcium mobilization by estrogen.

    PubMed

    Armour, K J; Lehane, D B; Pakdel, F; Valotaire, Y; Graham, R; Russell, R G; Henderson, I W

    1997-07-07

    RT-PCR was undertaken on total RNA extracts from bone and scales of the rainbow trout, Oncorhynchus mykiss. The rainbow trout estrogen receptor (ER)-specific primers used amplified a single product of expected size from each tissue which, using Southern blotting, strongly hybridized with a 32P-labelled rtER probe under stringent conditions. These data provide the first in vivo evidence of ER mRNA in bone and scale tissues of rainbow trout and suggest that the effects of estrogen observed in this study (increased bone mineral and decreased scale mineral contents, respectively) may be mediated directly through ER.

  14. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy.

    PubMed

    Blackburn, Heather L; Ellsworth, Darrell L; Shriver, Craig D; Ellsworth, Rachel E

    2015-03-01

    The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment. This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies. Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA) n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable. Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary.

  15. Estrogenic Activity of Hyperforin in MCF-7 Human Breast Cancer Cells Transfected with Estrogen Receptor.

    PubMed

    Kwon, Joseph; Oh, Kyung Seo; Cho, Se-Young; Bang, Mi Ae; Kim, Hwan Seon; Vaidya, Bipin; Kim, Duwoon

    2016-11-01

    Hyperforin, a major active compound of St. John's wort extract, affects estrogenic activity. In this study, the compound evoked estrogen response element-dependent luciferase activity and cell proliferation in MCF-7 cells. Hyperforin-induced cell proliferation was significantly inhibited by the estrogen receptor antagonist ICI 182,780. These results suggested that hyperforin had estrogenic and cell proliferation activities, which were stimulated via the estrogen receptor. Compared to 17 β -estradiol, hyperforin showed significantly lower estrogenic activity and cell proliferation. The mechanism underlying the estrogenic activity of hyperforin was unknown, therefore, in this study, for the first time, the expression and post-translational modification of proteins were determined and compared among control, 17 β -estradiol-treated, and hyperforin-treated cells using proteomic techniques. A total of 453 proteins were identified, of which 282 proteins were significantly modulated in hyperforin-treated cells compared to 17 β -estradiol-treated cells. Ingenuity pathway analysis also demonstrated that hyperforin treatment induced less cell proliferation than 17 β -estradiol by downregulating estrogen receptor 1. Protein network analysis showed that cell proliferation was regulated mainly by cyclin D1 and extracellular signal-regulated kinases. In conclusion, although, hyperforin exhibited lower estrogenic activity than 17 β -estradiol, the compound induced lower levels of cancer cell proliferation in vitro . Georg Thieme Verlag KG Stuttgart · New York.

  16. Dynamic monitoring of GPER-mediated estrogenic effects in breast cancer associated fibroblasts: An alternative role of estrogen in mammary carcinoma development.

    PubMed

    Luo, Haojun; Liu, Manran; Luo, Shujuan; Yu, Tenghua; Wu, Chengyi; Yang, Guanglun; Tu, Gang

    2016-08-01

    Cancer associated fibroblasts (CAFs) are crucial contributors to breast cancer development. Estrogen affects mammary stroma in both physiological and pathophysiological conditions. We show here that estrogen (G-protein coupled) receptor (GPER) could be detected by immunohistochemistry in stromal fibroblasts of primary breast cancers. The presence of GPER expression was further confirmed by immunofluorescence and quantitative PCR in CAFs isolated from primary breast cancers. Based on dynamic monitoring by real time cell analyzer (RTCA) system, 17-β-estradiol (E2) as well as GPER specific agonist G1 were observed to trigger transient cell index increasing within an hour in a dosage-dependent manner in breast CAFs. In addition, E2 and G1 stimulated intracellular calcium modulation and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 within seconds and minutes in CAFs, respectively. Moreover, E2 and G1 promoted cell proliferation of breast CAFs measured by RTCA monitoring, cell viability assay and cell cycle analysis, and this promotion could be blocked by a GPER-selective antagonist G15. Interestingly, dynamic RTCA monitoring indicated that E2 increased adhesion of resuspended cells, and microscopy confirmed that E2 stimulated cell spreading. Both the adhesion and spreading were proposed to be mediated by GPER, since G1 also stimulated these effects similar to E2, and G15 reduced them. Moreover, GPER was found to mediate migration that was increased by E2 and G1 but reduced by G15 in RTCA cell migration assay and transwell assay. Accordingly, GPER mediates not only rapid actions but also slow effects including adhesion/spreading, proliferation and migration in breast CAFs. Estrogen is likely to affect tumor associated stroma and contributes to mammary carcinoma development through CAFs. Copyright © 2016. Published by Elsevier Inc.

  17. Effects-based chemical category approach for prioritization of low affinity estrogenic chemicals.

    PubMed

    Hornung, M W; Tapper, M A; Denny, J S; Kolanczyk, R C; Sheedy, B R; Hartig, P C; Aladjov, H; Henry, T R; Schmieder, P K

    2014-01-01

    Regulatory agencies are charged with addressing the endocrine disrupting potential of large numbers of chemicals for which there is often little or no data on which to make decisions. Prioritizing the chemicals of greatest concern for further screening for potential hazard to humans and wildlife is an initial step in the process. This paper presents the collection of in vitro data using assays optimized to detect low affinity estrogen receptor (ER) binding chemicals and the use of that data to build effects-based chemical categories following QSAR approaches and principles pioneered by Gilman Veith and colleagues for application to environmental regulatory challenges. Effects-based chemical categories were built using these QSAR principles focused on the types of chemicals in the specific regulatory domain of concern, i.e. non-steroidal industrial chemicals, and based upon a mechanistic hypothesis of how these non-steroidal chemicals of seemingly dissimilar structure to 17ß-estradiol (E2) could interact with the ER via two distinct binding types. Chemicals were also tested to solubility thereby minimizing false negatives and providing confidence in determination of chemicals as inactive. The high-quality data collected in this manner were used to build an ER expert system for chemical prioritization described in a companion article in this journal.

  18. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study.

    PubMed

    Flores, Roberto; Shi, Jianxin; Fuhrman, Barbara; Xu, Xia; Veenstra, Timothy D; Gail, Mitchell H; Gajer, Pawel; Ravel, Jacques; Goedert, James J

    2012-12-21

    High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation. Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences), high] and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05. In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57-0.70, P=0.03-0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal β-glucuronidase (R=0.36, P=0

  19. Bioassay- versus analytically-derived estrogen equivalents: Ramifications for monitoring

    EPA Science Inventory

    Due to concern for possible endocrine-related effects on aquatic vertebrates, environmental estrogens (EEs) are a growing focus of surface water contaminant monitoring programs. Some efforts utilize measurement of a targeted set of chemicals known to act as estrogen receptor (ER)...

  20. Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydrogenases

    PubMed Central

    Engeli, Roger T.; Rohrer, Simona R.; Vuorinen, Anna; Herdlinger, Sonja; Kaserer, Teresa; Leugger, Susanne; Schuster, Daniela

    2017-01-01

    Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17β-HSD2. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17β-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17β-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17β-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo. PMID:28925944

  1. The Measurement of Estrogens

    NASA Astrophysics Data System (ADS)

    Holder, Geoff; Makin, Hugh L. J.; Bradlow, H. Leon

    Biologists use the word ‘estrogen' when referring to molecules which have the ability to induce uterine growth or vaginal cornification in the immature or ovariectomized rodent. The word estrogen was derived from two Greek words - oistros meaning frenzy and gennein - to beget. Chemists and biochemists, however, often restrict their use of this term to molecules that contain a characteristic 18-carbon steroid nucleus with an aromatic (phenolic) A-ring, both those that are biologically active estrogens and those without biologic activity but which are of intrinsic interest, such as the estrogen conjugates. This chapter is concerned only with these steroid compounds. The structure and inter-relationship of some common estrogens are given in Fig. 8.1. In addition to the biological estrogens, there are a wide variety of both natural and synthetic compounds which have estrogenic activity when measured by one or another parameter. While many of the assay procedures described in this review are applicable to these compounds, their application to non C18-steroids will not be discussed here. Methodology for these non-steroidal compounds can be found in reviews by Wang et al. (2002), Wu et al. (2004), Muir (2006), and Delmonte and Rader (2006). While not wishing to downgrade the importance of previous work in the estrogen field, the authors have taken a deliberate decision to exclude most publications prior to 1975, not because these do not have value but simply because space is not unlimited and readers of the present chapter might be expected to be seeking information about methodology which is less than 30 years old. Readers seeking pre-1975 information in this area can find it in Oakey and Holder (1995).

  2. Effects of High Estrogen Levels on Monocyte Chemoattractant Protein-1 and Wound Healing

    PubMed Central

    Plackett, Timothy P.; Gregory, Meredith S.; Kovacs, Elizabeth J.

    2015-01-01

    Objective: Herein, we tested the effects of high levels of supplemental estrogen treatment on cutaneous wound healing. Approach: Female mice were implanted with a 17β-estradiol (E2) secreting pellet or placebo before receiving a full-thickness dermal excisional wound. Mice receiving the E2 pellet attained hormone levels that are comparable to those achieved during pregnancy. At 1, 3, and 5 days after injury, the dermal excision wound was examined for their histologic appearance, rate of closure, and chemokine levels. Results: Wound closure, assessed by percent reepithelialization, was slower in E2-treated mice relative to placebo (42.6%±6.6% vs. 70.0%±5.3%, respectively, 3 days after injury). In addition, there was a marked reduction in the subepithelial inflammatory infiltrate and granulation tissue in E2-treated mice relative to placebo. Wound levels of monocyte chemoattractant protein-1 (MCP-1) were increased by 3 days after injury and continued to rise at 5 days after injury in placebo-treated mice (p<0.01). By contrast, MCP-1 levels were significantly reduced at 3 and 5 days after injury in E2-treated mice relative to placebo-treated controls (p<0.01). This attenuation could be reversed by treatment with an estrogen receptor antagonist. Innovation: High levels of estrogen are able to suppress normal wound closure. Conclusion: Dermal wound healing can be altered by manipulating the gonadal steroid hormone levels. In particular, high levels of estrogen can be utilized to slow down the rate of wound healing through a reduction in the inflammatory response. PMID:25713751

  3. Estrogen and colorectal cancer incidence and mortality.

    PubMed

    Lavasani, Sayeh; Chlebowski, Rowan T; Prentice, Ross L; Kato, Ikuko; Wactawski-Wende, Jean; Johnson, Karen C; Young, Alicia; Rodabough, Rebecca; Hubbell, F Allan; Mahinbakht, Ali; Simon, Michael S

    2015-09-15

    The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86-2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P < .001). The use of estrogen alone in postmenopausal women with prior hysterectomy does not influence the incidence of colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with

  4. Is Homepathy Effective for Hot Flashes and other Estrogen-Withdrawal Symptoms in Breast Cancer Survivors? A Preliminary Randomized Controlled Trial

    DTIC Science & Technology

    2000-04-01

    AD__________ Award Number: DAMD17-99-1-9438 TITLE: Is Homeopathy Effective for Hot Flashes and Other Estrogen-Withdrawal Symptoms in Breast Cancer...Mar 00) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Is Homeopathy Effective for Hot Flashes and Other Estrogen- DAMD17-99-1-9438 Withdrawal Symptoms in...there is evidence that homeopathy is an effective treatment to improve the quality of life in breast cancer survivors who are experiencing hot flashes

  5. Cumulative estrogen exposure and prospective memory in older women.

    PubMed

    Hesson, Jacqueline

    2012-10-01

    This study looked at cumulative lifetime estrogen exposure, as estimated with a mathematical index (Index of Cumulative Estrogen Exposure (ICEE)) that included variables (length of time on estrogen therapy, age at menarche and menopause, postmenopausal body mass index, time since menopause, nulliparity and duration of breastfeeding) known to influence estrogen levels across the life span, and performance on prospective and retrospective memory measures in a group of 50 postmenopausal women (mean age=69.3years) who, if they were current or former users of estrogen therapy, had started therapy within 5years of menopause. The ICEE was found to be a significant predictor of performance on the Prospective Memory task (F(1)=4.21, p=.046, η(p)(2)=.084). No significant relationship was noted between the ICEE and performance on measures of retrospective memory. The results suggest that the level of cumulative lifetime exposure to estrogen a woman has influences her prospective memory performance later in life and that the influence of reproductive and biological markers of endogenous estrogen exposure are relevant factors to consider when studying the effect of estrogen therapy on cognitive functioning in postmenopausal women. In addition, the finding that performance on a measure of prospective memory, but not performance on measures of retrospective memory, was associated with the ICEE adds further support to the theory that the frontal cortex may be especially sensitive to estrogen. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. THE ESTROGENS / CHROMIUM INTERACTION IN THE NITRIC OXIDE GENERATION.

    PubMed

    Sawicka, Ewa; Piwowar, Agnieszka; Musiala, Tomasz; Dlugosz, Anna

    2017-05-01

    The interaction of estrogens with environmental toxins in free radicals generation: reactive oxygen species (ROS) or reactive nitrogen species (RNS) which participates in cancerogenesis is not yet recognized. Chromium(VI) is widely present in environment. One of its toxicity pathway is free radicals generation. Estrogens have the ability to scavenge free radicals, but may also act as prooxidants. Both chromium(VI) and estrogens are classified by International Agency for Research on Cancer (IARC) as carcinogens, so synergistic effect seems very dangerous. The interaction of chromium and estrogens in ROS generation are partly described but there are no reports on estrogen/chromium interaction on nitric oxide (NO) generation. The aim of the study was to examine the interaction of chromium(VI) and 17-p-estradiol (E2) on NO level in human blood as well as the role of E2 metabolites: 4-hydroxyestradiol (4-OHE2) and 16a-hydroxyestrone (16α-OHE1) in these processes. The NO level was estimated with the diagnostic kit (Nitric Oxide Colorimetric Detection Kit from Arbor Assays) in human blood in vitm. The results showed that Cr(VI) in used concentration (0.5; 1.0 and 5.0 gg/mL) decreases significantly NO level in blood, acting antagonistically to E2 and 4-OHE2. Estrogens (E2, 4-OHE2 and 16α-OHEI) do not protect against inhibiting effect of Cr(VI) on nitric oxide generation in blood because after combined exposure the decreased production of NO in blood was noted. In conclusion, presented results provide the information about the character of estrogen/Cr(VI) interaction in NO level in human blood. It is important knowledge for cardio protected effect e.g., hormone replacement therapy in environmental or occupational exposure to Cr(VI), chromium supplementation, also important for cancer risk evaluation.

  7. Selective Estrogen Receptor Modulator (SERM)-like Activities of Diarylheptanoid, a Phytoestrogen from Curcuma comosa, in Breast Cancer Cells, Pre-osteoblast Cells, and Rat Uterine Tissues.

    PubMed

    Thongon, Natthakan; Boonmuen, Nittaya; Suksen, Kanoknetr; Wichit, Patsorn; Chairoungdua, Arthit; Tuchinda, Patoomratana; Suksamrarn, Apichart; Winuthayanon, Wipawee; Piyachaturawat, Pawinee

    2017-05-03

    Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 μM) and antagonist at high concentrations (10-50 μM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.

  8. G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis.

    PubMed

    Sharma, Geetanjali; Prossnitz, Eric R

    2017-01-01

    Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.

  9. Changes in plasma volume during bed rest - Effects of menstrual cycle and estrogen administration

    NASA Technical Reports Server (NTRS)

    Fortney, S. M.; Beckett, W. S.; Carpenter, A. J.; Davis, J.; Drew, H.

    1988-01-01

    The effect of increased blood estrogen concentration, caused either during normal menstrual cycles or by exogenous administration of premarin, on the bed-rest (BR) induced decrease in plasma volume (PV) was investigated. In women who underwent duplicate 11-day BR without estrogen supplementation, the PV was found to decrease significantly, during the first 5 days of BR, to a lower level at which it remained for the rest of the BR period. In women who began BR in the periovulatory stage of the menstrual cycle, the loss of PV was delayed, while women who began BR during other stages of the cycle exhibited the usual trend of the PV decrease during the BR. In women who underwent a single 12-day BR period while taking premarin (1.25 mg/day), PV was found to decrease during the first 4-5 days of BR, but then returned toward the pre-BR level during the remainder of the BR, indicating that estrogens have a role in stabilizing body fluid volume.

  10. Estrogen Biology: New Insights into GPER Function and Clinical Opportunities

    PubMed Central

    Prossnitz, Eric R.; Barton, Matthias

    2014-01-01

    Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen’s rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and certain drugs such as SERMs and SERDs in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine. PMID:24530924

  11. Estrogen deficiency inhibits the odonto/osteogenic differentiation of dental pulp stem cells via activation of the NF-κB pathway.

    PubMed

    Wang, Yanping; Yan, Ming; Yu, Yan; Wu, Jintao; Yu, Jinhua; Fan, Zhipeng

    2013-06-01

    Various factors can affect the functions of dental pulp stem cells (DPSCs). However, little knowledge is available about the effects of estrogen deficiency on the differentiation of DPSCs. In this study, an estrogen-deficient rat model was constructed and multi-colony-derived DPSCs were obtained from the incisors of ovariectomized (OVX) or sham-operated rats. Odonto/osteogenic differentiation and the possible involvement of the nuclear factor kappa B (NF-κB) pathway in the OVX-DPSCs/Sham-DPSCs of these rats were then investigated. OVX-DPSCs presented decreased odonto/osteogenic capacity and an activated NF-κB pathway, as compared with Sham-DPSCs. When the cellular NF-κB pathway was specifically inhibited by BMS345541, the odonto/osteogenic potential in OVX-DPSCs was significantly upregulated. Thus, estrogen deficiency down-regulated the odonto/osteogenic differentiation of DPSCs by activating NF-κB signaling and inhibition of the NF-κB pathway effectively rescued the decreased differentiation potential of DPSCs.

  12. Aroclor1254 interferes with estrogen receptor-mediated neuroprotection against beta-amyloid toxicity in cholinergic SN56 cells.

    PubMed

    Bang, Yeojin; Lim, Juhee; Kim, Sa Suk; Jeong, Hyung Min; Jung, Ki-Kyung; Kang, Il-Hyun; Lee, Kwang-Youl; Choi, Hyun Jin

    2011-10-01

    Because estrogen plays important neurotrophic and neuroprotective roles in the brain by activating estrogen receptors (ERs), disruption of normal estrogen signaling can leave neurons vulnerable to a variety of insults, including β-amyloid peptide (Aβ). Aroclor1254 (A1254) belongs to the endocrine-disrupting chemical (EDC) polychlorinated biphenyls and has anti-estrogenic properties. In the present study, we evaluated the effect of A1254 on the protective activity of estrogen against Aβ toxicity in differentiated cholinergic SN56 cells. Aged Aβ25-35 causes apoptotic cell death in differentiated SN56 cells, and the cytotoxic evidences are effectively rescued by estrogen. We found that A1254 abolishes the neuroprotective activity of estrogen against Aβ toxicity, and attenuates the suppressive effect of estrogen on Aβ-induced tau phosphorylation and JNK activation. The effects of A1254 on the neuroprotective effects of estrogen in Aβ toxicity are very similar to the effects of the estrogen receptor antagonist ICI182,780. Thus, exposure to EDCs that have anti-estrogenic activity might interfere with normal estrogen-activated neuroprotective signaling events and leave neurons more vulnerable to dangerous stimuli. Our present results provide new understanding of the mechanisms contributing to the harmful effects of EDCs on the function and viability of neurons, and the possible relevance of EDCs in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. The Role and Use of Estrogens Following Trauma.

    PubMed

    Weniger, Maximilian; Angele, Martin K; Chaudry, Irshad H

    2016-09-01

    Several lines of evidence indicate that female sex is a protective factor in trauma and hemorrhage. In both clinical and experimental studies, proestrus females have been shown to have better chances of survival and reduced rates of posttraumatic sepsis. Estrogen receptors are expressed in a variety of tissues and exert genomic, as well as nongenomic effects. By improving cardiac, pulmonary, hepatic, and immune function, estrogens have been shown to prolong survival in animal models of hemorrhagic shock. Despite encouraging results from experimental studies, retrospective clinical studies have not clearly pointed to advantages of estrogens following trauma-hemorrhage, which may be due to insufficient study design. Therefore, this review aims to give an overview on the current evidence and emphasizes on the importance of further clinical investigation on estrogens following trauma.

  14. Medium- and Long-Term Effects of Estrogenic Contaminants on the Middle River Po Fish Community as Reconstructed from a Sediment Core.

    PubMed

    Viganò, Luigi; Loizeau, J-L; Mandich, A; Mascolo, G

    2016-11-01

    Recent studies showed that endocrine active compounds (EDs) capable to induce fish gonadal histopathologies, plasma vitellogenin and thyroid disruption, are transported by the River Lambro to the River Po, potentially affecting the fish community of the main Italian river. To assess whether fish relative abundance, composition and health were impaired by the River Lambro, a 3-year survey was undertaken in the main river. Results showed that the tributary supports in the River Po a denser fish community (+43 %), with a higher total biomass (+35 %). The survey also showed niche- and sensitivity-dependent effects, so that three benthopelagic species (bleak, topmouth gudgeon, and bitterling) were, for example, more abundant downstream from the tributary (up to 3.4×), but their sizes were significantly smaller. The present fish community was then compared with that described 30 years before in the same area of the Po River. This comparison highlighted that some fish species have disappeared and many have severely declined. To better evaluate this contrast, a sediment core of the Lambro tributary was analysed for the time trends of natural estrogens (E1, E2, E3), bisphenol A and alkylphenols. The results showed that during the last 50 years the River Lambro has been exposed to high estrogenic activities (16.1 ± 9.3 ng E2 equivalents/g), which inevitably affected also the River Po. In addition, at the time of the previous survey, six species of the main river had skewed sex ratios toward all-female populations, providing evidence that EDs and particularly (xeno)estrogens were already affecting the long-term viability of fish populations. Estrogens thus can be ascribed among the causal factors of fish qualitative and quantitative decline of the River Po, although long-term effects have been likely mitigated by nonconfinement of fish populations and nutrient enrichment.

  15. Estrogens and Coronary Artery Disease: New Clinical Perspectives.

    PubMed

    Meyer, M R; Barton, M

    2016-01-01

    In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the "classical" receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development. © 2016 Elsevier Inc. All rights reserved.

  16. Bioassay of estrogenicity and chemical analyses of estrogens in streams across the United States associated with livestock operations

    EPA Science Inventory

    Animal manures, used as a nitrogen source for crop production, are often associated with negative impacts on nutrient levels in surface water. The concentration of estrogens in streams from these manures is of concern due to potential endocrine disruption in aquatic species. S...

  17. Nandrolone and stanozolol induce Leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system.

    PubMed

    Chimento, Adele; Sirianni, Rosa; Zolea, Fabiana; De Luca, Arianna; Lanzino, Marilena; Catalano, Stefania; Andò, Sebastiano; Pezzi, Vincenzo

    2012-05-01

    Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer. Copyright © 2011 Wiley Periodicals, Inc.

  18. Androgens and estrogens in benign prostatic hyperplasia: past, present and future

    PubMed Central

    Nicholson, Tristan M.; Ricke, William A.

    2011-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs. PMID:21620560

  19. Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Bebo, Bruce F; Dehghani, Babak; Foster, Scott; Kurniawan, Astrid; Lopez, Francisco J; Sherman, Larry S

    2009-05-01

    Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.

  20. Binding and transactivation of the largemouth bass estrogen receptors by model compounds

    EPA Science Inventory

    Environmental estrogens (EEs) are chemicals in the environment that can elicit adverse effects on estrogen (E2) signaling by binding with the estrogen receptors (ERs). In largemouth bass (LMB), the physiological actions of E2 are primarily mediated via three receptors (ERα, ERßb ...

  1. Designer interface peptide grafts target estrogen receptor alpha dimerization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chakraborty, S.; Asare, B.K.; Biswas, P.K., E-mail: pbiswas@tougaloo.edu

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization.more » Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

  2. The role of estrogen and androgen receptors in bone health and disease

    PubMed Central

    2014-01-01

    Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis. PMID:24042328

  3. Bioanalytical and instrumental analysis of estrogenic activities in drinking water sources from Yangtze River Delta.

    PubMed

    Hu, Xinxin; Shi, Wei; Cao, Fu; Hu, Guanjiu; Hao, Yingqun; Wei, Si; Wang, Xinru; Yu, Hongxia

    2013-02-01

    The estrogenic activities of source water from Yangtze River, Huaihe River, Taihu Lake and groundwater in Yangtze River Delta in the dry and wet season were determined by use of reporter gene assays based on African green monkey kidney (CV-1) cell lines. Higher estrogenic activities were observed in the dry season, and the estrogenic potentials in water samples from Taihu Lake were greater than other river basins. None of the samples from groundwater showed estrogen receptor (ER) agonist activity. The 17β-Estradiol (E2) equivalents (EEQs) of water samples in the dry season ranged from 9.41×10(-1) to 1.20×10(1) ng E2 L(-1). In the wet season, EEQs of all the water samples were below the detection limit as 9.00×10(-1) ng E2 L(-1) except for one sample from Huaihe River. The highest contribution of E2 was detected in Yangtze River as 99% of estrogenic activity. Nonylphenol (NP, 100% detection rate) and octylphenol (OP, 100% detection rate) might also be responsible for the estrogenic activities in water sources. Potential health risk induced by the estrogenic chemicals in source water may be posed to the residents through water drinking. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Hemodynamic and metabolic effects of estrogen plus progestin therapy in hypertensive postmenopausal women treated with an ACE-inhibitor or a diuretic.

    PubMed

    Posadzy-Malaczynska, Anna; Rajpold, Katarzyna; Woznicka-Leskiewicz, Lucyna; Marcinkowska, Justyna

    2015-01-01

    The aim of the study was to assess the hemodynamic and metabolic actions of estrogen plus progestin therapy (EPT) in hypertensive, postmenopausal women treated with perindopril (ACEI) or hydrochlorothiazide (HCTZ). A group of normotensive postmenopausal women was also studied. 100 hypertensive and 40 normotensive postmenopausal women were recruited for the study. The hypertensive females were randomly assigned to receive ACEI or HCTZ for 12 months. The patients of the ACEI group and the patients of the HCTZ group, as well as normotensives, were further subdivided into two subgroups each. One subgroup received estrogen plus progestin therapy (EPT+), the other subgroup received no hormone replacement (EPT-). Combined hormone replacement with transdermal patches releasing 17β-estradiol and norethisterone was used. Office and 24-hour ambulatory blood pressure was measured at baseline and during follow-up. Renal plasma flow (RPF) was measured using the clearance of [125I]-iodohippuran. Pulse wave velocity (PWV) was determined with an automatic device. In normotensive postmenopausal women, transdermal estrogen plus progestin therapy increases RPF and insulin sensitivity, decreases PWV, decreases total and LDL cholesterol, and decreases uric acid serum levels. Perindopril (4 mg/day) and hydrochlorothiazide (25 mg/day) were equally effective in reducing blood pressure in postmenopausal, hypertensive subjects. In these females, perindopril increased RPF and decreased PWV and plasma insulin levels. These effects of the ACEI were not altered by estrogen plus progestin therapy. Hydrochlorothiazide decreased RPF and increased plasma insulin and uric acid concentrations in hypertensive subjects whom were not receiving estrogen plus progestin therapy. The unfavorable metabolic and hemodynamic actions of the diuretic were counteracted by estrogen plus progestin therapy. Concomitant estrogen plus progestin therapy may be a method to avoid unfavorable hemodynamic and metabolic

  5. Infant formula feeding alters the proliferative status of neonatal mammary glands independent of estrogen signaling

    USDA-ARS?s Scientific Manuscript database

    Soy infant formula contains many phytochemicals, including phytoestrogens, which are structurally similar to estradiol (E2). The mammary gland is particularly sensitive to estrogens, and there are concerns that use of soy-based infant formulas may potentially have adverse effects on mammary tissue ...

  6. G Protein-coupled Estrogen Receptor Protects from Atherosclerosis

    PubMed Central

    Meyer, Matthias R.; Fredette, Natalie C.; Howard, Tamara A.; Hu, Chelin; Ramesh, Chinnasamy; Daniel, Christoph; Amann, Kerstin; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R.

    2014-01-01

    Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity. PMID:25532911

  7. 9-cis-retinoic acid represses estrogen-induced expression of the very low density apolipoprotein II gene.

    PubMed

    Schippers, I J; Kloppenburg, M; Snippe, L; Ab, G

    1994-11-01

    The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen-inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concentrated on a potential RXR recognition site, which deviates at only one position from a perfect direct A/GGGTCA repeat spaced by one nucleotide (DR-1) and was earlier identified as a common HNF-4/COUP-TF recognition site. However, band shift analysis revealed that this imperfect DR-1 motif does not interact with RXR alpha-homodimers. In accordance with this observation we found that this regulatory element does not mediate transactivation through RXR alpha in the presence of 9-cis-RA. However, our experiments revealed another, unexpected, effect of 9-cis-RA. Instead of stimulating, 9-cis-RA attenuated estrogen-induced expression of transfected estrogen-responsive VLDL-CAT reporter plasmids. This repression appeared to take place through the main estrogen response element (ERE) of the gene. Importantly, 9-cis-RA also strongly repressed the estrogen-induced expression of the endogenous apoVLDLII gene in cultured chicken hepatoma cells.

  8. Estrogen replacement therapy, Alzheimer's disease, and mild cognitive impairment.

    PubMed

    Mulnard, Ruth A; Corrada, Marìa M; Kawas, Claudia H

    2004-09-01

    This article highlights the latest findings regarding estrogen replacement therapy in the treatment and prevention of Alzheimer's disease (AD) and mild cognitive impairment in women. Despite considerable evidence from observational studies, recent randomized clinical trials of conjugated equine estrogens, alone and in combination with progestin, have shown no benefit for either the treatment of established AD or for the short-term prevention of AD, mild cognitive impairment, or cognitive decline. Based on the evidence, there is no role at present for estrogen replacement therapy in the treatment or prevention of AD or cognitive decline, despite intriguing results from the laboratory and from observational studies. However, numerous questions remain about the biologic effects of estrogens on brain structure and function. Additional basic and clinical investigations are necessary to examine different forms and dosages of estrogens, other populations, and the relevance of timing and duration of exposure.

  9. Bone marrow oxytocin mediates the anabolic action of estrogen on the skeleton

    USDA-ARS?s Scientific Manuscript database

    Estrogen withdrawal in women due to natural or artificial menopause is followed by rapid bone loss, osteoporosis, and a high fracture risk. Replacement with estrogen prevents this bone loss and reduces the risk of fracture. Estrogen uses two mechanisms to exert this effect: it inhibits bone resorpti...

  10. Executive function and attention are preserved in older surgically menopausal monkeys receiving estrogen or estrogen plus progesterone.

    PubMed

    Voytko, Mary Lou; Murray, Rhonda; Higgs, Casey J

    2009-08-19

    Animal models of menopause have been used to further define the cognitive processes that respond to hormone therapy and to investigate parameters that may influence the cognitive effects of estrogen. Many investigations in animals have focused on memory; however, the effects of hormone therapy on executive function and attention processes have not been well studied. Thus, the purpose of this set of investigations was to assess the effects of estrogen therapy alone or with progesterone on executive and attention processes in middle-aged ovariectomized monkeys. Monkeys were preoperatively trained on a modified version of the Wisconsin card sort task and on a visual cued reaction time task. Hormone therapy was initiated at the time of ovariectomy and cognitive function was reassessed at 2, 12, and 24 weeks postoperatively. Relative to monkeys receiving either of the estrogen therapies, monkeys receiving placebo were impaired in their ability to shift a cognitive set in the Wisconsin card sort task and were impaired in shifting visuospatial attention in the visual cued reaction time task. Our findings are consistent with clinical studies that indicate that hormone therapy can improve executive function and attention processes in postmenopausal women.

  11. Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM).

    PubMed

    Christgau, Stephan; Tankó, László B; Cloos, Paul A C; Mouritzen, Ulrik; Christiansen, Claus; Delaissé, Jean-Marie; Høegh-Andersen, Pernille

    2004-01-01

    Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women. To validate this observation, we investigated the effects of ovariectomy (OVX) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products (CTX-II). Furthermore, we investigated whether estrogen and levormeloxifene, a selective estrogen-receptor modulator (SERM), can prevent the OVX-induced changes in cartilage degradation. The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with levormeloxifene versus placebo. Sixty 6-month-old rats were divided in five groups. One group was subjected to sham and the others to OVX, followed by treatment with vehicle alone, estradiol or 0.2 mg/kg/day or 5 mg/kg/day of levormeloxifene. The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover. After study termination, hind knees were removed for histological analysis of erosions. The effect of levormeloxifene in post-menopausal women was assessed by measuring CTX-II in samples from 301 women who were participating in a phase II study of this SERM. OVX rats showed significant increases in the urinary excretion of CTX-II. After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats. Treatment with estrogen or levormeloxifene prevented the OVX-induced changes. There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 (r = 0.64, P < 0.001). In postmenopausal women treated with levormeloxifene, the urinary excretion of CTX-II was decreased by approximately 50% and restored CTX-II levels to the premenopausal range. This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans, suggesting

  12. Evaluation of the Biological Activity of Opuntia ficus indica as a Tissue- and Estrogen Receptor Subtype-Selective Modulator.

    PubMed

    An, Byoung Ha; Jeong, Hyesoo; Zhou, Wenmei; Liu, Xiyuan; Kim, Soolin; Jang, Chang Young; Kim, Hyun-Sook; Sohn, Johann; Park, Hye-Jin; Sung, Na-Hye; Hong, Cheol Yi; Chang, Minsun

    2016-06-01

    Phytoestrogens are selective estrogen receptor modulators (SERMs) with potential for use in hormone replacement therapy (HRT) to relieve peri/postmenopausal symptoms. This study was aimed at elucidating the molecular mechanisms underlying the SERM properties of the extract of Korean-grown Opuntia ficus-indica (KOFI). The KOFI extract induced estrogen response element (ERE)-driven transcription in breast and endometrial cancer cell lines and the expression of endogenous estrogen-responsive genes in breast cancer cells. The flavonoid content of different KOFI preparations affected ERE-luciferase activities, implying that the flavonoid composition likely mediated the estrogenic activities in cells. Oral administration of KOFI decreased the weight gain and levels of both serum glucose and triglyceride in ovariectomized (OVX) rats. Finally, KOFI had an inhibitory effect on the 17β-estradiol-induced proliferation of the endometrial epithelium in OVX rats. Our data demonstrate that KOFI exhibited SERM activity with no uterotrophic side effects. Therefore, KOFI alone or in combination with other botanical supplements, vitamins, or minerals may be an effective and safe alternative active ingredient to HRTs, for the management of postmenopausal symptoms. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  13. Contamination and Risk Assessment of Estrogens in Livestock Manure: A Case Study in Jiangsu Province, China.

    PubMed

    Xu, Pengcheng; Zhou, Xian; Xu, Defu; Xiang, Yanbing; Ling, Wanting; Chen, Mindong

    2018-01-12

    This study investigated the occurrence and contamination risk of estrogens in livestock manure in Jiangsu Province, China. Four estrogens-estriol (E3), 17β-estradiol (17β-E2), bisphenol A (BPA), and 17α-ethinyloestradiol (EE2)-were detected in livestock manure from hens, ducks, swine, and cows. The respective mean concentrations of each estrogen found in these manures were 289.8, 334.1, 330.3, and 33.7 μg/kg for E3; 38.6, 10.9, 52.9, and 38.8 μg/kg for 17β-E2; 63.6, 48.7, 51.9, and 11.7 μg/kg for BPA; and 14.3, 11.3, 25.1, and 21.8 μg/kg for EE2. Estrogens were most frequently detected at high concentrations in the manure of finishing pigs, followed by the manure of growing pigs and piglets. Estrogens can be partially degraded after banking up for seven days; yet, great quantities of estrogens remain in livestock manure. The total estradiol equivalent quantity (EEQ t ) estimated to be present in aquatic environments but originating from livestock waste was 10.5 ng/L, which was greater than the hazard baseline value (1 ng/L) and also higher than the proposed lowest observable effect concentration (10 ng/L) of E2 in aquatic environments. The results of our study demonstrate that livestock waste is an important source of estrogens, which may potentially affect the hormonal metabolism of aquatic organisms.

  14. ROLE OF ESTROGEN RECEPTOR-α ON FOOD DEMAND ELASTICITY

    PubMed Central

    Minervini, Vanessa; Rowland, Neil E.; Robertson, Kimberly L.; Foster, Thomas C.

    2016-01-01

    Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions. PMID:25869426

  15. Role of estrogen receptor-α on food demand elasticity.

    PubMed

    Minervini, Vanessa; Rowland, Neil E; Robertson, Kimberly L; Foster, Thomas C

    2015-05-01

    Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions. © Society for the Experimental Analysis of Behavior.

  16. Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1.

    PubMed

    Du, C; Xu, Y; Yang, K; Chen, S; Wang, X; Wang, S; Wang, C; Shen, M; Chen, F; Chen, M; Zeng, D; Li, F; Wang, T; Wang, F; Zhao, J; Ai, G; Cheng, T; Su, Y; Wang, J

    2017-04-01

    Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte (MK) differentiation and its deficiency will lead to megakaryoblastic leukemia. Here we show that estrogen can dose-dependently promote MK polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant upregulation of GATA1. Chromatin immunoprecipitation and a dual luciferase assay demonstrate that ERβ can directly bind the promoter region of GATA1 and activate its transcription. Steroid receptor coactivator 3 (SRC3) is involved in ERβ-mediated GATA1 transcription. The deficiency of ERβ or SRC3, similar to the inhibition of GATA1, leads to the impediment of estrogen-induced MK polyploidization and platelet production. Further investigations reveal that signal transducer and activator of transcription 1 signaling pathway downstream of GATA1 has a crucial role in estrogen-induced MK polyploidization, and ERβ-mediated GATA1 upregulation subsequently enhances nuclear factor erythroid-derived 2 expression, thereby promoting proplatelet formation and platelet release. Our study provides a deep insight into the molecular mechanisms of estrogen signaling in regulating thrombopoiesis and the pathogenesis of ER deficiency-related leukemia.

  17. miR-7-1 POTENTIATED ESTROGEN RECEPTOR AGONISTS FOR FUNCTIONAL NEUROPROTECTION IN VSC4.1 MOTONEURONS

    PubMed Central

    CHAKRABARTI, M.; BANIK, N. L.; RAY, S. K.

    2013-01-01

    Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERα agonist), Way200070 (WAY, ERβ agonist), and estrogen (EST, ERα and ERβ agonist) in preventing apoptosis in the calcium ionophore (CI) insulted VSC4.1 motoneurons. We determined that 200 nM CI induced 70% cell death. Treatment with 50 nM PPT, 100 nM WAY, and 150 nM EST induced overexpression of ERα, ERβ, and both receptors, respectively, at mRNA and protein levels. Treatment with ER agonists significantly upregulated miR-206, miR-17, and miR-7-1 in the CI insulted VSC4.1 motoneurons. Transfection with miR-206, miR-17, or miR-7-1 mimic potentiated WAY or EST to inhibit apoptosis in the CI insulted VSC4.1 motoneurons. Overexpression of miR-7-1 maximally increased efficacy of WAY and EST for down regulation of pro-apoptotic Bax and upregulation of anti-apoptotic Bcl-2. A search using miRDB indicated that miR-7-1 could inhibit expression of L-type Ca2+ channel protein alpha 1C (CPα1C). miR-7-1 overexpression and WAY or EST treatment down regulated CPα1C but upregulated p-Akt to trigger cell survival signaling. The same therapeutic strategy increased expression of the Ca2+/calmodulin-dependent protein kinase II beta (CaMKIIβ) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future to attenuate apoptosis of motoneurons in SCI. PMID

  18. Evaluation of the scientific underpinnings for identifying estrogenic chemicals in nonmammalian taxa using mammalian test systems.

    PubMed

    Ankley, Gerald T; LaLone, Carlie A; Gray, L Earl; Villeneuve, Daniel L; Hornung, Michael W

    2016-11-01

    The US Environmental Protection Agency has responsibility for assessing endocrine activity of more than 10 000 chemicals, a task that cannot reasonably be achieved solely through use of available mammalian and nonmammalian in vivo screening assays. Hence, it has been proposed that chemicals be prioritized for in vivo testing using data from in vitro high-throughput assays for specific endocrine system targets. Recent efforts focused on potential estrogenic chemicals-specifically those that activate estrogen receptor-alpha (ERα)-have broadly demonstrated feasibility of the approach. However, a major uncertainty is whether prioritization based on mammalian (primarily human) high-throughput assays accurately reflects potential chemical-ERα interactions in nonmammalian species. The authors conducted a comprehensive analysis of cross-species comparability of chemical-ERα interactions based on information concerning structural attributes of estrogen receptors, in vitro binding and transactivation data for ERα, and the effects of a range of chemicals on estrogen-signaling pathways in vivo. Overall, this integrated analysis suggests that chemicals with moderate to high estrogenic potency in mammalian systems also should be priority chemicals in nonmammalian vertebrates. However, the degree to which the prioritization approach might be applicable to invertebrates is uncertain because of a lack of knowledge of the biological role(s) of possible ERα orthologs found in phyla such as annelids. Further, comparative analysis of in vitro data for fish and reptiles suggests that mammalian-based assays may not effectively capture ERα interactions for low-affinity chemicals in all vertebrate classes. Environ Toxicol Chem 2016;35:2806-2816. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is

  19. Targeted estrogen delivery reverses the metabolic syndrome

    PubMed Central

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

    2013-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

  20. Effects of a phytoestrogen-containing soy extract on the growth-inhibitory activity of ICI 182 780 in an experimental model of estrogen-dependent breast cancer.

    PubMed

    Gallo, Daniela; Mantuano, Elisabetta; Fabrizi, Manuela; Ferlini, Cristiano; Mozzetti, Simona; De Stefano, Ilaria; Scambia, Giovanni

    2007-06-01

    The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogen-dependent breast cancer.

  1. Estrogen receptor expert system overview and examples

    EPA Science Inventory

    The estrogen receptor expert system (ERES) is a rule-based system developed to prioritize chemicals based upon their potential for binding to the ER. The ERES was initially developed to predict ER affinity of chemicals from two specific EPA chemical inventories, antimicrobial pe...

  2. Caffeine, coffee and tea intake and urinary estrogens and estrogen metabolites in premenopausal women

    PubMed Central

    Sisti, Julia S.; Hankinson, Susan E.; Caporaso, Neil E.; Gu, Fangyi; Tamimi, Rulla M.; Rosner, Bernard; Xu, Xia; Ziegler, Regina; Eliassen, A. Heather

    2015-01-01

    Background Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. Methods High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses’ Health Study II with mid-luteal phase urine samples and caffeine, coffee and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways and ratios by intake categories, and P-values for tests of linear trend. Results Compared to women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; P-trend=0.01) and 16-epiestriol (13% difference; P-trend=0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (P-trend=0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; P-trend=0.001) and 2-hydroxyestrone (52% difference; P-trend=0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1–3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; P-trend=0.01) and 17-epiestriol (48% difference; Ptrend=0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend=0.01). Conclusion Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Impact Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. PMID:26063478

  3. Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women.

    PubMed

    Sisti, Julia S; Hankinson, Susan E; Caporaso, Neil E; Gu, Fangyi; Tamimi, Rulla M; Rosner, Bernard; Xu, Xia; Ziegler, Regina; Eliassen, A Heather

    2015-08-01

    Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. ©2015 American Association for Cancer Research.

  4. Estrogenic modulation of inflammation-related genes in male rats following volume overload

    PubMed Central

    McLarty, Jennifer L.; Meléndez, Giselle C.; Levick, Scott P.; Bennett, Shanté; Sabo-Attwood, Tara; Brower, Gregory L.

    2012-01-01

    Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the β1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes. PMID:22274565

  5. FIELD DEPLOYABLE TECHNIQUES TO MONITOR EXPOSURE TO ENVIRONMENTAL ESTROGENS THROUGHOUT THE REPRODUCTIVE CYCLE OF WILD BIRDS

    EPA Science Inventory

    Concern about potential for endocrine disrupting chemicals to interfere with normal breeding behaviors of wildlife prompted this study of effects of exposure to environmental estrogens during the breeding cycle of wild birds. The house finch (Carpodacus mexicanus) was selected as...

  6. Steroid receptor coactivator-1 mediates estrogenic actions to prevent body weight gain in female mice

    USDA-ARS?s Scientific Manuscript database

    Estrogen receptor-alpha (ERalpha) expressed by hypothalamic proopiomelanocortin and steroidogenic factor-1 neurons largely mediates the antiobesity effects of estrogens in females. However, the critical molecular events that are coupled to ERalpha and mediate estrogenic effects on energy balance rem...

  7. The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

    PubMed

    van Vollenhoven, Ronald F; Houbiers, Jos G A; Buttgereit, Frank; In 't Hout, Joanna; Boers, Maarten; Leij, Susanne; Kvien, Tore K; Dijkmans, Ben A C; Szczepański, Leszek; Szombati, Istvan; Sierakowski, Stanislaw; Miltenburg, André M M

    2010-02-01

    Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

  8. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.

    PubMed

    Casadesus, Gemma; Garrett, Matthew R; Webber, Kate M; Hartzler, Anthony W; Atwood, Craig S; Perry, George; Bowen, Richard L; Smith, Mark A

    2006-01-01

    Estrogen and other sex hormones have received a great deal of attention for their speculative role in Alzheimer's disease (AD), but at present a direct connection between estrogen and the pathogenesis of AD remains elusive and somewhat contradictory. For example, on one hand there is a large body of evidence suggesting that estrogen is neuroprotective and improves cognition, and that hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later. However, on the other hand, studies such as the Women's Health Initiative demonstrate that HRT initiated in elderly women increases the risk of dementia. While estrogen continues to be investigated, the disparity of findings involving HRT has led many researchers to examine other hormones of the hypothalamic-pituitary-gonadal axis such as luteinising hormone (LH) and follicle-stimulating hormone. In this review, we propose that LH, rather than estrogen, is the paramount player in the pathogenesis of AD. Notably, both men and women experience a 3- to 4-fold increase in LH with aging, and LH receptors are found throughout the brain following a regional pattern remarkably similar to those neuron populations affected in AD. With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD. Mechanistically, we propose that elevated levels of LH may be a fundamental instigator responsible for the aberrant reactivation of the cell cycle that is seen in AD. Based on these aforementioned aspects, clinical trials underway with leuprolide acetate, a gonadotropin-releasing hormone agonist that ablates serum LH levels, hold great promise as a ready means of treatment in individuals afflicted with AD.

  9. GPER-independent effects of estrogen in rat aortic vascular endothelial cells.

    PubMed

    Ding, Q; Hussain, Y; Chorazyczewski, J; Gros, R; Feldman, R D

    2015-01-05

    GPER (aka GPR30) has been identified as an important mechanism by which estrogen mediates its effects. Previous studies from our laboratories and those of others have demonstrated that GPER activation mediates a range of vascular contractile and growth regulatory responses. However, the importance of GPER in mediating the actions of estradiol (E2) in rat aortic endothelial cells is unclear. Therefore, we sought to determine the importance of GPER vs. the "classical" estrogen receptor (ER) in mediating the endothelial growth regulatory effects of E2. To do this we assessed the effect of E2 in regulating phosphoERK content and apoptotic rates in rat aortic endothelial cells and the role of GPER in mediating these effects. E2 mediated a concentration-dependent inhibition of both ERK phosphorylation and serum deprivation-induced apoptosis with a maximal effect at a concentration of 10 nM. Pretreatment with the ER antagonist ICI 182780 abolished E2-mediated inhibition of both ERK phosphorylation and apoptosis. In contrast, pretreatment with GPER antagonist G15 had no significant effect on E2-mediated inhibition of ERK phosphorylation or on apoptosis. Further, downregulation of GPER expression with a GPER shRNA adenovirus did not block E2-mediated inhibitory effects on ERK phosphorylation and apoptosis. In fact, these inhibitory effects of E2 were further enhanced by GPER downregulation. Downregulation of ERα expression reversed the E2-mediated inhibitory effects to stimulatory effects. E2's phosphoERK and apoptosis stimulatory effects seen with ERα downregulation are attenuated by pretreatment with G15. In conclusion, in rat aortic endothelial cells, E2-mediated endothelial effects are predominantly driven by ER and not by GPER. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Is Estrogen a Therapeutic Target for Glaucoma?

    PubMed Central

    Dewundara, Samantha; Wiggs, Janey; Sullivan, David A.; Pasquale, Louis R.

    2016-01-01

    estrogen regulation, are associated with glaucoma. Conclusions Increasing evidence suggests that lifetime exposure to estrogen may alter the pathogenesis of glaucoma. Estrogen exposure may have a neuroprotective effect on the progression of POAG but further studies need to confirm this finding. The role of sex-specific preventive and therapeutic treatment may be on the horizon. PMID:26959139

  11. Hepatic Effects of Estrogen on Plasma Distribution of Small Dense Low-Density Lipoprotein and Free Radical Production in Postmenopausal Women.

    PubMed

    Nii, Shota; Shinohara, Koichi; Matsushita, Hiroshi; Noguchi, Yasuyuki; Watanabe, Kazushi; Wakatsuki, Akihiko

    2016-07-01

    Hepatic effects of estrogen therapy on low-density lipoprotein (LDL) subfraction or oxidative stress have not been previously evaluated. The purpose of the present study was to investigate whether the differential hepatic effects of estrogen affect plasma distribution of small dense LDL and free radical production in postmenopausal women. In all, 45 postmenopausal women were given 0.625 mg/day of oral conjugated equine estrogen (CEE) (n=15), 1.0 mg/day of oral 17β estradiol (E2) (n=15), or 50 μg/day of transdermal 17βE2 (n=15) for 3 months. Subjects received either estrogen alone or with dydrogesterone at 5 mg/day. Plasma concentrations of sex hormone-binding globulin (SHBG), lipids, metallic ions, and derivatives of reactive oxygen metabolites (d-ROMs) were measured. CEE, but not oral 17βE2, increased the plasma concentrations of triglyceride, copper (Cu), and d-ROMs and the ratio of small dense LDL/total LDL cholesterol, a marker for plasma distribution of small dense LDL. Transdermal 17βE2 decreased d-ROMs concentrations but did not significantly change other parameters. Plasma concentrations of SHBG increased in the 3 groups. Estrogen-induced changes in triglyceride correlated positively either with changes in SHBG (R=0.52, P=0.0002) or the ratio of small dense LDL/total LDL cholesterol (R=0.65, P<0.0001). Changes in Cu also correlated positively either with changes in SHBG (R=0.85, P<0.0001) or d-ROMs (R=0.86, P<0.0001). The hepatic effects of different routes or types of estrogen therapy may be associated with plasma distribution of small dense LDL and free radical production in postmenopausal women.

  12. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

    PubMed Central

    Clegg, Deborah J.; Hevener, Andrea L.

    2013-01-01

    Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. PMID:23460719

  13. Estrogen effects on cognition and hippocampal transcription in middle-aged mice.

    PubMed

    Aenlle, Kristina K; Kumar, Ashok; Cui, Li; Jackson, Travis C; Foster, Thomas C

    2009-06-01

    Young and middle-aged female mice were ovariectomized and given cyclic injections of either estradiol or vehicle treatments. During the fifth week after surgery the Morris water maze was used to assess cognitive function. Age and treatment effects emerged over the course of spatial training such that middle-aged vehicle treated mice exhibited deficits in acquiring a spatial search strategy compared to younger vehicle treated mice and middle-age estradiol treated mice. Following behavioral characterization, mice were maintained on their injection schedule until week seven and hippocampi were collected 24h after the last injection. Hippocampal RNA was extracted and genes responsive to age and estrogen were identified using cDNA microarrays. Estradiol treatment in middle-aged mice altered the expression of genes related to transcriptional regulation, biosynthesis, growth, neuroprotection, and elements of cell signaling pathways. Expression profiles for representative genes were confirmed in a separate set of animals using oligonucleotide arrays and RT-PCR. Our results indicate that estrogen treatment in middle-aged animals may promote hippocampal health during the aging process.

  14. Unique effects of energy versus estrogen deficiency on multiple components of bone strength in exercising women.

    PubMed

    Southmayd, E A; Mallinson, R J; Williams, N I; Mallinson, D J; De Souza, M J

    2017-04-01

    Many female athletes are energy and/or estrogen deficient, but the independent effects on bone health have not been isolated. Energy deficiency was detrimental at the tibia while estrogen deficiency was detrimental at the radius. Nutrition must be considered alongside menstrual recovery when addressing compromised bone health in female athletes. The purpose of this study was to describe volumetric bone mineral density (vBMD), bone geometry, and estimated bone strength in exercising women (n = 60) grouped according to energy status (energy replete (EnR: n = 30) vs. energy deficient (EnD: n = 30)) and estrogen status (estrogen replete (E 2 R: n = 33) vs. estrogen deficient (E 2 D: n = 27)), resulting in four distinct groups: EnR + E 2 R (n = 17), EnR + E 2 D (n = 13), EnD + E 2 R (n = 16), EnD + E 2 D (n = 14). Energy status was determined using the ratio of measured to predicted resting energy expenditure (mREE/pREE). Estrogen status was based on self-reported menstrual status confirmed by daily evaluation of urinary estrone-1-glucoronide (E1G), pregnanediol glucuronide (PdG), and luteinizing hormone (LH). Eumenorrheic women were considered E 2 R, amenorrheic women were E 2 D, and oligomenorrheic women were categorized based on history of menses in the past year. Bone was assessed using peripheral quantitative computed tomography (pQCT). EnD women exhibited lower total vBMD, trabecular vBMD, cortical area, and BSI at the distal tibia and lower total vBMD, smaller cortical area and cortical thickness, and larger endosteal circumference at the proximal tibia compared to EnR women (p < 0.042). E 2 D women had lower total and cortical vBMD, larger total and trabecular area, and lower BSI at the distal radius and lower cortical vBMD at the proximal radius compared to E 2 R women (p < 0.023). Energy and estrogen interacted to affect total and trabecular area at the distal tibia (p < 0.021). Efforts to correct energy deficiency, which in turn may

  15. Differential effects of selective estrogen receptor modulators on the vagina and its supportive tissues.

    PubMed

    Liang, Rui; Knight, Katrina; Nolfi, Alexis; Abramowitch, Steven; Moalli, Pamela A

    2016-02-01

    Some selective estrogen receptor modulators (SERMs) have been associated with increased incidence of urinary incontinence and pelvic organ prolapse. This study explored the effects of five SERMs on the function and matrix components of the vagina and its supportive tissues. Fifty-six rats were administered SERMs by oral gavage for 8 weeks (n = 8 for each SERM): raloxifene, tamoxifen, idoxifene, bazedoxifene at three different doses, and bazedoxifene with conjugated estrogens. Thirty-two rats were used as controls (n = 8 per group): sham operation (no ovariectomy), ovariectomy only, ovariectomy with vehicle gavage, and 17β-estradiol (subcutaneous). Vaginal supportive tissue complex was tested by uniaxial tensile testing. Total collagen content (hydroxyproline) and glycosaminoglycan content (Blyscan) were measured. Ovariectomy significantly decreased the mechanical integrity of the vagina and its supportive tissue complex, with a decrease in ultimate load and stiffness (all P < 0.05). Although 17β-estradiol supplementation maintained these properties similarly to sham operation, none of the SERMs was as effective--particularly idoxifene, bazedoxifene at higher doses, and bazedoxifene with conjugated estrogens (all P < 0.05). In addition, idoxifene and bazedoxifene induced increased total collagen content compared with sham or 17β-estradiol treatment (all P < 0.05). Glycosaminoglycan content did not change significantly. Unlike 17β-estradiol, SERM supplementation does not fully prevent ovariectomy-induced deterioration in the biomechanical properties of the vagina and its supportive tissues, with the effects of idoxifene and bazedoxifene being the least. The paradoxically increased collagen content in these two groups may be related to increased formation of nonfunctional collagen.

  16. Arsenic abrogates the estrogen-signaling pathway in the rat uterus

    PubMed Central

    2010-01-01

    Background Arsenic, a major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology. However, the exact molecular events leading to reproductive dysfunctions as a result of arsenic exposure are yet to be ascertained. This report evaluates the effect and mode of action of chronic oral arsenic exposure on the uterine physiology of mature female albino rats. Methods The effect of chronic oral exposure to arsenic at the dose of 4 microg/ml for 28 days was evaluated on adult female albino rats. Hematoxylin-eosin double staining method evaluated the changes in the histological architecture of the uterus. Circulating levels of gonadotropins and estradiol were assayed by enzyme-linked immunosorbent assay. Expression of the estrogen receptor and estrogen-induced genes was studied at the mRNA level by RT-PCR and at the protein level by immunohistochemistry and western blot analysis. Results Sodium arsenite treatment decreased circulating levels of estradiol in a dose and time-dependent manner, along with decrease in the levels of both LH and FSH. Histological evaluation revealed degeneration of luminal epithelial cells and endometrial glands in response to arsenic treatment, along with reduction in thickness of the longitudinal muscle layer. Concomitantly, downregulation of estrogen receptor (ER alpha), the estrogen-responsive gene - vascular endothelial growth factor (VEGF), and G1 cell cycle proteins, cyclin D1 and CDK4, was also observed. Conclusion Together, the results indicate that arsenic disrupted the circulating levels of gonadotropins and estradiol, led to degeneration of luminal epithelial, stromal and myometrial cells of the rat uterus and downregulated the downstream components of the estrogen signaling pathway. Since development and functional maintenance of the uterus is under the influence of estradiol, arsenic-induced structural degeneration may be attributed to the reduction in

  17. Calmodulin-like protein 3 is an estrogen receptor alpha coregulator for gene expression and drug response in a SNP, estrogen, and SERM-dependent fashion.

    PubMed

    Qin, Sisi; Ingle, James N; Liu, Mohan; Yu, Jia; Wickerham, D Lawrence; Kubo, Michiaki; Weinshilboum, Richard M; Wang, Liewei

    2017-08-18

    We previously performed a case-control genome-wide association study in women treated with selective estrogen receptor modulators (SERMs) for breast cancer prevention and identified single nucleotide polymorphisms (SNPs) in ZNF423 as potential biomarkers for response to SERM therapy. The ZNF423rs9940645 SNP, which is approximately 200 bp away from the estrogen response elements, resulted in the SNP, estrogen, and SERM-dependent regulation of ZNF423 expression and, "downstream", that of BRCA1. Electrophoretic mobility shift assay-mass spectrometry was performed to identify proteins binding to the ZNF423 SNP and coordinating with estrogen receptor alpha (ERα). Clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing was applied to generate ZR75-1 breast cancer cells with different ZNF423 SNP genotypes. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to SERMs and poly(ADP-ribose) polymerase (PARP) inhibitors. We identified calmodulin-like protein 3 (CALML3) as a key sensor of this SNP and a coregulator of ERα, which contributes to differential gene transcription regulation in an estrogen and SERM-dependent fashion. Furthermore, using CRISPR/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to SERMs and PARP inhibitors, alone or in combination, were observed not only in cells but also in a mouse xenograft model. Our results have demonstrated the mechanism by which the ZNF423 rs9940645 SNP might regulate gene expression and drug response as well as its potential role in achieving more highly individualized breast cancer therapy.

  18. Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles.

    PubMed

    Wagner, Martin; Oehlmann, Jörg

    2009-05-01

    Food consumption is an important route of human exposure to endocrine-disrupting chemicals. So far, this has been demonstrated by exposure modeling or analytical identification of single substances in foodstuff (e.g., phthalates) and human body fluids (e.g., urine and blood). Since the research in this field is focused on few chemicals (and thus missing mixture effects), the overall contamination of edibles with xenohormones is largely unknown. The aim of this study was to assess the integrated estrogenic burden of bottled mineral water as model foodstuff and to characterize the potential sources of the estrogenic contamination. In the present study, we analyzed commercially available mineral water in an in vitro system with the human estrogen receptor alpha and detected estrogenic contamination in 60% of all samples with a maximum activity equivalent to 75.2 ng/l of the natural sex hormone 17beta-estradiol. Furthermore, breeding of the molluskan model Potamopyrgus antipodarum in water bottles made of glass and plastic [polyethylene terephthalate (PET)] resulted in an increased reproductive output of snails cultured in PET bottles. This provides first evidence that substances leaching from plastic food packaging materials act as functional estrogens in vivo. Our results demonstrate a widespread contamination of mineral water with xenoestrogens that partly originates from compounds leaching from the plastic packaging material. These substances possess potent estrogenic activity in vivo in a molluskan sentinel. Overall, the results indicate that a broader range of foodstuff may be contaminated with endocrine disruptors when packed in plastics.

  19. Modulation of steroidogenesis and estrogen signalling in the estuarine killifish (Fundulus heteroclitus) exposed to ethinylestradiol.

    PubMed

    Hogan, Natacha S; Currie, Suzanne; LeBlanc, Sacha; Hewitt, L Mark; MacLatchy, Deborah L

    2010-06-10

    Previous studies have shown that mummichog (Fundulus heteroclitus; a lunar, asynchronous-spawning killifish of the western Atlantic) exposed to 17alpha-ethynylestradiol (EE2) exhibit decreased plasma reproductive steroid levels, decreased gonadal steroid production, increased plasma vitellogenin, decreased fecundity and impaired fertilization. The objective of this study was to determine the potential mechanisms by which EE2 depresses gonadal steroidogenesis and influences estrogen signalling in the mummichog. Adult recrudesced fish were exposed to the potent synthetic estrogen, ethinylestradiol (EE2; 0-270ng/L) for 14 days. Following exposure, gonadal tissue was removed and incubated for 24h with stimulators of steroidogenesis, including forskolin; 25-OH cholesterol; or pregnenolone. Testosterone production was decreased in basal, forskolin-stimulated and pregnenolone-stimulated EE2-exposed males, indicating effects on the steroidogenic pathway both at and downstream of cholesterol mobilization to P450 side-chain cleavage (P450scc) and/or P450scc conversion of cholesterol to pregnenolone. Hepatic transcript levels of estrogen receptor alpha (ERalpha) and vitellogenin were increased in EE2-treated males compared to control recrudescing males and females confirming an estrogenic response. Hepatic heat shock protein 90 (Hsp90), a chaperoning molecule involved in estrogen signalling, was not affected by EE2 exposure at either the transcript or protein level. However, higher levels of Hsp90 observed in the membrane fractions of female fish raise interesting questions regarding the influence of gender on Hsp90's role in estrogen signalling. These results demonstrate that EE2 can alter steroid production at specific sites within the steroidogenic pathway and can stimulate hepatic estrogen signalling, providing important information regarding the molecular mechanisms underlying the endocrine response of the mummichog to exogenous estrogen.

  20. Differential neonatal imprinting and regulation by estrogen of estrogen receptor subtypes alpha and beta and of the truncated estrogen receptor product (TERP-1) mRNA expression in the male rat pituitary.

    PubMed

    Tena-Sempere, M; Barreiro, M L; González, L C; Pinilla, L; Aguilar, E

    2001-11-01

    Two distinct nuclear estrogen receptors (ERs) have been identified, the classical one, renamed ERalpha, and the more recently cloned ERbeta. In a variety of tissues, gene expression of both receptor subtypes results in the generation of multiple transcripts encoding the full-length as well as several alternately spliced isoforms. In the rat pituitary, a truncated, tissue-specific variant of ERalpha, called TERP-1, has been identified and found able to modulate ERalpha and ERbeta activity. So far, its pattern of expression and hormonal regulation have been mostly studied in females. The present study was designed to analyze the pattern of expression of TERP-1 mRNA in the male rat pituitary at different stages of postnatal development, and to evaluate the impact of neonatal imprinting and estrogen treatment upon TERP-1 expression in the male pituitary. Assessment of TERP-1 mRNA levels by semi-quantitative RT-PCR, using a variant-specific primer pair, revealed that TERP-1 is also expressed in the male rat pituitary. Relative mRNA expression levels changed markedly during postnatal development, with moderate expression of the TERP-1 transcript at birth, barely detectable levels during the infantile-prepubertal period, and maximal values in adulthood. Expression of TERP-1 was sensitive to neonatal estrogen exposure, which resulted in a significant, persistent increase in mRNA levels from the infantile period until puberty. This phenomenon was not mimicked by neonatal blockade of endogenous GnRH. In addition, estrogen was able to acutely up-regulate pituitary TERP-1 mRNA expression levels in prepubertal (30-day-old) and adult (75-day-old) males. Interestingly, neonatal imprinting as well as acute estrogen treatment resulted in opposite effects on TERP-1 and full-length ERalpha and ERbeta transcripts, the latter being decreased under both conditions. In conclusion, our data indicate that TERP-1 mRNA is expressed in a developmentally regulated manner in the male rat

  1. Urinary Estrogen Metabolites in 2 Soy Trials with Premenopausal Women

    PubMed Central

    Maskarinec, Gertraud; Morimoto, Yukiko; Heak, Sreang; Isaki, Marissa; Steinbrecher, Astrid; Custer, Laurie; Franke, Adrian A.

    2012-01-01

    Background Soy consumption may protect against breast cancer through modification of estrogen metabolism. Objective We examined the effect of soy foods on urinary estrogens and the 2-hydroxy (OH)/16α-OH estrone (E1) ratio in 2 dietary interventions with premenopausal women. Methods BEAN1 was a 2-year randomized trial and BEAN2 a 13-month randomized crossover study. In both interventions, study participants consumed a high-soy diet with 2 soy food servings/day and a low-soy diet with <3 servings of soy/week. Urine samples were collected at baseline and at the end of the diet periods, analyzed for 9 estrogen metabolites by liquid chromatography mass spectrometry, and adjusted for creatinine levels. For BEAN1, 2 samples for 188 participants and for BEAN2, 3 samples for 79 women were analyzed. We applied mixed-effects regression models with log-transformed values of estrogen metabolites and soy intake as the exposure variable. Results In BEAN1, no effect of the high-soy diet on individual estrogen metabolites or hydroxylation pathways was observed. The median 2-OH/16α-OH E1 ratio decreased non-significantly in the intervention group from 6.2 to 5.2 as compared to 6.8 and 7.2 in the control group (p=0.63). In BEAN2, only 4-OHE1 was significantly lower after the high-soy diet. Interaction terms of the high-soy diet with equol producer status, ethnicity, and weight status revealed no significant effect modification. Conclusions Contrary to our hypothesis and some previous reports, the results from 2 well controlled dietary interventions do not support an effect of a high-soy diet on a panel of urinary estrogen metabolites and the 2-OH/16α-OHE1 ratio. PMID:22713773

  2. Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction.

    PubMed

    Xu, Pingwen; Zhu, Liangru; Saito, Kenji; Yang, Yongjie; Wang, Chunmei; He, Yanlin; Yan, Xiaofeng; Hyseni, Ilirjana; Tong, Qingchun; Xu, Yong

    2017-05-01

    Brain estrogen receptor-α (ERα) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERα expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic-pituitary-gonadal axis (HPG axis) and fertility. We report here that global deletion of a key downstream receptor for POMC peptide, the melanocortin 4 receptor (MC4R), did not affect normal negative feedback regulation of estrogen on the HPG axis, estrous cyclicity and female fertility. Furthermore, loss of the MC4R did not influence estrogenic regulation on food intake and body weight. These results indicate that the MC4R is not required for estrogen's effects on metabolic and reproductive functions. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Estrogen Metabolism and Breast Cancer

    PubMed Central

    Samavat, Hamed; Kurzer, Mindy S

    2015-01-01

    There is currently accumulating evidence that endogenous estrogens play a critical role in the development of breast cancer. Estrogens and their metabolites have been studied in both pre- and postmenopausal women with more consistent results shown in the latter population, in part because of large hormonal variations during the menstrual cycle and far fewer studies having been performed in premenopausal women. In this review we describe in detail estrogen metabolism and associated genetic variations, and provide a critical review of the current literature regarding the role of estrogens and their metabolites in breast cancer risk. PMID:24784887

  4. Long non-coding RNA MIAT is estrogen-responsive and promotes estrogen-induced proliferation in ER-positive breast cancer cells.

    PubMed

    Li, Yuehua; Jiang, Baohong; Wu, Xiaoping; Huang, Qin; Chen, Wenqi; Zhu, Hongbo; Qu, Xiaofei; Xie, Liming; Ma, Xin; Huang, Guo

    2018-05-21

    Estrogen drives the development and progression of estrogen receptor (ER)-positive breast cancer. However, the detailed mechanism underlying ER-driven carcinogenesis remains unclear despite extensive studies. Previously reports indicated higher expression of long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) in ER-positive breast cancer tissues than in ER-negative tissues. However, the functional relevance of MIAT in ER-positive breast cancer tumorigenesis was poorly understood. Here, we investigated the role of lncRNA MIAT in ER-positive breast cancer cells. MIAT was over-expressed in ER-positive breast cancer tissues and ER-positive breast cancer cell line MCF-7. Activating estrogen signaling by diethylstilbestrol (DES) led to a dose- and time-dependent up-regulation of MIAT in MCF-7 cells that was dependent on ERα, as evidenced by ERα silencing and pharmacological inhibition using ER antagonist ICI 182780. Silencing MIAT decreased DES-induced MCF-7 cell proliferation while overexpressing MIAT increased MCF-7 cell proliferation. Further mechanistic study identified that MIAT was critical for G1 to S phase cell cycle transition. Taken together, these results suggest that lncRNA MIAT is an estrogen-inducible lncRNA and a key regulator in ER-positive breast cancer cell growth. MIAT could serve as a potential biomarker and promising therapeutic target for ER-positive breast cancer. Copyright © 2018. Published by Elsevier Inc.

  5. Estrogen Protects Lenses against Cataract Induced by Transforming Growth Factor-β (TGFβ)

    PubMed Central

    Hales, Angela M.; Chamberlain, Coral G.; Murphy, Christopher R.; McAvoy, John W.

    1997-01-01

    Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-β (TGFβ) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFβ-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFβ and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFβ. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases. PMID:9016876

  6. CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lau, Wen Min; Doucet, Michele; Huang, David

    2013-07-26

    Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found thatmore » CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a

  7. Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival

    PubMed Central

    Liu, Suhuan; Le May, Cedric; Wong, Winifred P.S.; Ward, Robert D.; Clegg, Deborah J.; Marcelli, Marco; Korach, Kenneth S.; Mauvais-Jarvis, Franck

    2009-01-01

    OBJECTIVE We showed that 17β-estradiol (E2) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E2 activates nuclear estrogen receptors via an estrogen response element (ERE). E2 also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS We used mice and islets deficient in estrogen receptor-α (αERKO−/−), estrogen receptor-β (βERKO−/−), estrogen receptor-α and estrogen receptor-β (αβERKO−/−), and GPER (GPERKO−/−); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS We show that ERα protection of islet survival is ERE independent and that E2 favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO−/− mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO−/− mice and their islets, E2 partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E2 protection of islet survival is reproduced by a membrane-impermeant E2 formulation and a selective GPER agonist. Accordingly, GPERKO−/− mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS E2 protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival. PMID:19587358

  8. Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival.

    PubMed

    Liu, Suhuan; Le May, Cedric; Wong, Winifred P S; Ward, Robert D; Clegg, Deborah J; Marcelli, Marco; Korach, Kenneth S; Mauvais-Jarvis, Franck

    2009-10-01

    We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERalpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. We used mice and islets deficient in estrogen receptor-alpha (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(-/-) mice are susceptible to streptozotocin-induced insulin deficiency. E(2) protects beta-cell survival through ERalpha and ERbeta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival.

  9. Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease

    PubMed Central

    Rohan, Thomas E; Negassa, Abdissa; Chlebowski, Rowan T; Lasser, Norman L.; McTiernan, Anne; Schenken, Robert S.; Ginsberg, Mindy; Wassertheil-Smoller, Sylvia; Page, David L.

    2008-01-01

    Women with benign proliferative breast disease are at increased risk of subsequent breast cancer. Estrogens and progesterone exert proliferative effects on mammary epithelium and combined hormone replacement therapy has been associated with increased breast cancer risk. We tested the effect of conjugated equine estrogen plus progestin on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI trial of estrogen plus progestin, 16608 postmenopausal women were randomly assigned either to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate or to placebo. Baseline and annual breast exams and mammograms were required. The trial was terminated early (average follow-up, 5.5 years). We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. Overall, 178 incident cases of benign proliferative breast disease were ascertained in the estrogen plus progestin group and 99 in the placebo group. Use of estrogen plus progestin was associated with a 74% increase in risk of benign proliferative breast disease (hazard ratio 1.74, 95% CI 1.35-2.25). For benign proliferative breast disease without atypia the hazard ratio was 2.00 (95% CI 1.50-2.66), while for atypical hyperplasia it was 0.76 (95% CI 0.38-1.52). Risk varied little by levels of baseline characteristics. The results of this study suggest that use of estrogen plus progestin may increase the risk of benign proliferative breast disease. PMID:18725513

  10. The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity.

    PubMed

    Zhang, Bing; Zhou, Wen-Jie; Gu, Chun-Jie; Wu, Ke; Yang, Hui-Li; Mei, Jie; Yu, Jia-Jun; Hou, Xiao-Fan; Sun, Jian-Song; Xu, Feng-Yuan; Li, Da-Jin; Jin, Li-Ping; Li, Ming-Qing

    2018-05-14

    Endometriosis (EMS) is an estrogen-dependent gynecological disease with a low autophagy level of ectopic endometrial stromal cells (eESCs). Impaired NK cell cytotoxic activity is involved in the clearance obstruction of the ectopic endometrial tissue in the abdominopelvic cavity. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides, which have profound biological functions, such as anti-cancer activities. However, the role and mechanism of ginsenosides and metabolites in endometriosis are completely unknown. Here, we found that the compounds PPD, PPT, ginsenoside-Rg3 (G-Rg3), ginsenoside-Rh2 (G-Rh2), and esculentoside A (EsA) led to significant decreases in the viability of eESCs, particularly PPD (IC50 = 30.64 µM). In vitro and in vivo experiments showed that PPD promoted the expression of progesterone receptor (PR) and downregulated the expression of estrogen receptor α (ERα) in eESCs. Treatment with PPD obviously induced the autophagy of eESCs and reversed the inhibitory effect of estrogen on eESC autophagy. In addition, eESCs pretreated with PPD enhanced the cytotoxic activity of NK cells in response to eESCs. PPD decreased the numbers and suppressed the growth of ectopic lesions in a mouse EMS model. These results suggest that PPD plays a role in anti-EMS activation, possibly by restricting estrogen-mediated autophagy regulation and enhancing the cytotoxicity of NK cells. This result provides a scientific basis for potential therapeutic strategies to treat EMS by PPD or further structural modification.

  11. Distinct effects of 4-nonylphenol and estrogen-17β on expression of estrogen receptor α gene in smolting sockeye salmon

    USGS Publications Warehouse

    Luo, Qiong; Ban, Massatoshi; Ando, Hironori; Kitahashi, Takashi; Bhandari, Ramji K.; McCormick, Stephen D.; Urano, Akihisa

    2005-01-01

    Xenoestrogens such as 4-nonylphenol (4-NP) have been shown to affect the parr–smolt transformation, but their mechanisms of action are not known. We therefore examined effects of 4-NP and estradiol-17β (E2) on expression of estrogen receptor (ER) α gene in the liver, gill, pituitary and brain of sockeye salmon to elucidate molecular mechanisms of 4-NP and E2 and developmental differences in response during smolting. Fish were treated twice within a week with 4-NP (15 and 150 mg/kg BW), E2 (2 mg/kg BW) or only vehicle at three stages of smolting, pre-smolting in March, early smolting in April and late smolting in May. The absolute amounts of ERα mRNA were determined by real-time PCR. The basal amounts of ERα mRNA peaked in April in the liver, gill and pituitary. In March, E2 extensively increased the amounts in the liver, while 4-NP had no effects at this stage. In contrast, 4-NP (but not E2) decreased liver ERα mRNA in April. 4-NP also decreased the amount of ERα mRNA in the gill in April. In the pituitary, 4-NP increased ERα mRNA in March but decreased it in May. There were no significant effects in the brain. Changes in basal ERα mRNA observed in this study indicate that estrogen responsiveness of tissues may change during salmon smolting. Furthermore, 4-NP and E2 have different effects on expression of ERα gene in the liver and gill during smolting, and the response is dependent on smolt stage.

  12. Most plastic products release estrogenic chemicals: a potential health problem that can be solved.

    PubMed

    Yang, Chun Z; Yaniger, Stuart I; Jordan, V Craig; Klein, Daniel J; Bittner, George D

    2011-07-01

    Chemicals having estrogenic activity (EA) reportedly cause many adverse health effects, especially at low (picomolar to nanomolar) doses in fetal and juvenile mammals. We sought to determine whether commercially available plastic resins and products, including baby bottles and other products advertised as bisphenol A (BPA) free, release chemicals having EA. We used a roboticized MCF-7 cell proliferation assay, which is very sensitive, accurate, and repeatable, to quantify the EA of chemicals leached into saline or ethanol extracts of many types of commercially available plastic materials, some exposed to common-use stresses (microwaving, ultraviolet radiation, and/or autoclaving). Almost all commercially available plastic products we sampled--independent of the type of resin, product, or retail source--leached chemicals having reliably detectable EA, including those advertised as BPA free. In some cases, BPA-free products released chemicals having more EA than did BPA-containing products. Many plastic products are mischaracterized as being EA free if extracted with only one solvent and not exposed to common-use stresses. However, we can identify existing compounds, or have developed, monomers, additives, or processing agents that have no detectable EA and have similar costs. Hence, our data suggest that EA-free plastic products exposed to common-use stresses and extracted by saline and ethanol solvents could be cost-effectively made on a commercial scale and thereby eliminate a potential health risk posed by most currently available plastic products that leach chemicals having EA into food products.

  13. Estrogen levels modify scopolamine-induced amnesia in gonadally intact rats.

    PubMed

    de Macêdo Medeiros, André; Izídio, Geison Souza; Sousa, Diego Silveira; Macedo, Priscila Tavares; Silva, Anatildes Feitosa; Shiramizu, Victor Kenji Medeiros; Cabral, Alicia; Ribeiro, Alessandra Mussi; Silva, Regina Helena

    2014-08-04

    Previous studies suggested that estrogen plays a role in cognitive function by modulating the cholinergic transmission. However, most of the studies dealing with this subject have been conducted using ovariectomized rats. In the present study we evaluated the effects of physiological and supra-physiological variation of estrogen levels on scopolamine-induced amnesia in gonadally intact female rats. We used the plus-maze discriminative avoidance task (PMDAT) in order to evaluate anxiety levels and motor activity concomitantly to the memory performance. In experiment 1, female Wistar rats in each estrous cycle phase received scopolamine (1 mg/kg) or saline i.p. 20 min before the training session in the PMDAT. In experiment 2, rats in diestrus received estradiol valerate (1 mg/kg) or sesame oil i.m., and scopolamine (1 mg/kg) or saline i.p., 45 min and 20 min before the training, respectively. In experiment 3, rats in diestrus received scopolamine (1 mg/kg) or saline i.p. 20 min before the training, and estradiol valerate (1 mg/kg) or sesame oil i.m. immediately after the training session. In all experiments, a test session was performed 24 h later. The main results showed that: (1) scopolamine impaired retrieval and induced anxiolytic and hyperlocomotor effects in all experiments; (2) this cholinergic antagonist impaired acquisition only in animals in diestrus; (3) acute administration of estradiol valerate prevented the learning impairment induced by scopolamine and (4) interfered with memory consolidation process. The results suggest that endogenous variations in estrogen levels across the estrous cycle modulate some aspects of memory mediated by the cholinergic system. Indeed, specifically in diestrus, a stage with low estrogen levels, the impairment produced by scopolamine on the acquisition was counteracted by exogenous administration of the hormone, whereas the posttraining treatment potentiated the negative effects of scopolamine during the consolidation phase

  14. Vaginal estrogen: a dual-edged sword in postoperative healing of the vaginal wall.

    PubMed

    Ripperda, Christopher M; Maldonado, Pedro Antonio; Acevedo, Jesus F; Keller, Patrick W; Akgul, Yucel; Shelton, John M; Word, Ruth Ann

    2017-07-01

    Reconstructive surgery for pelvic organ prolapse is plagued with high failure rates possibly due to impaired healing or regeneration of the vaginal wall. Here, we tested the hypothesis that postoperative administration of local estrogen, direct injection of mesenchymal stem cells (MSCs), or both lead to improved wound healing of the injured vagina in a menopausal rat model. Ovariectomized rats underwent surgical injury to the posterior vaginal wall and were randomized to treatment with placebo (n = 41), estrogen cream (n = 47), direct injection of MSCs (n = 39), or both (n = 43). MSCs did not survive after injection and had no appreciable effects on healing of the vaginal wall. Acute postoperative administration of vaginal estrogen altered the response of the vaginal wall to injury with decreased stiffness, decreased collagen content, and decreased expression of transcripts for matrix components in the stromal compartment. Conversely, vaginal estrogen resulted in marked proliferation of the epithelial layer and increased expression of genes related to epithelial barrier function and protease inhibition. Transcripts for genes involved in chronic inflammation and adaptive immunity were also down-regulated in the estrogenized epithelium. Collectively, these data indicate that, in contrast to the reported positive effects of preoperative estrogen on the uninjured vagina, acute administration of postoperative vaginal estrogen has adverse effects on the early phase of healing of the stromal layer. In contrast, postoperative estrogen plays a positive role in healing of the vaginal epithelium after injury.

  15. Vaginal estrogen: a dual-edged sword in postoperative healing of the vaginal wall

    PubMed Central

    Ripperda, Christopher M.; Maldonado, Pedro Antonio; Acevedo, Jesus F.; Keller, Patrick W.; Akgul, Yucel; Shelton, John M.; Word, Ruth Ann

    2017-01-01

    Abstract Objective: Reconstructive surgery for pelvic organ prolapse is plagued with high failure rates possibly due to impaired healing or regeneration of the vaginal wall. Here, we tested the hypothesis that postoperative administration of local estrogen, direct injection of mesenchymal stem cells (MSCs), or both lead to improved wound healing of the injured vagina in a menopausal rat model. Methods: Ovariectomized rats underwent surgical injury to the posterior vaginal wall and were randomized to treatment with placebo (n = 41), estrogen cream (n = 47), direct injection of MSCs (n = 39), or both (n = 43). Results: MSCs did not survive after injection and had no appreciable effects on healing of the vaginal wall. Acute postoperative administration of vaginal estrogen altered the response of the vaginal wall to injury with decreased stiffness, decreased collagen content, and decreased expression of transcripts for matrix components in the stromal compartment. Conversely, vaginal estrogen resulted in marked proliferation of the epithelial layer and increased expression of genes related to epithelial barrier function and protease inhibition. Transcripts for genes involved in chronic inflammation and adaptive immunity were also down-regulated in the estrogenized epithelium. Conclusions: Collectively, these data indicate that, in contrast to the reported positive effects of preoperative estrogen on the uninjured vagina, acute administration of postoperative vaginal estrogen has adverse effects on the early phase of healing of the stromal layer. In contrast, postoperative estrogen plays a positive role in healing of the vaginal epithelium after injury. PMID:28169915

  16. Effect of adipose-derived mesenchymal stromal cells on tendon healing in aging and estrogen deficiency: an in vitro co-culture model.

    PubMed

    Veronesi, Francesca; Della Bella, Elena; Torricelli, Paola; Pagani, Stefania; Fini, Milena

    2015-11-01

    Aging and estrogen deficiency play a pivotal role in reducing tenocyte proliferation, collagen turnover and extracellular matrix remodeling. Mesenchymal stromal cells are being studied as an alternative for tendon regeneration, but little is known about the molecular events of adipose-derived mesenchymal stromal cells (ADSCs) on tenocytes in tendons compromised by aging and estrogen deficiency. The present in vitro study aims to compare the potential therapeutic effects of ADSCs, harvested from healthy young (sham) and aged estrogen-deficient (OVX) subjects, for tendon healing. An indirect co-culture system was set up with ADSCs, isolated from OVX or sham rats, and tenocytes from OVX rats. Cell proliferation, healing rate and gene expression were evaluated in both a standard culture condition and a microwound-healing model. It was observed that tenocyte proliferation, healing rate and collagen expression improved after the addition of sham ADSCs in both culture situations. OVX ADSCs also increased tenocyte proliferation and healing rate but less compared with sham ADSCs. Decorin and Tenascin C expression increased in the presence of OVX ADSCs. Findings suggest that ADSCs might be a promising treatment for tendon regeneration in advanced age and estrogen deficiency. However, some differences between allogenic and autologous cells were found and should be investigated in further in vivo studies. It appears that allogenic ADSCs improve tenocyte proliferation, collagen expression and the healing rate more than autologous cells. Autologous cells increase collagen expression only in the absence of an injury and increase Decorin and Tenascin C more than allogenic cells. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  17. Epileptogenic effects of G protein-coupled estrogen receptor 1 in the rat pentylenetetrazole kindling model of epilepsy.

    PubMed

    Kurt, Akif Hakan; Bosnak, Mehmet; Inan, Salim Yalcın; Celik, Ahmet; Uremis, Muhammed Mehdi

    2016-02-01

    G protein-coupled estrogen receptor 1 (GPER-1) has been demonstrated in several parts of the brain and may play an important role in estrogen downstream signaling pathway. However, the effects of this receptor on epileptic seizure are not clearly known. Therefore, the effects of GPER-1 agonist, G-1, GPER-1 antagonist, G-15 and the main estrogenic hormone, 17β-estradiol were investigated on seizures and brain tissue oxidative damages induced by pentylenetetrazole (PTZ) in rats. In this study, 30 adult male Wistar albino rats were used. Due to intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35mg/kg) which was repeated 12 times every 48h, chemical kindling occurred and kindling seizure was recorded for 30min. The rats were injected with 17β-estradiol (5μg/kg, ip) or G-1 (5μg/kg, ip), G-15 (5μg/kg, ip), Saline, Ethanol and Dimethyl sulfoxide (DMSO) 30min before each dose of PTZ. Observed seizures were classified between the phase 0-5. Thirty minutes later when the last 12. PTZ administration, all rats were sacrificed and the brain cortex, hippocampus sections were removed and the tissue superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) levels on these tissues were studied. GPER1 agonist, G-1 and estrogenic hormone, 17β-estradiol significantly increased the development of PTZ kindling the seizures. However, GPER1 antagonist, G-15 did not change the development of PTZ kindling the seizures. In the cortex and hippocampus homogenates, the NO levels after G-1 administration had significantly increased (p<0.05) compared to the PTZ groups but SOD activities and MDA levels demonstrated no difference between the groups. This is the first study that explores that GPER-1 receptors have epileptogenic effect on PTZ-induced kindling rat. GPER1 may mediate the epileptogenic effect of estrogens by changing the oxidative or anti-oxidative parameters in the brain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences

  18. Estrogenic Activities of Fatty Acids and a Sterol Isolated from Royal Jelly

    PubMed Central

    Isohama, Yoichiro; Maruyama, Hiroe; Yamada, Yayoi; Narita, Yukio; Ohta, Shozo; Araki, Yoko; Miyata, Takeshi; Mishima, Satoshi

    2008-01-01

    We have previously reported that royal jelly (RJ) from honeybees (Apis mellifera) has weak estrogenic activity mediated by interaction with estrogen receptors that leads to changes in gene expression and cell proliferation. In this study, we isolated four compounds from RJ that exhibit estrogenic activity as evaluated by a ligand-binding assay for the estrogen receptor (ER) β. These compounds were identified as 10-hydroxy-trans-2-decenoic acid, 10-hydroxydecanoic acid, trans-2-decenoic acid and 24-methylenecholesterol. All these compounds inhibited binding of 17β-estradiol to ERβ, although more weakly than diethylstilbestrol or phytoestrogens. However, these compounds had little or no effect on the binding of 17β-estradiol to ERα. Expression assays suggested that these compounds activated ER, as evidenced by enhanced transcription of a reporter gene containing an estrogen-responsive element. Treatment of MCF-7 cells with these compounds enhanced their proliferation, but concomitant treatment with tamoxifen blocked this effect. Exposure of immature rats to these compounds by subcutaneous injection induced mild hypertrophy of the luminal epithelium of the uterus, but was not associated with an increase in uterine weight. These findings provide evidence that these compounds contribute to the estrogenic effect of RJ. PMID:18830443

  19. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Raghavan Rajagopalan

    The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful formore » targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies the proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.« less

  20. Bone Marrow Oxytocin Mediates the Anabolic Action of Estrogen on the Skeleton*

    PubMed Central

    Colaianni, Graziana; Sun, Li; Di Benedetto, Adriana; Tamma, Roberto; Zhu, Ling-Ling; Cao, Jay; Grano, Maria; Yuen, Tony; Colucci, Sylvia; Cuscito, Concetta; Mancini, Lucia; Li, Jianhua; Nishimori, Katsuhiko; Bab, Itai; Lee, Heon-Jin; Iqbal, Jameel; Young, W. Scott; Rosen, Clifford; Zallone, Alberta; Zaidi, Mone

    2012-01-01

    Estrogen uses two mechanisms to exert its effect on the skeleton: it inhibits bone resorption by osteoclasts and, at higher doses, can stimulate bone formation. Although the antiresorptive action of estrogen arises from the inhibition of the MAPK JNK, the mechanism of its effect on the osteoblast remains unclear. Here, we report that the anabolic action of estrogen in mice occurs, at least in part, through oxytocin (OT) produced by osteoblasts in bone marrow. We show that the absence of OT receptors (OTRs) in OTR−/− osteoblasts or attenuation of OTR expression in silenced cells inhibits estrogen-induced osteoblast differentiation, transcription factor up-regulation, and/or OT production in vitro. In vivo, OTR−/− mice, known to have a bone formation defect, fail to display increases in trabecular bone volume, cortical thickness, and bone formation in response to estrogen. Furthermore, osteoblast-specific Col2.3-Cre+/OTRfl/fl mice, but not TRAP-Cre+/OTRfl/fl mice, mimic the OTR−/− phenotype and also fail to respond to estrogen. These data attribute the phenotype of OTR deficiency to an osteoblastic rather than an osteoclastic defect. Physiologically, feed-forward OT release in bone marrow by a rising estrogen concentration may facilitate rapid skeletal recovery during the latter phases of lactation. PMID:22761429

  1. Estrogen Signaling in Metabolic Inflammation

    PubMed Central

    Monteiro, Rosário; Teixeira, Diana; Calhau, Conceição

    2014-01-01

    There is extensive evidence supporting the interference of inflammatory activation with metabolism. Obesity, mainly visceral obesity, is associated with a low-grade inflammatory state, triggered by metabolic surplus where specialized metabolic cells such as adipocytes activate cellular stress initiating and sustaining the inflammatory program. The increasing prevalence of obesity, resulting in increased cardiometabolic risk and precipitating illness such as cardiovascular disease, type 2 diabetes, fatty liver, cirrhosis, and certain types of cancer, constitutes a good example of this association. The metabolic actions of estrogens have been studied extensively and there is also accumulating evidence that estrogens influence immune processes. However, the connection between these two fields of estrogen actions has been underacknowledged since little attention has been drawn towards the possible action of estrogens on the modulation of metabolism through their anti-inflammatory properties. In the present paper, we summarize knowledge on the modification inflammatory processes by estrogens with impact on metabolism and highlight major research questions on the field. Understanding the regulation of metabolic inflammation by estrogens may provide the basis for the development of therapeutic strategies to the management of metabolic dysfunctions. PMID:25400333

  2. Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics.

    PubMed

    Collongues, Nicolas; Patte-Mensah, Christine; De Seze, Jérôme; Mensah-Nyagan, Ayikoe-Guy; Derfuss, Tobias

    2018-06-01

    Neuroprotection and remyelination are two unmet needs in the treatment of multiple sclerosis (MS). Therapeutic potential has been identified with sexual hormones, supported in women by a decrease in MS activity during the pregnancy, in men by a greater severity of symptoms and a faster progression than in women. Areas covered: The therapeutic effect of testosterone and estrogens is reviewed. Both hormones have demonstrated an anti-inflammatory effect. Testosterone has an effect in protecting neurons in culture against glutamate-induced toxicity and oxidative stress, and stimulates myelin formation and regeneration mediated through the neural androgen receptor. In experimental autoimmune encephalomyelitis model, estrogens significantly decrease inflammation in the central nervous system via ERα, while its action on ERβ leads to myelin and axon reparation. Estriol therapy in two phase 2 trials showed a decrease in clinical disease activity and inflammatory parameters in MRI. However, evidence of a therapeutic effect of testosterone is scarce. Expert commentary: Phase 3 trials with estriol as an add-on supplementation are now mandatory. Testosterone is another candidate to be tested in phase 2 trials. These hormones should be considered as an adjunctive therapy. New validated tools are needed to assess their effect on neuroprotection and remyelination.

  3. G-protein-coupled receptor 30 mediates the effects of estrogen on endothelial cell tube formation in vitro.

    PubMed

    Zhou, Liyuan; Chen, Hong; Mao, Xun; Qi, Hongbo; Baker, Philip N; Zhang, Hua

    2017-06-01

    The placenta is the exchange organ between the mother and the fetus. The inadequate function of this organ is associated with a number of pregnancy disorders. Hypoxia and oxidative stress during placental development may induce endothelial dysfunction, resulting in the reduction in the perfusion of the placenta. During pregnancy, the levels of estrogen are increased. Decreased estrogen levels have been reported in women with preeclampsia. However, whether estrogen is involved in placental angiogenesis remains unclear. In this study, we aimed to investigate the effects of estrogen on endothelial cell tube formation and to elucidate the underlying mechanisms. For this purpose, human umbilical vein endothelial cells (HUVECs) were cultured with 17‑β‑estradiol under conditions of hypoxia/reoxygenation (H/R). The total pipe length of the tube‑like structure on endothelial cells was measured. The expression levels of G‑protein‑coupled receptor 30 (GPR30) and endothelial nitric oxide synthase (eNOS) and Akt were also measured in the endothelial cells following treatment with 17‑β‑estradiol under H/R conditions by western blot analysis and immunostaining. We found that the total pipe length of the tube‑like structure on endothelial cells was significantly reduced. This reduction was reversed by treatment with 17‑β‑estradiol. The expression of GPR30 in endothelial cells was significantly increased following treatment with 17‑β‑estradiol under H/R conditions. Furthermore, the levels of eNOS and Akt in endothelial cells were also significantly increased following treatment with 17-β-estradiol under H/R conditions. The activation of eNOS was inhibited by wortmannin, an inhibitor of PI3K/Akt. Our data thus demonstrate that estrogen prevents the failure of endothelial cell tube formation induced by H/R. GPR30 plays an important role in these protective effects through the activation of eNOS and Akt in endothelial cells. Our data suggest that

  4. Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS.

    PubMed

    Ma, Bo; Li, Xiaotian; Zhang, Qi; Wu, Di; Wang, Guangji; A, Jiye; Sun, Jianguo; Li, Jing; Liu, Yinhui; Wang, Yonglu; Ying, Hanjie

    2013-10-15

    A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110 mg/kg/day for the prevention and 220 mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss. © 2013 Elsevier B.V. All rights reserved.

  5. Evaluation of Follicular Synchronization Caused by Estrogen Administration and Its Reproductive Outcome

    PubMed Central

    Wu, Bi; Shi, Yan; Gong, Xia; Yu, Lin; Chen, Qiuju; Wang, Jian; Sun, Zhaogui

    2015-01-01

    To evaluate multiple follicular development synchronization after estrogen stimulation in prepubertal mice, follicular responsiveness to gonadotropin superovulation, the prospective reproductive potential and ovarian polycystic ovary syndrome (PCOS)-like symptoms at adulthood, prepubertal mice were intraperitoneally injected with estrogen to establish an animal model with solvent as control. When synchronized tertiary follicles in ovaries, in vitro oocyte maturation and fertilization rates, blastocyst formation rate, developmental potential into offspring by embryo transfer, adult fertility and PCOS-like symptoms, and involved molecular mechanisms were focused, it was found that estrogen stimulation (10μg/gBW) leads to follicular development synchronization at the early tertiary stage in prepubertal mice; reproduction from oocytes to offspring could be realized by means of the artificial reproductive technology though the model mice lost their natural fertility when they were reared to adulthood; and typical symptoms of PCOS, except changes in inflammatory pathways, were not remained up to adulthood. So in conclusion, estrogen can lead to synchronization in follicular development in prepubertal mice, but does not affect reproductive outcome of oocytes, and no typical symptoms of PCOS remained at adulthood despite changes related to inflammation. PMID:26010950

  6. Stanniocalcin 2 is an estrogen-responsive gene coexpressed with the estrogen receptor in human breast cancer.

    PubMed

    Bouras, Toula; Southey, Melissa C; Chang, Andy C; Reddel, Roger R; Willhite, Dorian; Glynne, Richard; Henderson, Michael A; Armes, Jane E; Venter, Deon J

    2002-03-01

    Differences in gene expression are likely to explain the phenotypic variation between hormone-responsive and hormone-unresponsive breast cancers. In this study, DNA microarray analysis of approximately 10,000 known genes and 25,000 expressed sequence tag clusters was performed to identify genes induced by estrogen and repressed by the pure antiestrogen ICI 182 780 in vitro that correlated with estrogen receptor (ER) expression in primary breast carcinomas in vivo. Stanniocalcin (STC) 2 was identified as one of the genes that fulfilled these criteria. DNA microarray hybridization showed a 3-fold induction of STC2 mRNA expression in MCF-7 cells in < or = 3 h of estrogen exposure and a 3-fold repression in the presence of antiestrogen (one-way ANOVA, P < 0.0005). In 13 ER-positive and 12 ER-negative breast carcinomas, the microarray-derived mRNA levels observed for STC2 correlated with tumor ER mRNA (Pearson's correlation, r = 0.85; P < 0.0001) and ER protein status (Spearman's rank correlation, r = 0.73; P < 0.0001). The expression profile of STC2 was further confirmed by in situ hybridization and immunohistochemistry on a larger cohort of 236 unselected breast carcinomas using tissue microarrays. STC2 mRNA and protein expression were found to be associated with tumor ER status (Fisher's exact test, P < 0.005). The related gene, STC1, was also examined and shown to be associated with ER status in breast carcinomas (Fisher's exact test, P < 0.05). This study demonstrates the feasibility of using global gene expression data derived from an in vitro model to pinpoint novel estrogen-responsive genes of potential clinical relevance.

  7. Dangguijakyak-san ameliorates memory deficits in ovariectomized mice by upregulating hippocampal estrogen synthesis.

    PubMed

    Hwang, Deok-Sang; Kim, Namkwon; Choi, Jin Gyu; Kim, Hyo Geun; Kim, Hocheol; Oh, Myung Sook

    2017-11-25

    Dangguijakyak-san (DJS) is an herbal formulation that has been clinically applicable for treating postmenopausal symptoms and neurological disorders. It is reported that hippocampal estrogen attenuates memory impairment via neuroprotection and synaptogenesis. However, the effect of DJS on hippocampal estrogen synthesis remains unknown. In this study, we explored the effect of DJS and its neuroprotective mechanism against memory impairment in ovariectomized (OVX) mice, with respect to hippocampal estrogen stimulation. Cell cultures were prepared from the hippocampi of 18-day-old embryos from timed pregnant Sprague-Dawley rats. The hippocampi were dissected, collected, dissociated, and plated in 60-mm dishes. The cells were treated with DJS for 48 h and the supernatant was collected to determine estrogen levels. Female ICR mice (8-weeks-old) were housed for 1 week and ovariectomy was performed to remove the influence of ovary-synthesized estrogens. Following a 2-week post-surgical recovery period, the mice were administrated with DJS (50 and 100 mg/kg/day, p.o.) or 17β-estradiol (200 μg/kg/day, i.p.) once daily for 21 days. Hippocampal and serum estrogen levels were determined using enzyme-linked immunosorbent assay kit. Memory behavioral tests, western blot, and immunohistochemical analyses were performed to evaluate the neuroprotective effects of DJS in this model. DJS treatment promoted estrogen synthesis in primary hippocampal cells and the hippocampus of OVX mice, resulting in the amelioration of OVX-induced memory impairment. Hippocampal estrogen stimulated by DJS treatment contributed to the activation of cAMP response element-binding protein and synaptic protein in OVX mice. DJS may attenuate memory deficits in postmenopausal women via hippocampal estrogen synthesis.

  8. Epidemiology of estrogen and dementia in women with Down syndrome.

    PubMed

    Schupf, Nicole; Lee, Joseph H; Pang, Deborah; Zigman, Warren B; Tycko, Benjamin; Krinsky-McHale, Sharon; Silverman, Wayne

    2018-01-01

    Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia. Polymorphisms in genes associated with estrogen receptor activity and in genes for estrogen biosynthesis affecting endogenous estrogen are related to age at onset and cumulative incidence of dementia, and may serve as biomarkers of risk. To date, no clinical trials of estrogen or hormone replacement therapy (ERT/HRT) have been published for women with Down syndrome. While findings from clinical trials of ERT or HRT for dementia have generally been negative among women in the neurotypical population, the short interval between menopause and onset of cognitive decline, together with a more positive balance between potential benefits and risks, suggests an opportunity to evaluate the efficacy of ERT/HRT for delaying or preventing dementia in this high risk population, although questions concerning the optimal formulation and timing of the hormone therapy are not yet resolved. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Estrogenic effect of the phytoestrogen biochanin A in zebrafish, Danio rerio, and brown trout, Salmo trutta.

    PubMed

    Holbech, Henrik; Schröder, Kristoffer D; Nielsen, Marie L; Brande-Lavridsen, Nanna; Holbech, Bente Frost; Bjerregaard, Poul

    2013-11-15

    Isoflavones with estrogenic activity produced in Fabaceae plants are known to leach from agricultural areas to freshwater systems, but the effect of waterborne isoflavones in fish has not been thoroughly characterized. Therefore, the estrogenic effect of waterborne biochanin A was investigated in zebrafish (Danio rerio) and juvenile brown trout (Salmo trutta). Exposure of juvenile brown trout to 10 μg biochanin AL(-1) or higher caused marked vitellogenin induction after 9-10 days of exposure and so did exposure to 186 μg biochanin AL(-1) for 6h. Following 8d of exposure, a NOEC for induction of vitellogenin production in male zebrafish was 70 and LOEC 114 μg biochanin AL(-1). Exposure to 209 μg biochanin AL(-1) from hatch to 60 days post hatch (dph) caused a skewing of the sex ratio toward more phenotypic female zebrafish, but did not cause induction of vitellogenin in male and undifferentiated fish. (1) biochanin A elicits estrogenic effects in trout at environmentally realistic concentrations, (2) brown trout plasma vitellogenin concentrations respond to lower biochanin A exposure concentrations than vitellogenin concentrations in zebrafish homogenates and (3) concerning vitellogenin induction, the hypothesis should be tested if short term tests with zebrafish may show a higher sensitivity than partial life cycle tests. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Simultaneous determination of UV-filters and estrogens in aquatic invertebrates by modified quick, easy, cheap, effective, rugged, and safe extraction and liquid chromatography tandem mass spectrometry

    Treesearch

    Ke He; Anne Timm; Lee Blaney

    2017-01-01

    tUltraviolet-filters (UV-filters) and estrogens have attracted increased attention as contaminants of emerging concern (CECs) due to their widespread occurrence in the environment. Most of these CECs are hydrophobic and have the potential to accumulate in aquatic organisms. To date, co-analysis of UV-filters and estrogens has not been reported due, in part, to the...

  11. ASSAYS FOR ENDOCRINE DISRUPTING CHEMICALS: BEYOND ENVIRONMENTAL ESTROGENS

    EPA Science Inventory

    Recent popular and scientific articles have reported the presence of estrogenic and other hormone mimicking chemicals in the environment and their potential for causing reproductive dysfunction in humans and wildlife. The purpose of this session was to present the best available,...

  12. The Effect of a Home-Based Walking Intervention on Quality of Life Body Composition and Estrogen Metabolism in Postmenopausal Breast Cancer Survivors

    DTIC Science & Technology

    2003-09-01

    the effect of a 12-week home-based walking intervention on quality of life , body composition, and estrogen metabolism in survivors of breast cancer...randomized to the walking intervention will report higher levels of quality of life , experience less weight gain, and have more favorable estrogen

  13. The Effect of a Home-Based Walking Intervention on Quality of Life, Body Composition, and Estrogen Metabolism in Postmenopausal Breast Cancer Survivors

    DTIC Science & Technology

    2004-09-01

    the effect of a 12-week home-based walking intervention on quality of life , body composition, and estrogen metabolism in survivors of breast cancer...randomized to the walking intervention will report higher levels of quality of life , experience less weight gain, and have more favorable estrogen

  14. The polymorphism of estrogen receptor α is important for metabolic consequences associated with menopause.

    PubMed

    Pinkas, Jarosław; Gujski, Mariusz; Wierzbińska-Stępniak, Anna; Owoc, Alfred; Bojar, Iwona

    2016-01-01

    Menopause is associated with multiple health and metabolic consequences resulting from the decrease in estrogens level. Women at postmenopausal age are burdened with a higher risk of cardiovascular diseases, and the main cause of mortality in this group is ischemic heart disease. Estrogen deficiency is related, among other things, with frequent occurrence of dislipidemia, cessation of the beneficial effect of estrogens on the vascular wall, increase in body weight characterized by unfavourable redistribution of fatty tissue, with an increased amount of visceral fat and reduction of so-called non-fatty body mass. Estrogens exert an effect on metabolism, mainly through the genomic mechanism. The presence of α and β estrogen receptors was found in many tissues and organs. Recently, attention was paid to the fact that the effect of estrogens action on tissues and organs may depend not only on distribution, but also on their polymorphic types. The article presents the latest approach to the problem of metabolic consequences resulting from menopause, according to the possessed α estrogen receptor polymorphism (ERα).Genes encoding for ERα have many polymorphic variants, the most important of which from the clinical aspect are two single nucleotide polymorphisms (SNPs) - Xba1 and PvuII. The review of literature indicates that ERα polymorphisms are of great importance with respect to the effect of estrogens on the functioning of the body of a woman after menopause, and may imply the development of many pathological states, including the prevention or development of metabolic disorders. Identifying ERα polymorphisms may be useful in case of estrogen therapy for menopausal women who may benefit from it.

  15. Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction

    USDA-ARS?s Scientific Manuscript database

    Brain estrogen receptor-a (ERa) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERa expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic–pituitary–gonadal...

  16. GPER - novel membrane estrogen receptor

    PubMed Central

    Zimmerman, Margaret A.; Budish, Rebecca A.; Kashyap, Shreya; Lindsey, Sarah H.

    2016-01-01

    The recent discovery of the G protein-coupled estrogen receptor (GPER) presents new challenges and opportunities for understanding the physiology, pathophysiology, and pharmacology of many diseases. This review will focus on the expression and function of GPER in hypertension, kidney disease, atherosclerosis, vascular remodeling, heart failure, reproduction, metabolic disorders, cancer, environmental health, and menopause. Furthermore, this review will highlight the potential of GPER as a therapeutic target. PMID:27154744

  17. Tamoxifen regulation of bone growth and endocrine function in the ovariectomized rat: discrimination of responses involving estrogen receptor α/estrogen receptor β, G protein-coupled estrogen receptor, or estrogen-related receptor γ using fulvestrant (ICI 182780).

    PubMed

    Fitts, James M; Klein, Robert M; Powers, C Andrew

    2011-07-01

    Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-γ (ERRγ) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ERα/ERβ, is inactive on ERRγ, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ERα/ERβ versus ERRγ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ERα/ERβ. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ERα/ERβ. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ERα/ERβ. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ERα/ERβ contribute to tamoxifen effects on body weight, bone growth, and pituitary function.

  18. Estrogen and phenol red free medium for osteoblast culture: study of the mineralization ability.

    PubMed

    de Faria, A N; Zancanela, D C; Ramos, A P; Torqueti, M R; Ciancaglini, P

    2016-08-01

    To design an estrogen and phenol red free medium for cell culture and check its effectiveness and safety on osteoblast growth it is necessary to maintain the estrogen receptors free for tests. For this purpose, we tested some modifications of the traditional culture media: estrogen depleted fetal bovine serum; estrogen charcoal stripped fetal bovine serum and phenol red free α-MEM. The aim of this work is to examine the effects of its depletion in the proliferation, differentiation, and toxicity of mesenchymal stromal cells differentiated into osteoblasts to obtain an effective interference free culture medium for in vitro studies, focused on non-previously studied estrogen receptors. We performed viability tests using the following techniques: MTT, alkaline phosphatase specific activity, formation of mineralized matrix by Alizarin technique and analysis of SEM/EDX of mineralized nodules. The results showed that the culture media with estrogen free α-MEM + phenol red free α-MEM did not impact viability, alkaline phosphatase activity and mineralization of the osteoblasts culture compared to control. In addition, its nodules possess Ca/P ratio similar to hydroxyapatite nodules on the 14th and 21st day. In conclusion, the modified culture medium with phenol red free α-MEM with estrogen depleted fetal bovine serum can be safely used in experiments where the estrogen receptors need to be free.

  19. Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD).

    PubMed

    Sahin, Nilfer; Altun, Hatice; Kurutaş, Ergül Belge; Fındıklı, Ebru

    2018-05-20

    Estrogen has a crucial role in the regulation of reproductive and neuroendocrine function and exerts its effects through two classes of receptors, nuclear and membrane estrogen receptors (mERs). G protein-coupled estrogen receptor 1 (GPER) is a member of mERs, and despite limited research on the levels of GPER in patients with psychiatric diseases, a role of GPER in such conditions has been suggested. Here we evaluated serum estrogen and GPER levels in children with attention deficit hyperactivity disorder (ADHD) in relation to their age- and gender-matched healthy controls. A total of 82 children were included in the study, 47 drug- naïve patients with ADHD (age: 6-12 years; male/female: 34/13) and 35 healthy controls (age: 6-12 years; male/female: 19/16). The subgroups according to ADHD types were inattentive, hyperactive/impulsive, and combined. Serum estrogen was measured using an immunoassay system, while serum GPER was determined using a commercial sandwich enzyme-linked immunosorbent assay kit. Estrogen levels in children with ADHD were similar as in control group, while GPER levels were significantly lower in ADHD group compared to controls (p < 0.05). Logistic regression analysis showed a significant association between GPER levels and ADHD (p < 0.05), and no association between estrogen levels and ADHD (p > 0.05). No significant differences were found in GPER and estrogen levels between ADHD subgroups (p > 0.05). To the best of our knowledge, this study is the first to investigate estrogen and GPER levels in ADHD. Our preliminary findings suggest a relationship between serum GPER levels and ADHD, and this should be further investigated.

  20. Estrogenic activity of lambda-cyhalothrin in the MCF-7 human breast carcinoma cell line.

    PubMed

    Zhao, Meirong; Zhang, Ying; Liu, Weiping; Xu, Chao; Wang, Lumei; Gan, Jianying

    2008-05-01

    Synthetic pyrethroids are widely used in both agricultural and urban environments for insect control. Lambda-cyhalothrin (LCT) is one of the most common pyrethroids and is used mainly for controlling mosquitoes, fleas, cockroaches, flies, and ants around households. Previous studies have addressed the environmental behaviors and acute toxicities of LCT, but little is known about its chronic toxicity, such as estrogen-like activity. In the present study, the estrogenic potential of LCT was evaluated using the MCF-7 human breast carcinoma cell line. The in vitro E-screen assay showed that 10(-7) M LCT could significantly promote MCF-7 cell proliferation, with a relative proliferative effect ratio of 45%. The cell proliferation induced by LCT could be blocked completely, however, by the addition of 10(-9) M of the estrogen receptor (ER)-antagonist ICI 182,780. The semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) results showed that the Trefoil factor 1 (pS2) and progesterone receptor gene expression were up-regulated by 10(-7) M LCT for 2- and 1.5-fold, respectively. On the other hand, RT-PCR, Western blot analysis, and immunofluorescent assay demonstrated that LCT significantly repressed the mRNA and protein expression levels of ERalpha and ERbeta. These observations indicate that LCT possesses estrogenic properties and may function as a xenoestrogen, likely via a mechanism similar to that of 17beta-estradiol. The endocrine-disruption potential of LCT should be considered when assessing the safety of this compound in sensitive environmental compartments.

  1. Contamination and Risk Assessment of Estrogens in Livestock Manure: A Case Study in Jiangsu Province, China

    PubMed Central

    Xu, Pengcheng; Zhou, Xian; Xu, Defu; Xiang, Yanbing; Ling, Wanting; Chen, Mindong

    2018-01-01

    This study investigated the occurrence and contamination risk of estrogens in livestock manure in Jiangsu Province, China. Four estrogens—estriol (E3), 17β-estradiol (17β-E2), bisphenol A (BPA), and 17α-ethinyloestradiol (EE2)—were detected in livestock manure from hens, ducks, swine, and cows. The respective mean concentrations of each estrogen found in these manures were 289.8, 334.1, 330.3, and 33.7 μg/kg for E3; 38.6, 10.9, 52.9, and 38.8 μg/kg for 17β-E2; 63.6, 48.7, 51.9, and 11.7 μg/kg for BPA; and 14.3, 11.3, 25.1, and 21.8 μg/kg for EE2. Estrogens were most frequently detected at high concentrations in the manure of finishing pigs, followed by the manure of growing pigs and piglets. Estrogens can be partially degraded after banking up for seven days; yet, great quantities of estrogens remain in livestock manure. The total estradiol equivalent quantity (EEQt) estimated to be present in aquatic environments but originating from livestock waste was 10.5 ng/L, which was greater than the hazard baseline value (1 ng/L) and also higher than the proposed lowest observable effect concentration (10 ng/L) of E2 in aquatic environments. The results of our study demonstrate that livestock waste is an important source of estrogens, which may potentially affect the hormonal metabolism of aquatic organisms. PMID:29329262

  2. Synthesis and evaluation of 2-halogenated-1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylenes as potential estrogen receptor-targeted radiodiagnostic and radiotherapeutic agents.

    PubMed

    Hanson, Robert N; Tongcharoensirikul, Pakamas; Barnsley, Kelton; Ondrechen, Mary Jo; Hughes, Alun; DeSombre, Eugene R

    2015-04-01

    A series of three 1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylene derivatives was prepared and evaluated as potential estrogen receptor imaging agents. The compounds display high binding affinity compared to estradiol, with the 2-iodo and 2-bromo-derivatives expressing higher affinity than the parent 2-nonhalogenated derivative. Evaluation in immature female rats also indicate that the compounds were all full estrogenic agonists with potencies in the same order of activity (I∼Br>H). Computational analysis of the interactions between the ligands and ERα-LBD demonstrated positive contribution of halide to binding properties. In preparation for studies using the radiohalogenated analogs, the corresponding protected 2-(tributylstannyl) derivative was prepared and converted to the corresponding 2-iodo-product. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Glyphosate induces growth of estrogen receptor alpha positive cholangiocarcinoma cells via non-genomic estrogen receptor/ERK1/2 signaling pathway.

    PubMed

    Sritana, Narongrit; Suriyo, Tawit; Kanitwithayanun, Jantamas; Songvasin, Benjaporn Homkajorn; Thiantanawat, Apinya; Satayavivad, Jutamaad

    2018-06-08

    Previous studies showed that glyphosate stimulates breast cancer cell growth via estrogen receptors. The present study investigated the effect of glyphosate on the estrogen signaling pathway involved in the induction of cholangiocarcinoma (CCA) cell growth. HuCCA-1, RMCCA-1 and MMNK-1 were chosen for comparison. The effects of glyphosate on cell growth, cell cycle and molecular signaling pathways were measured. The results showed that HuCCA-1 cells expressed estrogen receptor alpha (ERα), while ERα was not detected in RMCCA-1 and MMNK-1 cells. ERα was mostly expressed in cytoplasmic compartment of HuCCA-1 cells. Estradiol (E2) (10 -11 -10 -5  M) induced cell proliferation in HuCCA-1 but not in RMCCA-1 and MMNK-1 cells. Glyphosate at the same concentration range also induced HuCCA-1 cell proliferation. The S phase of the cell cycle, and protein levels of the cyclin family were significantly increased after treatment of glyphosate or E2. Both compounds also induced the expression of proliferative signaling-related proteins including ERα, VEGFR2, pERK, PI3K(p85), and PCNA. These effects of glyphosate and E2 were abolished by the ER antagonist, 4-hydroxytamoxifen and U0126, a MEK inhibitor. The data from this study indicate that glyphosate can induce cell growth in ERα positive CCA cells through non-genomic estrogen receptor/ERK1/2 signaling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Mitochondria, Estrogen and Female Brain Aging

    PubMed Central

    Lejri, Imane; Grimm, Amandine; Eckert, Anne

    2018-01-01

    Mitochondria play an essential role in the generation of steroid hormones including the female sex hormones. These hormones are, in turn, able to modulate mitochondrial activities. Mitochondria possess crucial roles in cell maintenance, survival and well-being, because they are the main source of energy as well as of reactive oxygen species (ROS) within the cell. The impairment of these important organelles is one of the central features of aging. In women’s health, estrogen plays an important role during adulthood not only in the estrous cycle, but also in the brain via neuroprotective, neurotrophic and antioxidant modes of action. The hypestrogenic state in the peri- as well as in the prolonged postmenopause might increase the vulnerability of elderly women to brain degeneration and age-related pathologies. However, the underlying mechanisms that affect these processes are not well elucidated. Understanding the relationship between estrogen and mitochondria might therefore provide better insights into the female aging process. Thus, in this review, we first describe mitochondrial dysfunction in the aging brain. Second, we discuss the estrogen-dependent actions on the mitochondrial activity, including recent evidence of the estrogen—brain-derived neurotrophic factor and estrogen—sirtuin 3 (SIRT3) pathways, as well as their potential implications during female aging. PMID:29755342

  5. Characterizing the Growth Kinetics in Estrogen Responsive T47D Cells After Exposure to 2000 Environmental Chemicals

    EPA Science Inventory

    There is a need to develop high-throughput screening (HTS) tests capable of testing thousands of environmental chemicals for endocrine disrupting potential. The estrogen signaling pathway is a known xenobiotic target that has been implicated in a variety of adverse health effects...

  6. ESTROGEN INDUCED VITELLOGENIN MRNA AND PROTEIN IN SHEEPSHEAD MINNOW (CYPRINODON VARIEGATUS)

    EPA Science Inventory

    Many environmentally persistent xenobiotic chemicals appear to disrupt normal endocrine function by acting as ligands for endogenous steroid receptors, including the estrogen receptor. Xenobiotics that bind to the estrogen receptor may elicit several effects, one of which is acti...

  7. Effects of the environmental estrogenic contaminants bisphenol A and 17α-ethinyl estradiol on sexual development and adult behaviors in aquatic wildlife species

    USGS Publications Warehouse

    Bhandari, Ramji K.; Deem, Sharon L.; Holliday, Dawn K.; Jandegian, Caitlin M.; Kassotis, Christopher D.; Nagel, Susan C.; Tillitt, Donald E.; vom Saal, Frederick S.; Rosenfeld, Cheryl S.

    2015-01-01

    Endocrine disrupting chemicals (EDCs), including the mass-produced component of plastics, bisphenol A (BPA) are widely prevalent in aquatic and terrestrial habitats. Many aquatic species, such as fish, amphibians, aquatic reptiles and mammals, are exposed daily to high concentrations of BPA and ethinyl estradiol (EE2), estrogen in birth control pills. In this review, we will predominantly focus on BPA and EE2, well-described estrogenic EDCs. First, the evidence that BPA and EE2 are detectable in almost all bodies of water will be discussed. We will consider how BPA affects sexual and neural development in these species, as these effects have been the best characterized across taxa. For instance, such chemicals have been in many cases reported to cause sex-reversal of males to females. Even if these chemicals do not overtly alter the gonadal sex, there are indications that several EDCs might demasculinize male-specific behaviors that are essential for attracting a mate. In so doing, these chemicals may reduce the likelihood that these males reproduce. If exposed males do reproduce, the concern is that they will then be passing on compromised genetic fitness to their offspring and transmitting potential transgenerational effects through their sperm epigenome. We will thus consider how diverse epigenetic changes might be a unifying mechanism of how BPA and EE2 disrupt several processes across species. Such changes might also serve as universal species diagnostic biomarkers of BPA and other EDCs exposure. Lastly, the evidence that estrogenic EDCs-induced effects in aquatic species might translate to humans will be considered.

  8. GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release.

    PubMed

    Filardo, Edward J; Thomas, Peter

    2005-10-01

    Heterotrimeric G proteins and seven-transmembrane-spanning (7TM) receptors are implicated in rapid estrogen signaling. The orphan 7TM receptor GPR30 is linked to estrogen-mediated activation of adenylyl cyclase, release of epidermal growth factor (EGF)-related ligands, and specific estrogen binding. GPR30 acts independently of estrogen receptors, ERalpha and ERbeta, and probably functions as a heptahelical ER. 7TM receptors elicit signals that stimulate second messengers, and convey intracellular signals via EGF receptors. Identification of GPR30 as a Gs-coupled 7TM receptor that triggers release of heparin-binding EGF establishes its role in cell signaling cascades initiated by estrogens, and explains their capacity to activate second messengers and promote EGF-like effects. Thus, estrogen can signal by the same mechanism as various other hormones, through a specific 7TM receptor.

  9. MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.

    PubMed

    Chakrabarti, M; Banik, N L; Ray, S K

    2014-01-03

    Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERα agonist), Way200070 (WAY, ERβ agonist), and estrogen (EST, ERα and ERβ agonist) in preventing apoptosis in the calcium ionophore (CI)-insulted ventral spinal cord 4.1 (VSC4.1) motoneurons. We determined that 200 nM CI induced 70% cell death. Treatment with 50 nM PPT, 100 nM WAY, and 150 nM EST induced overexpression of ERα, ERβ, and both receptors, respectively, at mRNA and protein levels. Treatment with ER agonists significantly upregulated miR-206, miR-17, and miR-7-1 in the CI-insulted VSC4.1 motoneurons. Transfection with miR-206, miR-17, or miR-7-1 mimic potentiated WAY or EST to inhibit apoptosis in the CI-insulted VSC4.1 motoneurons. Overexpression of miR-7-1 maximally increased efficacy of WAY and EST for down regulation of pro-apoptotic Bax and upregulation of anti-apoptotic Bcl-2. A search using microRNA database (miRDB) indicated that miR-7-1 could inhibit the expression of L-type Ca(2+) channel protein alpha 1C (CPα1C). miR-7-1 overexpression and WAY or EST treatment down regulated CPα1C but upregulated p-Akt to trigger cell survival signaling. The same therapeutic strategy increased expression of the Ca(2+)/calmodulin-dependent protein kinase II beta (CaMKIIβ) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI-insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future

  10. Sexual characteristics of male guppies Poecilia reticulata serve as effect biomarkers of estrogens

    NASA Astrophysics Data System (ADS)

    Tian, Hua; Li, Yun; Wang, Wei; Zhao, Fei; Gao, Su; Ru, Shaoguo

    2017-10-01

    Guppies (Poecilia reticulata) are considered a candidate model species for the identification and testing of endocrine-disrupting chemicals. Male guppies may be used to address the challenge of making potential linkages between alterations of biomarkers, both at the cellular and organ level, and adverse outcomes. In the present study, a predictive relationship between sex characteristics and reproductive output was observed in male guppies that underwent a long-term toxicity test with 0.5 μg/L 17β-estradiol administered during the juvenile period. Radioimmunoassay and western blot analyses demonstrated that 17β-estradiol exposure caused a significant increase in testicular 17β-estradiol levels as well as the induction of exposure biomarkers, namely hepatic vitellogenin. Exposure to 17β-estradiol also caused a significant decrease in testosterone levels, which consequently reduced the gonadosomatic index, sperm counts, and the coloration index. These changes of male sexual characteristics further translated into adverse influences on reproduction, as measured by a decrease in off spring production and survival rate. Our results suggest that the above-mentioned sexual characteristics of male guppies may be considered potential in vivo biomarkers of estrogen effects on reproduction.

  11. Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women.

    PubMed

    Graham, Bronwyn M; Milad, Mohammed R

    2013-02-15

    Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140). Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Determination of water quality, toxicity and estrogenic activity in a nearshore marine environment in Rio de Janeiro, Southeastern Brazil.

    PubMed

    do Nascimento, Marilia Teresa Lima; Santos, Ana Dalva de Oliveira; Felix, Louise Cruz; Gomes, Giselle; de Oliveira E Sá, Mariana; da Cunha, Danieli Lima; Vieira, Natividade; Hauser-Davis, Rachel Ann; Baptista Neto, José Antonio; Bila, Daniele Maia

    2018-03-01

    Endocrine disrupting compounds (EDCs) can be found in domestic sewage, wastewater treatment plant effluents, natural water, rivers, lakes and in the marine environment. Jurujuba Sound, located in the state of Rio de Janeiro, Southeastern Brazil, receives untreated sewage into its waters, one the main sources of aquatic contamination in this area. In this context, the aim of the present study was to evaluate the estrogenic potential of water sampled from different depths and from areas with differential contamination levels throughout Jurujuba Sound. Water quality was evaluated and acute toxicity assays using Allviibrio fischeri were conducted, while estrogenic activity of the water samples was determined by a Yeast Estrogen Screening assay (YES). Water quality was mostly within the limits established for marine waters by the Brazilian legislation, with only DOC and ammoniacal nitrogen levels above the maximum permissible limits. No acute toxicity effects were observed in the Allivibrio fisheri assay. The YES assay detected moderate estrogenic activity in bottom water samples from 3 sampling stations, ranging from 0.5 to 3.2ngL -1 , as well as in one surface water sample. Estrogenic activity was most frequently observed in samples from the bottom of the water column, indicating adsorption of estrogenic compounds to the sediment. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Evaluation of toxicity and estrogenicity of the landfill-concentrated leachate during advanced oxidation treatment: chemical analyses and bioanalytical tools.

    PubMed

    Wang, Guifang; Lu, Gang; Zhao, Jiandi; Yin, Pinghe; Zhao, Ling

    2016-08-01

    Landfill-concentrated leachate from membrane separation processes is a potential pollution source for the surroundings. In this study, the toxicity and estrogenicity potentials of concentrated leachate prior to and during UV-Fenton and Fenton treatments were assessed by a combination of chemical (di (2-ethylhexyl) phthalate and dibutyl phthalate were chosen as targets) and biological (Daphnia magna, Chlorella vulgaris, and E-screen assay) analyses. Removal efficiencies of measured di (2-ethylhexyl) phthalate and dibutyl phthalate were more than 97 % after treatment with the two methods. Biological tests showed acute toxicity effects on D. magna tests in untreated concentrated leachate samples, whereas acute toxicity on C. vulgaris tests was not observed. Both treatment methods were found to be efficient in reducing acute toxicity effects on D. magna tests. The E-screen test showed concentrated leachate had significant estrogenicity, UV-Fenton and Fenton treatment, especially the former, were effective methods for reducing estrogenicity of concentrated leachate. The EEQchem (estradiol equivalent concentration) of all samples could only explain 0.218-5.31 % range of the EEQbio. These results showed that UV-Fenton reagent could be considered as a suitable method for treatment of concentrated leachate, and the importance of the application of an integrated (biological + chemical) analytical approach for a comprehensive evaluation of treatment suitability.

  14. Estrogens, Neuroinflammation, and Neurodegeneration

    PubMed Central

    Villa, Alessandro; Vegeto, Elisabetta; Poletti, Angelo

    2016-01-01

    Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a critical review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurological disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases. PMID:27196727

  15. Association of environmental chemicals & estrogen metabolites in children.

    PubMed

    Ihde, Erin Speiser; Loh, Ji Meng; Rosen, Lawrence

    2015-12-17

    . No associations were found between the urine levels of chemicals and estrogen metabolites. Endocrine disrupting environmental chemicals were detected in all children in the study, with measurable levels of 4NP in nearly 1/3 of subjects. This is the first known published study of 4NP levels in American children. No associations were found between the urine levels of chemicals tested and estrogen metabolites. The presence of multiple chemicals in a majority of children's urine coupled with increasing prevalence of pediatric hormonal disorders warrants further research to elucidate potential causal mechanisms in pre- and post-pubertal children.

  16. Estrogen improves the proliferation and differentiation of hBMSCs derived from postmenopausal osteoporosis through notch signaling pathway.

    PubMed

    Fan, Jin-Zhu; Yang, Liu; Meng, Guo-Lin; Lin, Yan-shui; Wei, Bo-Yuan; Fan, Jing; Hu, Hui-Min; Liu, Yan-Wu; Chen, Shi; Zhang, Jin-Kang; He, Qi-Zhen; Luo, Zhuo-Jing; Liu, Jian

    2014-07-01

    Estrogen deficiency is the main reason of bone loss, leading to postmenopausal osteoporosis, and estrogen replacement therapy (ERT) has been demonstrated to protect bone loss efficiently. Notch signaling controls proliferation and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, imperfect estrogen-responsive elements (EREs) were found in the 5'-untranslated region of Notch1 and Jagged1. Thus, we examined the molecular and biological links between estrogen and the Notch signaling in postmenopausal osteoporosis in vitro. hBMSCs were obtained from healthy women and patients with postmenopausal osteoporosis. Notch signaling molecules were quantified using real-time polymerase chain reaction (real-time PCR) and Western Blot. Luciferase reporter constructs with putative EREs were transfected into hBMSCs and analyzed. hBMSCs were transduced with lentiviral vectors containing human Notch1 intracellular domain (NICD1). We also used N-[N-(3, 5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester, a γ-secretase inhibitor, to suppress the Notch signaling. We found that estrogen enhanced the Notch signaling in hBMSCs by promoting the expression of Jagged1. hBMSCs cultured with estrogen resulted in the up-regulation of Notch signaling and increased proliferation and differentiation. Enhanced Notch signaling could enhance the proliferation and differentiation of hBMSCs from patients with postmenopausal osteoporosis (OP-hBMSCs). Our results demonstrated that estrogen preserved bone mass partly by activating the Notch signaling. Because long-term ERT has been associated with several side effects, the Notch signaling could be a potential target for treating postmenopausal osteoporosis.

  17. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer.

    PubMed

    Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

    2015-12-29

    The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.

  18. Estrogen Modulation of MgATPase Activity of Nonmuscle Myosin-II-B Filaments

    PubMed Central

    Gorodeski, George I.

    2008-01-01

    The study tested the hypothesis that estrogen controls epithelial paracellular resistance through modulation of myosin. The objective was to understand how estrogen modulates non-muscle myosin-II-B (NMM-II-B), the main component of the cortical actomyosin in human epithelial cervical cells. Experiments used human cervical epithelial cells CaSki as a model, and end points were NMM-II-B phosphorylation, filamentation, and MgATPase activity. The results were as follows: 1) treatment with estrogen increased phosphorylation and MgATPase activity and decreased NMM-II-B filamentation; 2) estrogen effects could be blocked by antisense nucleotides for the estrogen receptor-α and by ICI-182,780, tamoxifen, and the casein kinase-II (CK2) inhibitor, 5,6-dichloro-1-β-(D)-ribofuranosylbenzimidazole and attenuated by AG1478 and PD98059 (inhibitors of epithelial growth factor receptor and ERK/MAPK) but not staurosporine [blocker of protein kinase C (PKC)]; 3) treatments with the PKC activator sn-1,2-di-octanoyl diglyceride induced biphasic effect on NMM-II-B MgATPase activity: an increase at 1 nM to 1 μM and a decrease in activity at more than 1 μM; 4) sn-1,2-dioctanoyl diglyceride also decreased NMM-II-B filamentation in a monophasic and saturable dose dependence (EC50 1–10 μM); 5) when coincubated directly with purified NMM-II-B filaments, both CK2 and PKC decreased filamentation and increased MgATPase activity; 6) assays done on disassembled NMM-II-B filaments showed MgATPase activity in filaments obtained from estrogen-treated cells but not estrogen-depleted cells; and 7) incubations in vitro with CK2, but not PKC, facilitated MgATPase activity, even in disassembled NMM-II-B filaments. The results suggest that estrogen, in an effect mediated by estrogen receptor-α and CK2 and involving the epithelial growth factor receptor and ERK/MAPK cascades, increases NMM-II-B MgATPase activity independent of NMM-II-B filamentation status. PMID:17023528

  19. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

    USDA-ARS?s Scientific Manuscript database

    Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice spe...

  20. The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes.

    PubMed

    Botelho, Mónica C; Alves, Helena; Barros, Alberto; Rinaldi, Gabriel; Brindley, Paul J; Sousa, Mário

    2015-06-01

    Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. Schistosomiasis haematobia also appears to negatively influence fertility, and is particularly associated with female infertility. Given that estrogens and estrogen receptors are key players in human reproduction, we speculate that schistosome estrogen-like molecules may contribute to infertility through hormonal imbalances. Here, we review recent findings on the role of estrogens and estrogen receptors on both carcinogenesis and infertility associated with urogenital schistosomiasis and discuss the basic hormonal mechanisms that might be common in cancer and infertility. Copyright © 2015 Elsevier Ltd. All rights reserved.