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1
Albiñana, Virginia, Maria Bernabeu-Herrero, Roberto Zarrabeitia, Carmelo Bernabeu, and Luisa Botella. "Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells." Thrombosis and Haemostasis 103, no. 03 (2010): 441–51. http://dx.doi.org/10.1160/th09-07-0425.
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SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.
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Albiñana, Virginia, Angel M. Cuesta, Isabel de Rojas-P, Eunate Gallardo-Vara, Lucía Recio-Poveda, Carmelo Bernabéu, and Luisa María Botella. "Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding." Journal of Clinical Medicine 9, no. 6 (June 6, 2020): 1766. http://dx.doi.org/10.3390/jcm9061766.
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The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.
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Abramenko, Nikita, Fréderic Vellieux, Petra Tesařová, Zdeněk Kejík, Robert Kaplánek, Lukáš Lacina, Barbora Dvořánková, et al. "Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences." International Journal of Molecular Sciences 22, no. 12 (June 18, 2021): 6551. http://dx.doi.org/10.3390/ijms22126551.
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COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.
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Zarrabeitia, Roberto, Luisa Ojeda-Fernandez, Lucia Recio, Carmelo Bernabéu, José Parra, Virginia Albiñana, and Luisa Botella. "Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia." Thrombosis and Haemostasis 115, no. 06 (2016): 1167–77. http://dx.doi.org/10.1160/th15-03-0239.
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SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients’ quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).
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Pentikäinen, Virve, Krista Erkkilä, Laura Suomalainen, Martti Parvinen, and Leo Dunkel. "Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in Vitro*." Journal of Clinical Endocrinology & Metabolism 85, no. 5 (May 1, 2000): 2057–67. http://dx.doi.org/10.1210/jcem.85.5.6600.
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Abstract The necessity of estrogens for male fertility was recently discovered in studies on both estrogen receptor α knockout and aromatase (cyp 19 gene) knockout mice. However, direct testicular effects of estrogens in male reproduction have remained unclear. Here we studied the protein expression of ERα and the recently described estrogen receptor β in the human seminiferous epithelium and evaluated the role of 17β-estradiol, the main physiological estrogen, in male germ cell survival. Interestingly, both estrogen receptors α and β were found in early meiotic spermatocytes and elongating spermatids of the human testis. Furthermore, low concentrations of 17β-estradiol (10−9 and 10−10 mol/L) effectively inhibited male germ cell apoptosis, which was induced in vitro by incubating segments of human seminiferous tubules without survival factors (i.e. serum and hormones). Dihydrotestosterone, which, in addition to estradiol, is an end metabolite of testosterone, was also capable of inhibiting testicular apoptosis, but at a far higher concentration (10−7 mol/L) than estradiol. Thus, estradiol appears to be a potent germ cell survival factor in the human testis. The novel findings of the present study together with the previously reported indirect effects of estrogens on male germ cells indicate the importance of estrogens for the normal function of the testis.
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Dama, Aida, Chiara Baggio, Carlotta Boscaro, Mattia Albiero, and Andrea Cignarella. "Estrogen Receptor Functions and Pathways at the Vascular Immune Interface." International Journal of Molecular Sciences 22, no. 8 (April 20, 2021): 4254. http://dx.doi.org/10.3390/ijms22084254.
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Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes. Gender dependence of endothelial biology, either through the action of sex hormones or sex chromosome-related factors, is becoming increasingly evident. Accordingly, cardiometabolic risk increases as women transition to menopause. Estrogen pathways control angiogenesis progression through complex mechanisms. The classic ERs have been acknowledged to function in mediating estrogen effects on glucose metabolism, but 17β-estradiol also rapidly promotes endothelial glycolysis by increasing glucose transporter 1 (GLUT1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels through GPER-dependent mechanisms. Estrogens alter monocyte and macrophage phenotype(s), and induce effects on other estrogen-responsive cell lineages (e.g., secretion of cytokines/chemokines/growth factors) that impact macrophage function. The pharmacological modulation of ERs for therapeutic purposes, however, is particularly challenging due to the lack of ER subtype selectivity of currently used agents. Identifying the determinants of biological responses to estrogenic agents at the vascular immune interface and developing targeted pharmacological interventions may result in novel improved therapeutic solutions.
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Jordan, V. Craig. "The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer." Endocrine-Related Cancer 22, no. 1 (October 22, 2014): R1—R31. http://dx.doi.org/10.1530/erc-14-0448.
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The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective ‘chemical therapy’ proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.
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Sonnenschein, C., A. M. Soto, M. F. Fernandez, N. Olea, M. F. Olea-Serrano, and M. D. Ruiz-Lopez. "Development of a marker of estrogenic exposure in human serum." Clinical Chemistry 41, no. 12 (December 1, 1995): 1888–95. http://dx.doi.org/10.1093/clinchem/41.12.1888.
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Abstract The deleterious, disruptive effects of estrogen mimics on the endocrine system were discovered after the compounds were released into the environment. Their chemical structure does not obviously resemble that of steroid hormones; hence, their estrogenic effects were totally unexpected. In addition to occupational exposures, environmental estrogens may have played a role in decreasing the quantity and quality of human semen during the last 50 years and in increasing the incidences of testicular cancer and cryptorchidism in men and breast cancer in women and men in industrialized countries. Testing the environmental estrogen hypothesis will require developing appropriate biomarkers of exposure and measuring these biomarkers at developmental points where exposure is critical. We report the ongoing development of a method to extract and separate xenoestrogens from ovarian estrogens with human serum as a source, followed by determination of xenoestrogen concentration by a bioassay. We also critically assess bioassays currently available to measure the cumulative effect of xenoestrogens, e.g., (a) the E-SCREEN assay, which measures the proliferative effect of estrogens on their target cells, and (b) the induction by estrogens of specific gene products, such as progesterone receptor and pS2.
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Martin, Olwenn, Tassos Shialis, John Lester, Mark Scrimshaw, Alan Boobis, and Nikolaos Voulvoulis. "Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis." Ciência & Saúde Coletiva 13, no. 5 (October 2008): 1601–18. http://dx.doi.org/10.1590/s1413-81232008000500024.
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Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The only quantitative summary estimate of the link between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago; other reviews of the link between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α-mediated mode of action was specifically explored. Eight studies were included, investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.
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Bernard, Daniel J., George E. Bentley, Jacques Balthazart, Fred W. Turek, and Gregory F. Ball. "Androgen Receptor, Estrogen Receptor α, and Estrogen Receptorβ Show Distinct Patterns of Expression in Forebrain Song Control Nuclei of European Starlings1." Endocrinology 140, no. 10 (October 1, 1999): 4633–43. http://dx.doi.org/10.1210/endo.140.10.7024.
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Abstract In songbirds, singing behavior is controlled by a discrete network of interconnected brain nuclei known collectively as the song control system. Both the development of this system and the expression of singing behavior in adulthood are strongly influenced by sex steroid hormones. Although both androgenic and estrogenic steroids have effects, androgen receptors (AR) are more abundantly and widely expressed in song nuclei than are estrogen receptors (ERα). The recent cloning of a second form of the estrogen receptor in mammals, ERβ, raises the possibility that a second receptor subtype is present in songbirds and that estrogenic effects in the song system may be mediated via ERβ. We therefore cloned the ERβ complementary DNA (cDNA) from a European starling preoptic area-hypothalamic cDNA library and used in situ hybridization histochemistry to examine its expression in forebrain song nuclei, relative to the expression of AR and ERα messenger RNA (mRNA), in the adjacent brain sections. The starling ERβ cDNA has an open reading frame of 1662-bp, predicted to encode a protein of 554 amino acids. This protein shares greater than 70% sequence identity with ERβ in other species. We report that starling ERβ is expressed in a variety of tissues, including brain, pituitary, skeletal muscle, liver, adrenal, kidney, intestine, and ovary. Similar to reports in other songbird species, we detected AR mRNA-containing cells in several song control nuclei, including the high vocal center (HVc), the medial and lateral portions of the magnocellular nucleus of the anterior neostriatum, and the robust nucleus of the archistriatum. We detected ERα expression in the medial portion of HVc (also called paraHVc) and along the medial border of the caudal neostriatum. ERβ was not expressed in HVc, in the medial and lateral portions of the magnocellular nucleus of the anterior neostriatum, in the robust nucleus of the archistriatum, or in area X. In contrast, ERβ mRNA-containing cells were detected in the caudomedial neostriatum and medial preoptic area in a pattern reminiscent of P450 aromatase expression in the same brain regions in other songbirds. These data suggest that estrogenic effects on the song system are not mediated via ERβ-producing cells within song nuclei. Nonetheless, the overlapping expression of ERβ- and aromatase-producing cells in the caudomedial neostriatum suggests that locally synthesized estrogens may act via ERβ, in addition to ERα, to mediate seasonal or developmental effects on nearby song nuclei (e.g. HVc).
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Traboulsi, T., M. El Ezzy, J. L. Gleason, and S. Mader. "Antiestrogens: structure-activity relationships and use in breast cancer treatment." Journal of Molecular Endocrinology 58, no. 1 (January 2017): R15—R31. http://dx.doi.org/10.1530/jme-16-0024.
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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.
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Peng, Ning, John T. Clark, Jeevan Prasain, Helen Kim, C. Roger White, and J. Michael Wyss. "Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 3 (September 2005): R771—R775. http://dx.doi.org/10.1152/ajpregu.00147.2005.
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Both endogenous and dietary estrogens reduce hypertension and enhance cognitive abilities in estrogen-depleted female spontaneously hypertensive rats (SHR). Many of the beneficial effects of estrogens/phytoestrogens also appear to be provided by other polyphenols (e.g., proanthocyanidins) in grape seed, which lack appreciable estrogenic receptor binding. The present study tested the hypothesis that similar to phytoestrogens, proanthrocyanidins in grape seed polyphenols reduce salt-sensitive hypertension in young, estrogen-depleted SHR. SHR were ovariectomized at 4 wk of age and placed on phytoestrogen-free diets with or without 0.5% grape seed extract added and with high (8.0%) or basal (0.6%) NaCl. After 10 wk on the diets, grape proanthrocyanidin supplementation significantly reduced arterial pressure in the rats fed the basal (10 mmHg) and high (26 mmHg)-NaCl diet, compared with the nonsupplemented controls. In vitro superoxide production was significantly reduced (23%) by the grape seed polyphenols. Spatial learning (8-arm-radial maze) in the SHR on the basal NaCl diets was improved by dietary grape seed polyphenols. These results indicate that grape seed polyphenols decrease arterial pressure in SHR, probably via an antioxidant mechanism.
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Pachlinger, Robert, Rudolf Mitterbauer, Gerhard Adam, and Joseph Strauss. "Metabolically Independent and Accurately Adjustable Aspergillus sp. Expression System." Applied and Environmental Microbiology 71, no. 2 (February 2005): 672–78. http://dx.doi.org/10.1128/aem.71.2.672-678.2005.
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ABSTRACT Filamentous fungi are well-established expression hosts often used to produce extracellular proteins of use in the food and pharmaceutical industries. The expression systems presently used in Aspergillus species rely on either strong constitutive promoters, e.g., that for glyceraldehyde-3-phosphate dehydrogenase, or inducible systems derived from metabolic pathways, e.g., glaA (glucoamylase) or alc (alcohol dehydrogenase). We describe for Aspergillus nidulans and Aspergillus niger a novel expression system that utilizes the transcriptional activation of the human estrogen receptor by estrogenic substances. The system functions independently from metabolic signals and therefore can be used with low-cost, complex media. A combination of positive and negative regulatory elements in the promoter drives the expression of a reporter gene, yielding a linear dose response to the inducer. The off status is completely tight, yet the system responds within minutes to induction and reaches a level of expression of up to 15% of total cell protein after 8 h. Both Aspergillus species are very sensitive to estrogenic substances, and low-cost inducers function in the picomolar concentration range, at which estrogenic substances also can be found in the environment. Given this high sensitivity to estrogens, Aspergillus cells carrying estrogen-responsive units could be used to detect xenoestrogens in food or in the environment.
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Yamashina, Masahiro, Takahiro Tsutsui, Yoshihisa Sei, Munetaka Akita, and Michito Yoshizawa. "A polyaromatic receptor with high androgen affinity." Science Advances 5, no. 4 (April 2019): eaav3179. http://dx.doi.org/10.1126/sciadv.aav3179.
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Biological receptors distinguish and bind steroid sex hormones, e.g., androgen-, progestogen-, and estrogen-type hormones, with high selectivity. To date, artificial molecular receptors have been unable to discriminate between these classes of biosubstrates. Here, we report that an artificial polyaromatic receptor preferentially binds a single molecule of androgenic hormones, known as “male” hormones (indicated with m), over progestogens and estrogens, known as “female” hormones (indicated with f), in water. Competitive experiments established the binding selectivity of the synthetic receptor for various sex hormones to be testosterone (m) > androsterone (m) >> progesterone (f) > β-estradiol (f) > pregnenolone (f) > estriol (f). These bindings are driven by the hydrophobic effect, and the observed selectivity arises from multiple CH-π contacts and hydrogen-bonding interactions in the semirigid polyaromatic cavity. Furthermore, micromolar fluorescence detection of androgen was demonstrated using the receptor containing a fluorescent dye in water.
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Gajęcka, M. "The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches." Polish Journal of Veterinary Sciences 15, no. 4 (December 1, 2012): 685–91. http://dx.doi.org/10.2478/v10181-012-0106-3.
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Abstract Zearalenone is an estrogenic mycotoxin that often contaminates plant material used in the production of feeds for companion animals. Small daily doses of ingested zearalenone - a competitive substrate modulating the activity of enzymes participating in estrogen biosynthesis at the pre-receptor level - can induce subclinical symptoms of hyperestrogenism in bitches. The objective of this study was to determine the effects of low zearalenone doses on the presence of estrogen receptors in the ovaries of pre-pubertal Beagle bitches. The bitches were divided into three groups of 10 animals each: experimental group I - 50 μg zearalenone/kg body weight administered once daily per os; experimental group II - 75 μg zearalenone/kg body weight administered once daily per os; control group - placebo containing no ZEN administered per os. The animals were ovariorectomized at the end of the experiment, at 112 days of age. Estrogen receptors were detected in ovarian specimens by immunohistochemical methods. The results revealed an absence of estrogen receptors alpha in all groups. In both experimental groups a decrease in the positive response of estrogen receptors beta in specified structures of ovaries was observed. Very low α-zearalenol levels probably attested to the slowing down (hypostimulation) of the biotransformation process. Overall, zearalenone intoxication led to hyperestrogenism during a specific developmental stage of pre-pubertal bitches. As regards hormesis, the threshold dose of zearalenone (adaptive capability) was exceeded in the ovaries of experimental group II animals. The results obtained in both experimental groups suggest that long-term exposure to low-dose zearalenone intoxication decreased the degree of estrogen receptors beta staining in particular structures of ovaries in the experimental bitches, which initiated epigenetic modification mechanisms that inhibited ovarian development.
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Tena-Sempere, M., J. Navarro, L. Pinilla, LC Gonzalez, I. Huhtaniemi, and E. Aguilar. "Neonatal exposure to estrogen differentially alters estrogen receptor alpha and beta mRNA expression in rat testis during postnatal development." Journal of Endocrinology 165, no. 2 (May 1, 2000): 345–57. http://dx.doi.org/10.1677/joe.0.1650345.
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The biological actions of estrogens on target cells are mediated by two nuclear receptors: the estrogen receptor (ER) alpha and the recently characterized ER beta. In the male rat, the physiological role of estrogens involves multiple actions, from masculinization of brain areas related to reproductive function and sexual behavior to regulation of testicular development and function. Paradoxically, however, administration of high doses of estrogen during the critical period of neonatal differentiation results in an array of defects in the reproductive axis that permanently disrupt male fertility. The focus of this study was to characterize the effects and mechanism(s) of action of neonatal estrogenization on the pattern of testicular ER alpha and beta gene expression during postnatal development. To this end, groups of male rats were treated at day 1 of age with estradiol benzoate (500 microg/rat), and testicular ER alpha and ER beta mRNA levels were assayed by semi-quantitative RT-PCR from the neonatal period until puberty (days 1-45 of age). Furthermore, the expression of androgen receptor (AR) mRNA was evaluated, given the partially overlapping pattern of tissue distribution of ER alpha, ER beta and AR messages in the developing rat testis. In addition, potential mechanisms for neonatal estrogen action were explored. Thus, to discriminate between direct effects and indirect actions through estrogen-induced suppression of serum gonadotropins, the effects of neonatal estrogenization were compared with those induced by blockade of gonadotropin secretion with a potent LHRH antagonist in the neonatal period. Our results indicate that neonatal exposure to estrogen differentially alters testicular expression of alpha and beta ER messages: ER alpha mRNA levels, as well as those of AR, were significantly decreased, whereas relative and total expression levels of ER beta mRNA increased during postnatal/prepubertal development after neonatal estrogen exposure, a phenomenon that was not mimicked by LHRH antagonist treatment. It is concluded that the effect of estrogen on the expression levels of ER alpha and beta mRNAs probably involves a direct action on the developing testis, and cannot be attributed to estrogen-induced suppression of gonadotropin secretion during the neonatal period.
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Márton, Éva, Alexandra Varga, Lajos Széles, Lóránd Göczi, András Penyige, Bálint Nagy, and Melinda Szilágyi. "The Cell-Free Expression of MiR200 Family Members Correlates with Estrogen Sensitivity in Human Epithelial Ovarian Cells." International Journal of Molecular Sciences 21, no. 24 (December 20, 2020): 9725. http://dx.doi.org/10.3390/ijms21249725.
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Exposure to physiological estrogens or xenoestrogens (e.g., zearalenone or bisphenol A) increases the risk for cancer. However, little information is available on their significance in ovarian cancer. We present a comprehensive study on the effect of estradiol, zearalenone and bisphenol A on the phenotype, mRNA, intracellular and cell-free miRNA expression of human epithelial ovarian cell lines. Estrogens induced a comparable effect on the rate of cell proliferation and migration as well as on the expression of estrogen-responsive genes (GREB1, CA12, DEPTOR, RBBP8) in the estrogen receptor α (ERα)-expressing PEO1 cell line, which was not observable in the absence of this receptor (in A2780 cells). The basal intracellular and cell-free expression of miR200s and miR203a was higher in PEO1, which was accompanied with low ZEB1 and high E-cadherin expression. These miRNAs showed a rapid but intermittent upregulation in response to estrogens that was diminished by an ERα-specific antagonist. The role of ERα in the regulation of the MIR200B-MIR200A-MIR429 locus was further supported by publicly available ChIP-seq data. MiRNA expression of cell lysates correlated well with cell-free miRNA expression. We conclude that cell-free miR200s might be promising biomarkers to assess estrogen sensitivity of ovarian cells.
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Zhao, Zhuo, Hao Wang, Jewell A. Jessup, Sarah H. Lindsey, Mark C. Chappell, and Leanne Groban. "Role of estrogen in diastolic dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 5 (March 1, 2014): H628—H640. http://dx.doi.org/10.1152/ajpheart.00859.2013.
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The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.
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van den Berg, M., T. Sanderson, N. Kurihara, and A. Katayama. "Role of metabolism in the endocrine-disrupting effects of chemicals in aquatic and terrestrial systems." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 1917–32. http://dx.doi.org/10.1351/pac200375111917.
Full textAbstract:
This review describes the role of metabolism with endocrine active substances. Many modern synthetic compounds are readily metabolized to more polar forms that often contain hydroxy groups. This presence of polar groups and aromatic moieties in the parent compound or metabolite can play an important role in the mechanism of endocrine disruption. In addition, phase II metabolism (e.g., glucuronidation) can also lead to deactivation of the endocrine properties. In the case of bisphenol A and alkylphenols, metabolism can be considered as a detoxification mechanism as glucuronides decrease of inhibit binding to the estrogen receptors. In the case of phthalate esters, the primary metabolites, the monoesters, and further degraded metabolites do not interact with the estrogen receptor either. In contrast, the demethylation of methoxychlor in fish and other vertebrate species leads to metabolites with an increased affinity for the estrogen receptor. Certain PCB metabolites with hydroxy groups on the para position without vicinal chlorines have estrogenic activity, but these metabolites are not relevant for the environment. PCB metabolites with methylsulfonyl groups are commonly found in environmental biota and have been associated with several endocrine, developmental, and reproductive effects. Some DDT metabolites bind weakly to the estrogen receptor, but the major biotransformation product p,p-DDE is an androgen receptor (AR) antagonist. Vinclozolin is an anti-androgen and this effect appears to caused by two of its more water-soluble metabolites. The chloro-s-triazines exhibit an in vitro induction of aromatase, but their dealkylated metabolites show a decrease or lack of this effect. It is recognized that common metabolic processes can differ strongly among species that complicates ecotoxicological risk assessment of endocrine active substances. In conclusion, the testing of metabolites for endocrine-disrupting properties should be encouraged in the future to establish a better risk assessment process. An appendix containing levels and half-lives of various endocrine-disrupting chemicals in the environment and in wildlife is included at the end of this article.
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Callewaert, Filip, Mieke Sinnesael, Evelien Gielen, Steven Boonen, and Dirk Vanderschueren. "Skeletal sexual dimorphism: relative contribution of sex steroids, GH–IGF1, and mechanical loading." Journal of Endocrinology 207, no. 2 (August 31, 2010): 127–34. http://dx.doi.org/10.1677/joe-10-0209.
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Structural gender differences in bone mass – characterized by wider but not thicker bones – are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. GH–IGF1 action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-α or -β (ERα or ERβ) following aromatization into estrogens. Both the AR and ERα pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERα-mediated effects in males may – at least partly – depend on interaction with IGF1. In addition, sex hormones and their receptors have an impact on the mechanical sensitivity of the growing skeleton. AR and ERβ signaling may limit the osteogenic response to loading in males and females respectively, while ERα may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between the sexes, but depends on gender differences in GH–IGF1 and mechanical sensitivity to loading as well.
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Wu, Y., H. W. Xiao, Z. H. Liang, A. L. Pan, J. Shen, J. S. Pi, Y. J. Pu, J. P. Du, and Z. H. Chen. "Differential expression profiling of estrogen receptor in the ovaries of two egg duck (Anas platyrhynchos) breeds." Czech Journal of Animal Science 59, No. 5 (May 19, 2014): 238–43. http://dx.doi.org/10.17221/7404-cjas.
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In the present study, quantitative real-time PCR was employed to investigate expression profiling and expression difference of ESR1 and ESR2 in ovaries of Shaoxing duck and Jingjiang duck during three laying stages. Results showed the expression levels of ESR1 and ESR2 in ovaries were increased from the age of the first egg to the age of 500 days in both duck breeds. The expression of ESR1 in Shaoxing duck was lower than that in Jingjiang duck for the age of the first egg and of 180 days, and for the age of 500 days it was higher in Shaoxing duck than in Jingjiang duck. The ESR2 showed converse expression profiling in the two duck breeds. The results suggest that ESR1 and ESR2 mediate the process of egg laying in ducks, and that ESR2 may play a more important role for the ovary during egg-laying stages and may be closely related to the laying performance of the ducks.
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Pinteur, Claudie, Benoit Julien, Nathalie Véga, Hubert Vidal, Danielle Naville, and Brigitte Le Magueresse-Battistoni. "Impact of Estrogen Withdrawal and Replacement in Female Mice along the Intestinal Tract. Comparison of E2 Replacement with the Effect of a Mixture of Low Dose Pollutants." International Journal of Environmental Research and Public Health 18, no. 16 (August 17, 2021): 8685. http://dx.doi.org/10.3390/ijerph18168685.
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Postmenopausal women represent a vulnerable population towards endocrine disruptors due to hormonal deficit. We previously demonstrated that chronic exposure of ovariectomized C57Bl6/J mice fed a high-fat, high-sucrose diet to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate, and bisphenol A triggered metabolic alterations in the liver but the intestine was not explored. Yet, the gastrointestinal tract is the main route by which pollutants enter the body. In the present study, we investigated the metabolic consequences of ovarian withdrawal and E2 replacement on the various gut segments along with investigating the impact of the mixture of pollutants. We showed that genes encoding estrogen receptors (Esr1, Gper1 not Esr2), xenobiotic processing genes (e.g., Cyp3a11, Cyp2b10), and genes related to gut homeostasis in the jejunum (e.g., Cd36, Got2, Mmp7) and to bile acid biosynthesis in the gut (e.g., Fgf15, Slc10a2) and liver (e.g., Abcb11, Slc10a1) were under estrogen regulation. Exposure to pollutants mimicked some of the effects of E2 replacement, particularly in the ileum (e.g., Esr1, Nr1c1) suggesting that the mixture had estrogen-mimetic activities. The present findings have important implications for the understanding of estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.
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Vanderschueren, Dirk, Liesbeth Vandenput, Steven Boonen, Marie K. Lindberg, Roger Bouillon, and Claes Ohlsson. "Androgens and Bone." Endocrine Reviews 25, no. 3 (June 1, 2004): 389–425. http://dx.doi.org/10.1210/er.2003-0003.
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Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERα. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERα pathways are involved in androgen action on radial bone growth. ERβ may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERα.
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Wilkinson, Jennifer M., Steven Hayes, David Thompson, Pamela Whitney, and Kun Bi. "Compound Profiling Using a Panel of Steroid Hormone Receptor Cell-Based Assays." Journal of Biomolecular Screening 13, no. 8 (July 25, 2008): 755–65. http://dx.doi.org/10.1177/1087057108322155.
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A major focus in the current discovery of drugs targeting nuclear receptors (NRs) is identifying drugs with reduced side effects by improving selectivity, not only from other receptors but also by selective modulation of the NR of interest. Cellular assays not only provide valuable information on functional activity, potency, and selectivity but also are ideally suited for differentiating partial agonists and antagonists. The ability to partially activate a receptor is believed to be closely tied to the ability to selectively modulate the NR, resulting in expression of a subset of the normally regulated genes. To this end, the authors have built a complete panel of cell-based steroid hormone receptor assays for the androgen receptor, estrogen receptor alpha, estrogen receptor beta, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor by stably engineering a Gal4 DNA-binding domain/nuclear receptor ligand-binding domain fusion protein into an upstream activation sequence beta-lactamase reporter cell line. Each assay was validated with known agonists and antagonists for correct pharmacology and high-throughput compatibility. To demonstrate the utility of these assays, the authors profiled 35 pharmacologically relevant compounds in a dose-response format against the panel in both agonist and antagonist modes. The results demonstrated that selective estrogen receptor modulators can be identified and differentiated, as well as mixed and partial agonists and antagonists easily detected in the appropriate assays. Importantly, a comparison of the chimeric assays with full-length reporter gene assay data from the literature shows a good degree of correlation in terms of selectivity and pharmacology of important ligands. Taken together, these steroid hormone receptor assays provide good selectivity, sensitivity, and appropriate pharmacology for high-throughput screening and selectivity profiling of modulators of steroid hormone receptors. ( Journal of Biomolecular Screening 2008:755-765)
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Merchenthaler, Istvan, Malcolm Lane, Christina Stennett, Min Zhan, Vien Nguyen, Katalin Prokai-Tatrai, and Laszlo Prokai. "Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model." Pharmaceuticals 13, no. 6 (June 10, 2020): 119. http://dx.doi.org/10.3390/ph13060119.
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Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.
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Bonenfant, M., PR Provost, R. Drolet, and Y. Tremblay. "Localization of type 1 17beta-hydroxysteroid dehydrogenase mRNA and protein in syncytiotrophoblasts and invasive cytotrophoblasts in the human term villi." Journal of Endocrinology 165, no. 2 (May 1, 2000): 217–22. http://dx.doi.org/10.1677/joe.0.1650217.
Full textAbstract:
The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play a key role in the synthesis of sex steroids. The hallmark of this family of enzymes is the interconversion, through their oxydoreductive reactivity at position C17, of 17-keto- and 17beta-hydroxy-steroids. Because this reaction essentially transforms steroids having low binding activity for the steroid receptor to their more potent 17beta-hydroxysteroids isoforms, it is crucial to the control of the physiological activities of both estrogens and androgens. The human placenta produces large amounts of progesterone and estrogens throughout pregnancy. The placental type 1 17beta-HSD enzyme (E17beta-HSD) catalyzes the reduction of the low activity estrogen, estrone, into the potent estrogen, estradiol. We studied the cell-specific expression of type 1 17beta-HSD in human term placental villous tissue by combining in situ hybridization to localize type 1 17beta-HSD mRNA with immunohistochemistry using an antibody against human placental lactogen, a trophoblast marker. Immunolocalization of E17beta-HSD was also performed. To ascertain whether other steroidogenic enzymes are present in the same cell type, cytochrome P450 cholesterol side-chain cleavage (P450scc), P450 aromatase, and type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were also localized by immunostaining. Our results showed that the syncytium is the major steroidogenic unit of the fetal term villi. In fact, type 1 17beta-HSD mRNA and protein, as well as P450scc, P450 aromatase, and 3beta-HSD immunoreactivities were found in these cells. In addition, our results revealed undoubtedly that extravillous cytotrophoblasts (CTBs), e.g. those from which cell columns of anchoring villous originate, also express the type 1 17beta-HSD gene. However, CTBs lying beneath the syncytial layer, e.g. those from which syncytiotrophoblasts develop, contained barely detectable amounts of type 1 17beta-HSD mRNA as determined by in situ hybridization. These findings, along with those from other laboratories confirm the primordial role of the syncytium in the synthesis of steroids during pregnancy. In addition, our results indicate for the first time that CTBs differentiating along the invasive pathway contain type 1 17beta-HSD mRNA.
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Pauklin, Siim, Isora V. Sernández, Gudrun Bachmann, Almudena R. Ramiro, and Svend K. Petersen-Mahrt. "Estrogen directly activates AID transcription and function." Journal of Experimental Medicine 206, no. 1 (January 12, 2009): 99–111. http://dx.doi.org/10.1084/jem.20080521.
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The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase (AID) deaminates cytosines at immunoglobulin (Ig) loci, initiating somatic hypermutation (SHM) and class switch recombination (CSR). Protein levels of nuclear AID are tightly controlled, as unregulated expression can lead to alterations in the immune response. Furthermore, hyperactivation of AID outside the immune system leads to oncogenesis. Here, we demonstrate that the estrogen–estrogen receptor complex binds to the AID promoter, enhancing AID messenger RNA expression, leading to a direct increase in AID protein production and alterations in SHM and CSR at the Ig locus. Enhanced translocations of the c-myc oncogene showed that the genotoxicity of estrogen via AID production was not limited to the Ig locus. Outside of the immune system (e.g., breast and ovaries), estrogen induced AID expression by >20-fold. The estrogen response was also partially conserved within the DNA deaminase family (APOBEC3B, -3F, and -3G), and could be inhibited by tamoxifen, an estrogen antagonist. We therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability.
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Sasanuma, Hiroyuki, Masataka Tsuda, Suguru Morimoto, Liton Kumar Saha, Md Maminur Rahman, Yusuke Kiyooka, Haruna Fujiike, et al. "BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes." Proceedings of the National Academy of Sciences 115, no. 45 (October 23, 2018): E10642—E10651. http://dx.doi.org/10.1073/pnas.1803177115.
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Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5′ ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5′ TOP2 adducts in G1phase. We show here that BRCA1 promotes MRE11-mediated removal of TOP2 adducts in G1phase. We disrupted theBRCA1gene in53BP1-deficient ER-positive breast cancer and B cells. The loss of BRCA1 caused marked increases of pathological TOP2ccs in G1phase following exposure to etoposide, which generates pathological TOP2ccs. We conclude that BRCA1 promotes the removal of TOP2 adducts from DSB ends for subsequent nonhomologous end joining.BRCA1-deficient cells showed a decrease in etoposide-induced MRE11 foci in G1phase, suggesting that BRCA1 repairs pathological TOP2ccs by promoting the recruitment of MRE11 to TOP2cc sites. BRCA1 depletion also leads to the increase of unrepaired DSBs upon estrogen treatment both in vitro in G1-arrested breast cancer cells and in vivo in epithelial cells of mouse mammary glands. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens as well as etoposide. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced pathological TOP2ccs throughout the cell cycle.
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Corinaldesi, Giorgio, and Christian Corinaldesi. "Management of Recurring Epistaxis in Hereditary Hemorrhagic Teleangectasia." Blood 106, no. 11 (November 16, 2005): 4061. http://dx.doi.org/10.1182/blood.v106.11.4061.4061.
Full textAbstract:
Abstract The hereditary hemorrhagic teleangectasia of Rendu-Osler-Weber (HHT), is an autosomal dominant disease with a genetic angiodysplasia affecting multiple organs: skin, lung, gastrointestinal and genitourinary tract, and brain; the diagnosis is based on the following criteria: familiarity, epistaxis, teleangectasies, and visceral arterovenous malformations with a different degree of expression. The HHT is genetically heterogeneous involving two loci: HHT-1 (chromosome 9q-34.1), and HHT-2 (chromosome 12q11-q14). The loci have been identified as endoglin (ENG) CD105, and activin receptor like-kinase-1 (ALK-1) serine/threonine kinase receptor type-1 of TGF-beta superfamily. We have studied a 52 years old patient presented with a story of recurrent bleeding and acute anemia secondary to strong epistaxis and upper bleeding: the endoscopic study disclosed multiple spots of duodeno-jejunal angiodysplasia with mucous angectasia spider-like 1–2 mm, macular spots, tortuous vessels. This patients also had frequent spontaneous epistaxis, in particular the management of most common anterior forms (locus Valsalvae, Kiesselbach area) is based on nostril pinching and the former abstersion of clots, irrigation with antifibrinolytic drugs and also on more packing with Lyofoam, Surgical, or Merocel leaflet or with Clauden or Vasenol lint which has to stay on site for 3–4 days with an antibiotic coverage, the relapsing cases were treated with sequential photocoagulation with argon-laser. In order to control high posterior epistaxis in case of emergency, the super-selective angiographic embolization with jelly sponge, polyvinyl-alcohol particles, detachable or endoscopic ultraligation of the anterior ethmoidal and or the sphenopalatine artery. All recurrent bleeding events responded to initial standard treatment strategies: blood transfusion with fresh frozen plasma, PRBC, drugs therapy including A-PCCS, tranexamic acid until 6 g/day, danazol, combined estrogen/progesterone therapy, octreotide (50 mcg iv followed by an infusion of 30 mcg/h for 5 days), anaemia required iron supplement. Recently severe clinical symptoms and a severe epistaxis and hematemesis combined with an hemodinamic instability required an urgent EGS followed by endoscopic therapy with termal probes together with high dose rFVII (220 mcg/kg), obtaining immediate benefit; no bleeding recurrence was detected after six months. This therapeutical approach may require some more studies, but it can be a great choice for controlling refractory re-bleeding in selected patients.
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Bosakova, Tereza, Antonin Tockstein, Natasa Sebkova, Ondrej Simonik, Hana Adamusova, Jana Albrechtova, Tomas Albrecht, Zuzana Bosakova, and Katerina Dvorakova-Hortova. "New Insight into Sperm Capacitation: A Novel Mechanism of 17β-Estradiol Signalling." International Journal of Molecular Sciences 19, no. 12 (December 12, 2018): 4011. http://dx.doi.org/10.3390/ijms19124011.
Full textAbstract:
17β-estradiol (estradiol) is a natural estrogen regulating reproduction including sperm and egg development, sperm maturation—called capacitation—and sperm–egg communication. High doses can increase germ cell apoptosis and decrease sperm count. Our aim was to answer the biological relevance of estradiol in sperm capacitation and its effect on motility and acrosome reaction to quantify its interaction with estrogen receptors and propose a model of estradiol action during capacitation using kinetic analysis. Estradiol increased protein tyrosine phosphorylation, elevated rate of spontaneous acrosome reaction, and altered motility parameters measured Hamilton-Thorne Computer Assisted Semen Analyzer (CASA) in capacitating sperm. To monitor time and concentration dependent binding dynamics of extracellular estradiol, high-performance liquid chromatography with tandem mass spectrometry was used to measure sperm response and data was subjected to kinetic analysis. The kinetic model of estradiol action during sperm maturation shows that estradiol adsorption onto a plasma membrane surface is controlled by Langmuir isotherm. After, when estradiol passes into the cytoplasm, it forms an unstable adduct with cytoplasmic receptors, which display a signalling autocatalytic pattern. This autocatalytic reaction suggests crosstalk between receptor and non-receptor pathways utilized by sperm prior to fertilization.
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Delbès, Géraldine, Christine Levacher, Catherine Pairault, Chrystèle Racine, Clotilde Duquenne, Andrée Krust, and René Habert. "Estrogen Receptor β-Mediated Inhibition of Male Germ Cell Line Development in Mice by Endogenous Estrogens during Perinatal Life." Endocrinology 145, no. 7 (July 1, 2004): 3395–403. http://dx.doi.org/10.1210/en.2003-1479.
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Abstract Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders and sperm abnormalities in adulthood. However, it is unknown whether endogenous concentrations of estrogens affect the establishment of the male fetal germ cell lineage. We addressed this question by studying the testicular development of mice in which the estrogen receptor (ER) β or the ERα gene was inactivated. The homozygous inactivation of ERβ (ERβ−/−) increased the number of gonocytes by 50% in 2- and 6-d-old neonates. The numbers of Sertoli and Leydig cells and the level of testicular testosterone production were unaffected, suggesting that estrogens act directly on the gonocytes. The increase in the number of gonocytes did not occur during fetal life but instead occurred just after birth, when gonocytes resumed mitosis and apoptosis. It seems to result from a decrease in the apoptosis rate evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and cleaved caspase-3 immunohistochemical detection. Last, mice heterozygous for the ERβ gene inactivation behaved similarly to their ERβ−/− littermates in terms of the number of gonocytes, apoptosis, and mitosis, suggesting that these cells are highly sensitive to the binding of estrogens to ERβ. ERα inactivation had no effect on the number of neonatal gonocytes and Sertoli cells. In conclusion, this study provides the first demonstration that endogenous estrogens can physiologically inhibit germ cell growth in the male. This finding may have important implications concerning the potential action of environmental estrogens.
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Weber, Miriam, Martin Wehling, and Ralf Lösel. "Proteins interact with the cytosolic mineralocorticoid receptor depending on the ligand." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 1 (July 2008): H361—H365. http://dx.doi.org/10.1152/ajpheart.00825.2007.
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Steroid receptors belonging to the superfamily of nuclear receptors do not exist as single monomeric proteins but mediate their effects by the interaction with numerous other proteins, e.g., cofactors for transcription, but also other proteins involved in cellular signaling. This interaction may be ligand dependent, which explains the differential effects of receptor ligands. Whereas some receptors, e.g., the estrogen receptor, have been studied in great detail, much less is known about proteins interacting with the mineralocorticoid receptor (MR). In this study, we aimed to identify interacting proteins using a proteomics approach involving tagged receptor constructs. After affinity isolation of MR complexes, blue native electrophoresis revealed the presence of several populations of MR complexes differing in size and composition. During the identification of interacting proteins, various heat shock proteins but also several previously undescribed potential interactors were found, including 14-3-3-ε. We also demonstrate here that the cytosolic MR in the presence of detergent interacts in a ligand-selective manner with glucose-regulated protein 78 and propionyl-CoA carboxylase-β precursor, which are found in the unliganded or aldosterone-containing complex but not with spironolactone.
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Djordjevic, Momcilo, Bozidar Jovanovic, Slobodanka Mitrovic, and Gordana Djordjevic. "Ectopic mammary tissue in vulva." Vojnosanitetski pregled 65, no. 5 (2008): 407–9. http://dx.doi.org/10.2298/vsp0805407d.
Full textAbstract:
Background. Ectopic mammary gland tissue is a residual tissue that persists during the embryologic development along ectodermal primitive milk streaks. Incomplete involution anywhere along the primitive milk streak can result in accessory or ectopic mammary tissue. Case report. A woman, 27-year old, admitted to Obstetrics and Gynecology Clinic Kragujevac for surgery, of goose-egg size, vulva tumor, of elastic consistency. Menarche started in 12 years of age, with the regular menstrual cycle, without previous gynecological diseases. The woman had one pregnancy terminated by cesarean section because of the multiple (twin) pregnancy. Excision of the tumor was completely done in the total endotracheal anesthesia. Pathohistologic (PH) findings was: Dysplasia fibrosa cystica simplex mammae, with focuses of sclerosing adenosis. Expression of estrogen (ER) and progesterone receptors (PR) were positive. Conclusion. Ectopic mammary tissue in vulva in adult period is very rarely seen, and can be changed pathologically as well as normally positioned breast tissue into benign cystic changes, benign tumors, adenomas and fibroadenomas and tumors. Cells with low ER/PR receptor level grow independently of estrogene stimulation and they could be resistant to hormonal therapy effects.
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Seifert, M., L. Wen, M. Alberti, U. Kausch, and B. Hock. "Biomonitoring: Integration of biological end-points into chemical monitoring." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 2451–59. http://dx.doi.org/10.1351/pac200375112451.
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Biomonitoring is currently performed at two levels, assessing exposure to pollutants and effects monitoring by bioassays. As an example for the first approach, vitellogenin (VTG) in male fish of Abramis brama as an endpoint for estrogen exposure is discussed. However, similar changes of VTG or VTG-like proteins in the hemolymph of mussels could not be detected. Enzyme-linked receptor assays for monitoring estrogenic effects at the molecular level serve as an example for the second category. Applications of the enzyme-linked receptor assay (ELRA) developed in our laboratory are presented. Detection limits of 0.02 μg/l 17β-estradiol were recently achieved with the chemiluminescent format. Although effect monitoring provides information in terms of toxicity equivalents, it is not possible to relate the signals to specific pollutants and their concentrations. For this purpose, chemical analysis is required. New approaches are reported for the direct coupling of bioassays and chemical analysis. This concept is defined as bioresponse-linked instrumental analysis. It combines biomolecular recognition, initiating a biological effect, and chemical analysis. In addition to the classical bioanalytical approaches, new strategies in genomics and proteomics have been developed. This may lead to multimarker approaches opening this area to environmental analytics.
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Mercer, Kelly E., Sudeepa Bhattacharyya, Neha Sharma, Mousumi Chaudhury, Haixia Lin, Laxmi Yeruva, and Martin J. Ronis. "Infant Formula Feeding Changes the Proliferative Status in Piglet Neonatal Mammary Glands Independently of Estrogen Signaling." Journal of Nutrition 150, no. 4 (November 5, 2019): 730–38. http://dx.doi.org/10.1093/jn/nxz273.
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ABSTRACT Background Soy infant formula contains isoflavones, which are able to bind to and activate estrogen receptor (ER) pathways. The mammary gland is sensitive to estrogens, raising concern that the use of soy formulas may promote premature development. Objective We aimed to determine if soy formula feeding increases mammary gland proliferation and differentiation in comparison to other infant postnatal diets. Methods White-Dutch Landrace piglets aged 2 d received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/(kg·d); M + E2), or milk formula supplemented with genistein (84 mg/L of diet; M + G) until day 21. Mammary gland proliferation and differentiation was assessed by histology, and real-time RT-PCR confirmation of differentially expressed genes identified by microarray analysis. Results Mammary terminal end bud numbers were 19–31% greater in the Milk, Soy, and M + G groups relative to the Sow and M + E2, P <0.05. Microarray analysis identified differentially expressed genes between each formula-fed group relative to the Sow (±1.7-fold, P <0.05). Real-time RT-PCR confirmed 2- to 4-fold increases in mRNA transcripts of genes involved in cell proliferation, insulin-like growth factor 1 (IGF1), fibroblast growth factor 10 (FGF10), and fibroblast growth factor 18 (FGF18), in all groups relative to the Sow, P <0.05. In contrast, genes involved in cell differentiation and ductal morphogenesis, angiotensin II receptor type 2 (AGTR2), microtubule associated protein 1b (MAP1B), and kinesin family member 26b (KIF26B), were significantly upregulated by 2-, 4-, and 13-fold, respectively, in the M + E2 group. Additionally, mRNA expression of ER-specific gene targets, progesterone receptor (PGR), was increased by 12-fold, and amphiregulin (AREG) and Ras-like estrogen regulated growth inhibitor (RERG) expression by 1.5-fold in the M + E2 group, P <0.05. In the soy and M + G groups, mRNA expressions of fatty acid synthesis genes were increased 2- to 4-fold. Conclusions Our data indicate soy formula feeding does not promote ER-signaling in the piglet mammary gland. Infant formula feeding (milk- or soy-based) may initiate proliferative pathways independently of estrogenic signaling.
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Tesarova, P., M. Kalousova, M. Jachymova, O. Mestek, L. Petruzelka, and T. Zima. "Receptor for advanced glycation end-products (RAGE) - soluble form (sRAGE) and gene polymorphisms in patients with breast cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21113. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21113.
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21113 Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression. No significant financial relationships to disclose.
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Marqusee, Ellen, Lewis E. Braverman, Jennifer E. Lawrence, Judith S. Carroll, and Ellen W. Seely. "The Effect of Droloxifene and Estrogen on Thyroid Function in Postmenopausal Women1." Journal of Clinical Endocrinology & Metabolism 85, no. 11 (November 1, 2000): 4407–10. http://dx.doi.org/10.1210/jcem.85.11.6975.
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Estrogen is known to increase serum T4-binding globulin (TBG) concentrations, thereby increasing serum total T4 concentrations. Serum free T4 concentrations, however, remain normal. Tamoxifen, a selective estrogen receptor modifier (SERM), also raises serum TBG concentrations, but whether newer SERMs with less stimulatory action on the endometrium do so is not known. We, therefore, compared the effect of droloxifene, a SERM, and conjugated equine estrogen on pituitary-thyroid function in normal postmenopausal women. Ten women were treated for 6 weeks with conjugated estrogen (Premarin), 0.625 mg/day, and droloxifene, 60 mg/day, in a double-blind crossover study with an intervening 4-week no-treatment period. We measured serum T4, T3, TBG, free T4 index, and TSH at baseline and at the end of each 6-week period. The baseline values were compared with the 6-week values using paired t tests. The mean (±sd) serum TBG concentrations increased significantly during both treatment periods (baseline, 1.5 ± 0.4 mg/dL; conjugated estrogens, 2.7 ± 0.6 mg/dL; droloxifene, 2.1 ± 0.6 mg/dL; P < 0.001 and P= 0.001, respectively). There were no significant changes in the serum free T4 index. Serum T4 and T3 concentrations increased during both treatment periods, however, the increase was significant only for T4 during the conjugated estrogen treatment period. The serum TSH concentrations increased significantly during both treatment periods (18% during conjugated estrogen and 11% during droloxifene), and the values remained within the normal range in all women. Administration of both conjugated estrogen and droloxifene for 6 weeks increases serum TSH and TBG concentrations, but does not alter free T4 index values in postmenopausal women.
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Kohno, Satomi. "Can Xenobiotics Alter the Sex Ratio of Crocodilians in the Wild?" Sexual Development 15, no. 1-3 (2021): 179–86. http://dx.doi.org/10.1159/000515724.
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All crocodilians exhibit temperature-dependent sex determination without sex chromosomes. This temperature dependency can be overridden by exposure to estrogen via estrogen receptor 1. Thus, the sex ratio of crocodilian species is vulnerable to estrogenic xenobiotics. Multiple investigations of the mechanism and effects of xenobiotics in crocodilian species have been conducted since the early 1990s. This review focuses on the impact of xenobiotics on sex determination rather than gonadal functions in crocodilians. The thermosensitive and estrogen-sensitive periods that commit the bipotential gonad to develop as an ovary end by stages 24.5 and 25.3, respectively. In contrast, it is ambiguous when the estrogen-sensitive stage begins for ovarian development, although the thermosensitive period for ovarian development initiates around developmental stage 15 at an extreme female-producing temperature of 30°C. To accurately assess the effect of xenoestrogens on sex ratio in crocodilians, it is critical to collect eggs before the sex-determining period and to incubate them under precisely controlled temperatures. A well-studied system of xenobiotic effects on crocodilians is Lake Apopka (FL, USA), an EPA superfund clean-up site heavily contaminated with Dieldrin, Endrin, and <i>p,p'</i>-DDE. The sum of estimated estrogenicity of xenobiotics measured in Lake Apopka was insufficient to activate the estrogen receptor 1 of <i>Alligator mississippiensis</i>, which is an essential receptor to induce ovarian development. Although juvenile <i>A. mississippiensis</i> showed gonadal alterations in sex hormone production and histology, the environmentally relevant concentration of xenobiotics in Lake Apopka was unlikely to alter the sex ratio of <i>A. mississippiensis.</i> Experimental exposure to xenobiotics such as 17α-ethynylestradiol, <i>p,p'</i>-dichlorodiphenyldichloroethylene, and 2,3,7,8-tetrachlorodibenzodioxin at environmentally relevant concentrations in ovo induced more female offspring in <i>A. mississippiensis</i> as compared with the control group. Bisphenol-A, atrazine, 2,4-dichlorophenoxyacetic acid, endosulfan, and Corexit did not alter the sex ratio of <i>A. mississippiensis</i> or <i>Caiman latirostris</i> under the tested conditions. Egg-incubation temperature has pronounced effects on estrogen sensitivity in crocodilian sex determination. Therefore, crocodilians are vulnerable to xenobiotic contamination and climate change in the wild. It is vital to further investigate the detailed mechanism and effects of environmental xenobiotics in crocodilian sex determination to mitigate their effect on sex ratio and conserve this ancient lineage.
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Andruska, Neal, Chengjian Mao, Mathew Cherian, Chen Zhang, and David J. Shapiro. "Evaluation of a Luciferase-Based Reporter Assay as a Screen for Inhibitors of Estrogen-ERα-Induced Proliferation of Breast Cancer Cells." Journal of Biomolecular Screening 17, no. 7 (April 12, 2012): 921–32. http://dx.doi.org/10.1177/1087057112442960.
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Estrogens, acting through estrogen receptor α (ERα), stimulate breast cancer proliferation, making ERα an attractive drug target. Since 384-well format screens for inhibitors of proliferation can be challenging for some cells, inhibition of luciferase-based reporters is often used as a surrogate end point. To identify novel small-molecule inhibitors of 17β-estradiol (E2)–ERα-stimulated cell proliferation, we established a cell-based screen for inhibitors of E2-ERα induction of an estrogen response element (ERE)3–luciferase reporter. Seventy-five “hits” were evaluated in tiered follow-up assays to identify where hits failed to progress and evaluate their effectiveness as inhibitors of E2-ERα-induced proliferation of breast cancer cells. Only 8 of 75 hits from the luciferase screen inhibited estrogen-induced proliferation of ERα-positive MCF-7 and T47D cells but not control ERα-negative MDA-MB-231 cells. Although 12% of compounds inhibited E2-ERα-stimulated proliferation in only one of the ERα-positive cell lines, 40% of compounds were toxic and inhibited growth of all the cell lines, and ~37% exhibited little or no ability to inhibit E2-ERα-stimulated cell proliferation. Representative compounds were evaluated in more detail, and a lead ERα inhibitor was identified.
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Chen, Yong-Heng, Jeong Hoon Kim, and Michael R. Stallcup. "GAC63, a GRIP1-Dependent Nuclear Receptor Coactivator." Molecular and Cellular Biology 25, no. 14 (July 2005): 5965–72. http://dx.doi.org/10.1128/mcb.25.14.5965-5972.2005.
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ABSTRACT Nuclear receptors (NRs) regulate target gene transcription through the recruitment of multiple coactivator complexes to the promoter regions of target genes. One important coactivator complex includes a p160 coactivator (GRIP1, SRC-1, or ACTR) and its downstream coactivators (e.g., p300, CARM1, CoCoA, and Fli-I), which contribute to transcriptional activation by protein acetylation, protein methylation, and protein-protein interactions. In this study, we identified a novel NR coactivator, GAC63, which binds to the N-terminal region of p160 coactivators as well as the ligand binding domains of some NRs. GAC63 enhanced transcriptional activation by NRs in a hormone-dependent and GRIP1-dependent manner in transient transfection assays and cooperated synergistically and selectively with other NR coactivators, including GRIP1 and CARM1, to enhance estrogen receptor function. Endogenous GAC63 was recruited to the estrogen-responsive pS2 gene promoter of MCF-7 cells in response to the hormone. Reduction of the endogenous GAC63 level by small interfering RNA inhibited transcriptional activation by the hormone-activated estrogen receptor. Thus, GAC63 is a physiologically relevant part of the p160 coactivator signaling pathway that mediates transcriptional activation by NRs.
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Straub, Rainer H. "The Complex Role of Estrogens in Inflammation." Endocrine Reviews 28, no. 5 (August 1, 2007): 521–74. http://dx.doi.org/10.1210/er.2007-0001.
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There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
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Lupu, Diana, Marcus O. D. Sjödin, Mukesh Varshney, Johan Lindberg, Felicia Loghin, and Joëlle Rüegg. "FLUOXETINE MODULATES SEX STEROID LEVELS IN VITRO." Medicine and Pharmacy Reports 90, no. 4 (October 30, 2017): 420–24. http://dx.doi.org/10.15386/cjmed-868.
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Background and aims. Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed against depression during and after pregnancy. However, these compounds cross the placenta and are found in breast milk, thus reaching, and possibly affecting, the fetus and infant during critical developmental stages. Fluoxetine (FLX), a widely used SSRI, can interfere with estrogen signaling, which is important for the development of female sex organs and certain brain areas, among others. Interference with estrogen signaling can take place on different levels, e.g., by affecting receptor activity or hormone levels. FLX has previously been shown to induce estrogen receptor-dependent transcription in vitro at high concentrations. In this study we set out to assess effects of FLX on estradiol levels in vitro.Methods. FLX was tested using the OECD recommended H295R model, a human adrenocortical carcinoma cell line that is able to produce all steroid hormones found in the gonads and adrenal glands, including estradiol and testosterone. H295R cells were incubated with different doses of FLX for 48h. Subsequently, concentrations of these two steroids were measured in cell culture medium after FLX exposure, using liquid chromatography coupled with tandem mass spectrometry. Aromatase mRNA expression was assessed using qPCR.Results. Fluoxetine significantly increased estradiol secretion in H295R cells after a 48h exposure at low, submicromolar concentrations, but showed no effects on testosterone levels or aromatase mRNA expression.Conclusion. Fluoxetine has the potential to interfere with estrogenic signaling by increasing estradiol secretion at low concentrations, which are relevant for fetal and adult human exposure.
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Dhar, Ruby, Arun Kumar, and Subhradip Karmakar. "Menopause and COVID19 severity: The missing link." Asian Journal of Medical Sciences 12, no. 9 (September 1, 2021): 1–3. http://dx.doi.org/10.3126/ajms.v12i9.38808.
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COVID-19 pandemic has far-reaching consequences on people with comorbidities like Diabetes Mellitus (DM), asthma, cardiovascular disease, and cancer. What seems unusual is an isolated observation that emerged from several independent studies worldwide. Postmenopausal females seem to suffer from severe COVID symptoms. Few of them also show an extended COVID symptom, also “LONG COVID.” Though the association appears strong, there are not enough credible studies to pin it down to the exact cause. We explored the possibility to see if postmenopausal females are at a higher risk for severe COVID and unravel this observation’s molecular pathogenesis. Research performed at King’s College London found that as estrogen levels in females drop in pre-menopause and menopause, they become vulnerable to COVID19 infection, suggesting that high estrogen levels may have a protective effect against the severity of COVID-19. This concept originated from the immune-modulatory and immune suppressive role of estradiol. Although both male and female sex steroids act primarily on the reproductive tissues and modulate their functions, increasing evidence suggests that sex steroids can also work on non-reproductive tissues like the CNS, immune systems, cardiovascular and skeletal systems, etc.Further, estrogen has an enormous effect both on the innate (macrophages/monocytes, neutrophils, NK cells, complement systems, APC-like dendritic cells (DC)], as well as on the adaptive (B and T cells) immune system. There are reports that estrogen may exhibit a pro-inflammatory response, whereas testosterone counteracts it. This could possibly be through an estrogen-mediated production of inflammatory cytokines like IFNγ, interleukin (IL) 6, TNF α. However, estrogen also has a profound anti-inflammatory effect. We need to remember that many of these observations are context and cell-type-specific with a delicate balance between pro and anti-inflammatory responses. There needs a deeper understanding of the reproductive events in females. Perimenopause, menopause, and postmenopause define the end of a woman’s reproductive years. These are the time when her monthly period stops. Whole perimenopause marks the beginning of this process, starting 8- 12 years before menopause. Menopause is the stage when her menstrual periods completely ceases for at least 12 months. Postmenopause is the stage after menopause that continues thereafter. Starting from perimenopause, menopause is marked by declining levels of estrogen((estrone (E1), 17β-estradiol (E2), estriol (E3)), and progesterone. However, there are complex hormonal and cytokine undercurrents to this rather simplistic profile. LH and FSH, however, seem to surge during this period. It currently not know what this LH/FSH surge means for the immune system. With the approach of menopause, there is the release of extracellular vesicles containing inflammasomes, which may be responsible for low-grade systemic inflammation.This cascade may build up significantly and contribute to a hyper-inflammatory environment. According to a survey by Global Health 50/50, though an equal number of males and females were tested positive for COVID-19, the males were largely presented with severe symptoms, thereby implying that the female hormones may have a protective role in the pathophysiology of COVID-19. Further clinical studies performed on the females showed that pre-menopausal females have a relatively mild disease, while menopausal females had moderate to severe illness. The menopausal group also has significantly more requirements for oxygen, ventilation support, and progression-to-severe disease with a prolonged hospital stay and mortality. This is further reinforced by the fact that estradiol modulates the immune cells, which could play an essential role in explaining why a lower incidence of COVID-19 is observed among women than in men. Even been a nuclear hormone, estrogen has cytoplasmic targets. The cytoplasmic activity of estrogen-activated ERα leads to PI3K induction. This, in turn, prevents the nuclear shuttling and transport of NF Menopause kB, resulting in reduced inflammation. The estrogen axis for inflammation is enormously complex, riddled by the different receptor types usage and post-receptor events. The presence of estrogen receptors (ESRs), ERα and ERβ, is of prime importance since the net outcome depends on ER subtypes in use. It seems that a preferential engagement of ERbeta promotes inflammation while ERalpha dampens it. It was further demonstrated that hypoxia, associated with inflammatory conditions, could also downregulate the expression of ERα, tipping the balance in favor of inflammation. Then there are interferon genes that cross talks with Estrogen receptor (ESR) signaling. Estrogen can also polarize toward a TH2 response eliciting a protective humoral response in addition to its capacity for activation of NK cells. Further, a wide variety of immune-modulatory roles is under estrogenic control. This involves the antigen-presenting dendritic cells, CD4+ and CD8+ T cell populations. Other than estrogen, progesterone also has a profound influence on the immune system. Progesterone was found to have an antiviral effect against SARS-CoV-2 in vitro. Mature NK CD56dimCD16+KIR+ cells overexpress the progesterone receptor and thus are hormone-sensitive. Though there are conflicting reports regarding the association of disease severity and mortality with estrogen levels, it is plausible that drastic alteration of these hormones at menopause could perturb the delicate balance creating an environment that enhances the immune response fueling the cytokine storm, the hallmark for COVID complications. Further research in this area is needed to decipher the intricate molecular details of this process for future risk mitigation and disease management.
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Pak, Toni R., Wilson C. J. Chung, Laura R. Hinds, and Robert J. Handa. "Estrogen Receptor-β Mediates Dihydrotestosterone-Induced Stimulation of the Arginine Vasopressin Promoter in Neuronal Cells." Endocrinology 148, no. 7 (July 1, 2007): 3371–82. http://dx.doi.org/10.1210/en.2007-0086.
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Arginine vasopressin (AVP) is a neuropeptide involved in the regulation of fluid balance, stress, circadian rhythms, and social behaviors. In the brain, AVP is tightly regulated by gonadal steroid hormones in discrete regions with gonadectomy abolishing and testosterone replacement restoring normal AVP expression in adult males. Previous studies demonstrated that 17β-estradiol, a primary metabolite of testosterone, is responsible for restoring most of the AVP expression in the brain after castration. However, 5α-dihydrotestosterone (DHT) has also been shown to play a role in the regulation of AVP expression, thus implicating the involvement of both androgen and estrogen receptors (ER). Furthermore, DHT, through its conversion to 5α-androstane-3β,17β-diol, has been shown to modulate estrogen response element-mediated promoter activity through an ER pathway. The present study addressed two central hypotheses: 1) that androgens directly modulate AVP promoter activity and 2) the effect is mediated by an estrogen or androgen receptor pathway. To that end, we overexpressed androgen receptor, ERβ, and ERβ splice variants in a neuronal cell line and measured AVP promoter activity using a firefly luciferase reporter assay. Our results demonstrate that DHT and its metabolite 5α-androstane-3β,17β-diol stimulate AVP promoter activity through ERβ in a neuronal cell line.
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Zárate, S., G. Jaita, V. Zaldivar, D. B. Radl, G. Eijo, J. Ferraris, D. Pisera, and A. Seilicovich. "Estrogens exert a rapid apoptotic action in anterior pituitary cells." American Journal of Physiology-Endocrinology and Metabolism 296, no. 4 (April 2009): E664—E671. http://dx.doi.org/10.1152/ajpendo.90785.2008.
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It is now accepted that estrogens not only stimulate lactotrope proliferation but also sensitize anterior pituitary cells to proapoptotic stimuli. In addition to their classical mechanism of action through binding to intracellular estrogen receptors (ERs), there is increasing evidence that estrogens exert rapid actions mediated by cell membrane-localized ERs (mERs). In the present study, we examined the involvement of membrane-initiated steroid signaling in the proapoptotic action of estradiol in primary cultures of anterior pituitary cells from ovariectomized rats by using estren, a synthetic estrogen with no effect on classical transcription and a cell-impermeable 17β-estradiol conjugate (E2-BSA). Both compounds induced cell death of anterior pituitary cells after 60 min of incubation as assessed by flow cytometry and the [3-(4,5-dimethylthiazol-2-yl)]-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Estren, E2, and E2-BSA induced apoptosis of lactotropes and somatotropes as evaluated by the deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and immunodetection of prolactin (PRL) and growth hormone (GH). The proapoptotic effect of E2-BSA was abrogated by ICI-182,780, an antagonist of ERs. The expression of membrane-associated ERα was observed in PRL- and GH-bearing cells. Our results indicate that estradiol is able to exert a rapid apoptotic action in anterior pituitary cells, especially lactotropes and somatotropes, by a mechanism triggered by mERs. This mechanism could be involved in anterior pituitary cell turnover.
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Mattsson, Anna, Jan A. Olsson, and Björn Brunström. "Selective estrogen receptor α activation disrupts sex organ differentiation and induces expression of vitellogenin II and very low-density apolipoprotein II in Japanese quail embryos." REPRODUCTION 136, no. 2 (August 2008): 175–86. http://dx.doi.org/10.1530/rep-08-0100.
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The Japanese quail (Coturnix japonica) is a widely used model species for studying the roles of steroid hormones in avian sex differentiation. The aim of the present study was to elucidate the significance of estrogen receptors α and β (ERα and ERβ) in normal sex differentiation of the reproductive organs in the Japanese quail and in xenoestrogen-induced disruption of reproductive organ differentiation. Real-time PCR indicated that ERα (ESR1) mRNA is expressed in both right and left gonads and Müllerian ducts (MDs) in both sexes during early morphological differentiation. ERβ (ESR2) transcripts were also detected in gonads and MDs, but at very low levels. Both receptor subtypes were expressed in the liver and may therefore mediate the expression of estrogen-regulated egg-yolk proteins. Aromatase mRNA was expressed at much higher levels in female than male gonads as early as embryonic day 5, indicating early sex differences in estrogen synthesis. Treatment with the ERα-selective agonist propyl pyrazole triol showed that frequently reported xenoestrogen effects, such as ovotestis formation, abnormal MD development, and hepatic expression of egg-yolk proteins, were induced by selective activation of ERα. Taken together, our results suggest that activation of ERα is crucial for estrogen-dependent sex differentiation of the reproductive organs and that ERα mediates xenoestrogen-induced toxicity during reproductive development in birds.
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Castillo, Alesha B., Jason W. Triplett, Fredrick M. Pavalko, and Charles H. Turner. "Estrogen receptor-β regulates mechanical signaling in primary osteoblasts." American Journal of Physiology-Endocrinology and Metabolism 306, no. 8 (April 15, 2014): E937—E944. http://dx.doi.org/10.1152/ajpendo.00458.2013.
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Mechanical loading is an important regulator in skeletal growth, maintenance, and aging. Estrogen receptors have a regulatory role in mechanically induced bone adaptation. Estrogen receptor-α (ERα) is known to enhance load-induced bone formation, whereas ERβ negatively regulates this process. We hypothesized that ERβ regulates mechanical signaling in osteoblasts. We tested this hypothesis by subjecting primary calvarial cells isolated from wild-type and ERβ-knockout mice (BERKO) to oscillatory fluid flow in the absence or presence of estradiol (E2). We found that the known responses to fluid shear stress, i.e., phosphorylation of the mitogen-activated protein kinase ERK and upregulation of COX-2 expression, were inhibited in BERKO cells in the absence of E2. Flow-induced increase in prostaglandin E2 (PGE2) release was not altered in BERKO cells in the absence of E2, but was increased when E2 was present. Additionally, immunofluorescence analysis and estrogen response element luciferase assays revealed increased ERα expression and flow- and ligand-induced nuclear translocation as well as transcriptional activity in BERKO cells in both the presence and absence of E2. Taken together, these data suggest that ERβ plays both ligand-dependent and ligand-independent roles in mechanical signaling in osteoblasts. Furthermore, our data suggest that one mechanism by which ERβ regulates mechanotransduction in osteoblasts may result from its inhibitory effect on ERα expression and function. Targeting estrogen receptors (e.g., inhibiting ERβ) may represent an effective approach for prevention and treatment of age-related bone loss.
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Hara, Yuko, Elizabeth M. Waters, Bruce S. McEwen, and John H. Morrison. "Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse." Physiological Reviews 95, no. 3 (July 2015): 785–807. http://dx.doi.org/10.1152/physrev.00036.2014.
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Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER α and ER β, there are membrane-bound ER α, ER β, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction.
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Kohno, Satomi, Melissa C. Bernhard, Yoshinao Katsu, Jianguo Zhu, Teresa A. Bryan, Brenna M. Doheny, Taisen Iguchi, and Louis J. Guillette. "Estrogen Receptor 1 (ESR1; ERα), not ESR2 (ERβ), Modulates Estrogen-Induced Sex Reversal in the American Alligator, a Species With Temperature-Dependent Sex Determination." Endocrinology 156, no. 5 (February 25, 2015): 1887–99. http://dx.doi.org/10.1210/en.2014-1852.
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All crocodilians and many turtles exhibit temperature-dependent sex determination where the temperature of the incubated egg, during a thermo-sensitive period (TSP), determines the sex of the offspring. Estrogens play a critical role in sex determination in crocodilians and turtles, as it likely does in most nonmammalian vertebrates. Indeed, administration of estrogens during the TSP induces male to female sex reversal at a male-producing temperature (MPT). However, it is not clear how estrogens override the influence of temperature during sex determination in these species. Most vertebrates have 2 forms of nuclear estrogen receptor (ESR): ESR1 (ERα) and ESR2 (ERβ). However, there is no direct evidence concerning which ESR is involved in sex determination, because a specific agonist or antagonist for each ESR has not been tested in nonmammalian species. We identified specific pharmaceutical agonists for each ESR using an in vitro transactivation assay employing American alligator ESR1 and ESR2; these were 4,4′,4′’-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), respectively. Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the TSP, and their sex was examined at the last stage of embryonic development. Estradiol-17β and PPT, but not WAY 200070, induced sex reversal at a MPT. PPT-exposed embryos exposed to the highest dose (5.0 μg/g egg weight) exhibited enlargement and advanced differentiation of the Müllerian duct. These results indicate that ESR1 is likely the principal ESR involved in sex reversal as well as embryonic Müllerian duct survival and growth in American alligators.
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Trapero, Carla, and Mireia Martín-Satué. "Purinergic Signaling in Endometriosis-Associated Pain." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8512. http://dx.doi.org/10.3390/ijms21228512.
Full textAbstract:
Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell–nerve and microglia–nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.