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Bartkowiak-Wieczorek J, Jaros A, Gajdzińska A, Wojtyła-Buciora P, Szymański I, Szymaniak J, Janusz W, Walczak I, Jonaszka G, Bienert A. The Dual Faces of Oestrogen: The Impact of Exogenous Oestrogen on the Physiological and Pathophysiological Functions of Tissues and Organs. Int J Mol Sci 2024; 25:8167. [PMID: 39125736 PMCID: PMC11311417 DOI: 10.3390/ijms25158167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Oestrogen plays a crucial physiological role in both women and men. It regulates reproductive functions and maintains various non-reproductive tissues through its receptors, such as oestrogen receptor 1/oestrogen receptor α (ESR1/Erα), oestrogen receptor 2/oestrogen receptor β (ESR2/Erβ), and G protein-coupled oestrogen receptor 1 (GPER). This hormone is essential for the proper functioning of women's ovaries and uterus. Oestrogen supports testicular function and spermatogenesis in men and contributes to bone density, cardiovascular health, and metabolic processes in both sexes. Nuclear receptors Er-α and Er-β belong to the group of transcription activators that stimulate cell proliferation. In the environment, compounds similar in structure to the oestrogens compete with endogenous hormones for binding sites to receptors and to disrupt homeostasis. The lack of balance in oestrogen levels can lead to infertility, cancer, immunological disorders, and other conditions. Exogenous endocrine-active compounds, such as bisphenol A (BPA), phthalates, and organic phosphoric acid esters, can disrupt signalling pathways responsible for cell division and apoptosis processes. The metabolism of oestrogen and its structurally similar compounds can produce carcinogenic substances. It can also stimulate the growth of cancer cells by regulating genes crucial for cell proliferation and cell cycle progression, with long-term elevated levels linked to hormone-dependent cancers such as breast cancer. Oestrogens can also affect markers of immunological activation and contribute to the development of autoimmune diseases. Hormone replacement therapy, oral contraception, in vitro fertilisation stimulation, and hormonal stimulation of transgender people can increase the risk of breast cancer. Cortisol, similar in structure to oestrogen, can serve as a biomarker associated with the risk of developing breast cancer. The aim of this review is to analyse the sources of oestrogens and their effects on the endogenous and exogenous process of homeostasis.
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Affiliation(s)
- Joanna Bartkowiak-Wieczorek
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Agnieszka Jaros
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.J.); (A.B.)
| | - Anna Gajdzińska
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Paulina Wojtyła-Buciora
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
- Department of Social Medicine and Public Health, Calisia University, 62-800 Kalisz, Poland
| | - Igor Szymański
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Julian Szymaniak
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Wojciech Janusz
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Iga Walczak
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Gabriela Jonaszka
- Physiology Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.G.); (P.W.-B.); (I.S.); (J.S.); (W.J.); (I.W.); (G.J.)
| | - Agnieszka Bienert
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.J.); (A.B.)
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Genetics, Treatment, and New Technologies of Hormone Receptor-Positive Breast Cancer. Cancers (Basel) 2023; 15:cancers15041303. [PMID: 36831644 PMCID: PMC9954687 DOI: 10.3390/cancers15041303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 02/12/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
The current molecular classification divides breast cancer into four major subtypes, including luminal A, luminal B, HER2-positive, and basal-like, based on receptor gene expression profiling. Luminal A and luminal B are hormone receptor (HR, estrogen, and/or progesterone receptor)-positive and are the most common subtypes, accounting for around 50-60% and 15-20% of the total breast cancer cases, respectively. The drug treatment for HR-positive breast cancer includes endocrine therapy, HER2-targeted therapy (depending on the HER2 status), and chemotherapy (depending on the risk of recurrence). In this review, in addition to classification, we focused on discussing the important aspects of HR-positive breast cancer, including HR structure and signaling, genetics, including epigenetics and gene mutations, gene expression-based assays, the traditional and new drugs for treatment, and novel or new uses of technology in diagnosis and treatment. Particularly, we have summarized the commonly mutated genes and abnormally methylated genes in HR-positive breast cancer and compared four common gene expression-based assays that are used in breast cancer as prognostic and/or predictive tools in detail, including their clinical use, the factors being evaluated, patient demographics, and the scoring systems. All these topic discussions have not been fully described and summarized within other research or review articles.
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PET Imaging of Estrogen Receptors for Gynecological Tumors. Clin Nucl Med 2022; 47:e481-e488. [PMID: 35675139 DOI: 10.1097/rlu.0000000000004258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT In the past few decades, PET with 18F-FDG has been used for the diagnosis of gynecological malignancies and is considered to be superior to conventional imaging methods in diagnostic accuracy for detecting metastatic lesions and local recurrence and in evaluating the treatment response. On the other hand, several gynecological tumors, such as endometrial cancer and leiomyoma, and breast cancer are estrogen-dependent, in which estrogen is essential for their development and progression. 18F-FES is an 18F-labeled compound of estradiol, the most bioactive type of estrogen, and 18F-FES PET has been well-established for diagnosis, staging, and posttherapeutic follow-up in patients with estrogen receptor-positive breast cancer. Compared with in vitro assessment of tumor biopsy material, PET imaging has the advantages of being able to measure in vivo tumor behavior, characterize the entire tumor burden, and capture the heterogeneity of the tumor phenotype. In this article, we review the phenotyping of estrogen-related gynecological tumors other than breast cancer using 18F-FES PET and demonstrate the additional value of 18F-FES PET to 18F-FDG PET in their diagnosis and prognostication. Moreover, promising PET tracers other than 18F-FES and 18F-FDG for the evaluation of estrogen-related gynecological tumors are introduced.
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Thabet RH, Gomaa AA, Matalqah LM, Shalaby EM. Vitamin D: an essential adjuvant therapeutic agent in breast cancer. J Int Med Res 2022; 50:3000605221113800. [PMID: 35883275 PMCID: PMC9340350 DOI: 10.1177/03000605221113800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 06/07/2022] [Indexed: 11/20/2022] Open
Abstract
Low serum levels of vitamin D have been reported as a risk factor for breast cancer. This narrative review provides an update on the impact of vitamin D on hormone receptors, notably estrogen receptor subunits, and gives insights on possible therapeutic interventions to overcome breast cancer. In addition, evidence that supports the beneficial use of vitamin D as adjuvant treatment of breast cancer is summarized. Vitamin D deficiency is significantly widespread in patients with triple-negative tumors. Several studies have observed a possible modulatory effect of vitamin D or its analogues on the expression of different hormone receptors in breast cancer and increased sensitivity to tamoxifen. Vitamin D possesses anti-inflammatory and immunomodulatory effects in patients with breast cancer, and the mechanism of action of vitamin D in patients with breast cancer is discussed. In conclusion, vitamin D appears to have a beneficial role in the prevention and management of breast cancer, however, large-scale, randomized controlled trials are needed to confirm the effects of vitamin D in breast cancer prevention or treatment.
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Affiliation(s)
- Romany H Thabet
- Department of Pharmacology, Faculty of Medicine, Assiut
University
- Department of Basic Medical Sciences, Faculty of Medicine,
Yarmouk University, Irbid-Jordan
| | - Adel A Gomaa
- Department of Pharmacology, Faculty of Medicine, Assiut
University
- Center for Research on Management of Age-Related Diseases,
Assiut University, Assiut, Egypt
| | - Laila M Matalqah
- Department of Basic Medical Sciences, Faculty of Medicine,
Yarmouk University, Irbid-Jordan
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Therapeutic Strategies and Potential Actions of Female Sex Steroid Hormones and Their Receptors in Colon Cancer Based on Preclinical Studies. Life (Basel) 2022; 12:life12040605. [PMID: 35455096 PMCID: PMC9032023 DOI: 10.3390/life12040605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 11/17/2022] Open
Abstract
Several epidemiological studies have reported that the use of female sex steroid hormones could reduce the risk of colon cancer (CRC). This review summarizes the available data related to estradiol (E2) and progesterone (P4) single and dual treatments in CRC male and female in vitro and in vivo models, mainly from preclinical studies, alongside their potential molecular mechanisms. Most of the studies showed that E2 exogenous treatment and/or reactivation of its beta receptor (ERβ) significantly inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis by modulating several molecular pathways. Likewise, the inhibition of ERα receptors produced similar antitumorigenic actions, both in vivo and in vitro, suggesting that E2 could have dual opposing roles in CRC that are dependent on the expression profile of its nuclear receptors. The available studies on P4 are scarce, and the results revealed that in vitro and in vivo treatments with natural and synthetic progesterone were also associated with promising tumoricidal actions. Nevertheless, the combination of E2 with P4 showed enhanced anticancer activities compared with their monotherapy protocols in male–female cell lines and animals. Collectively, the studies suggested that the female sex steroid hormones could provide a novel and effective therapeutic strategy against CRC.
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Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions. Biomedicines 2022; 10:biomedicines10040861. [PMID: 35453610 PMCID: PMC9029610 DOI: 10.3390/biomedicines10040861] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 12/17/2022] Open
Abstract
Estrogen is one of the most important female sex hormones, and is indispensable for reproduction. However, its role is much wider. Among others, due to its neuroprotective effects, estrogen protects the brain against dementia and complications of traumatic injury. Previously, it was used mainly as a therapeutic option for influencing the menstrual cycle and treating menopausal symptoms. Unfortunately, hormone replacement therapy might be associated with detrimental side effects, such as increased risk of stroke and breast cancer, raising concerns about its safety. Thus, tissue-selective and non-classical estrogen analogues have become the focus of interest. Here, we review the current knowledge about estrogen effects in a broader sense, and the possibility of using selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), phytoestrogens, and activators of non-genomic estrogen-like signaling (ANGELS) molecules as treatment.
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The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density. Drugs 2021; 81:1831-1858. [PMID: 34724173 PMCID: PMC8578161 DOI: 10.1007/s40265-021-01625-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 12/26/2022]
Abstract
Osteoporosis is a highly prevalent bone disease affecting more than 37.5 million individuals in the European Union (EU) and the United States of America (USA). It is characterized by low bone mineral density (BMD), impaired bone quality, and loss of structural and biomechanical properties, resulting in reduced bone strength. An increase in morbidity and mortality is seen in patients with osteoporosis, caused by the approximately 3.5 million new osteoporotic fractures occurring every year in the EU. Currently, different medications are available for the treatment of osteoporosis, including anti-resorptive and osteoanabolic medications. Bisphosphonates, which belong to the anti-resorptive medications, are the standard treatment for osteoporosis based on their positive effects on bone, long-term experience, and low costs. However, not only medications used for the treatment of osteoporosis can affect bone: several other medications are suggested to have an effect on bone as well, especially on fracture risk and BMD. Knowledge about the positive and negative effects of different medications on both fracture risk and BMD is important, as it can contribute to an improvement in osteoporosis prevention and treatment in general, and, even more importantly, to the individual's health. In this review, we therefore discuss the effects of both osteoporotic and non-osteoporotic medications on fracture risk and BMD. In addition, we discuss the underlying mechanisms of action.
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Abstract
This review article summarizes the clinical applications of established and emerging PET tracers in the evaluation of the 5 most common gynecologic malignancies: endometrial, ovarian, cervical, vaginal, and vulvar cancers. Emphasis is given to 2-deoxy-2-[18F]fluoro-d-glucose as the most widely used and studied tracer, with additional clinical tracers also explored. The common imaging protocols are discussed, including standard dose ranges and uptake times, established roles, as well as the challenges and future directions of these imaging techniques. The key points are emphasized with images from selected cases.
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Affiliation(s)
- Saul N Friedman
- Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA
| | - Malak Itani
- Section of Abdominal Imaging, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA
| | - Farrokh Dehdashti
- Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA.
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Bouras E, Papandreou C, Tzoulaki I, Tsilidis KK. Endogenous sex steroid hormones and colorectal cancer risk: a systematic review and meta-analysis. Discov Oncol 2021; 12:8. [PMID: 35201467 PMCID: PMC8777537 DOI: 10.1007/s12672-021-00402-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/02/2021] [Indexed: 12/24/2022] Open
Abstract
Preclinical data suggest that endogenous sex steroid hormones may be implicated in colorectal cancer (CRC) development, however, findings from epidemiological studies are conflicting. The aim of this systematic review and meta-analysis was to investigate the associations between endogenous concentrations of sex hormones and CRC risk. PubMed and Scopus were searched until June 2020 for prospective studies evaluating the association between pre-diagnostic plasma/serum concentrations of estradiol, testosterone and sex-hormone binding globulin (SHBG) and CRC risk. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using the inverse-variance weighted random-effects model based on the DerSimonian-Laird estimator. Eight studies were included in the meta-analysis after evaluating 3,859 non-duplicate records. Four of the eight studies had a nested case-control design, one study was a case-cohort and the rest three studies were cohort studies, and they included on average 295 cases (range:48-732) and 2,105 controls. No associations were found for endogenous sex steroid hormones in men or post-menopausal women with CRC risk, with evidence for substantial heterogeneity observed among women. Findings from this meta-analysis do not support presence of associations between pre-diagnostic concentrations of testosterone, estradiol and SHBG with incident CRC risk in men and post-menopausal women.
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Affiliation(s)
- Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
| | | | - Ioanna Tzoulaki
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, W2 1PG, UK
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, W2 1PG, UK.
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10
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Mitochondrial biogenesis in organismal senescence and neurodegeneration. Mech Ageing Dev 2020; 191:111345. [DOI: 10.1016/j.mad.2020.111345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 12/19/2022]
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Mbachu OC, Howell C, Simmler C, Garcia GRM, Skowron KJ, Dong H, Ellis SG, Hitzman RT, Hajirahimkhan A, Chen SN, Nikolic D, Moore TW, Vollmer G, Pauli GF, Bolton JL, Dietz BM. SAR Study on Estrogen Receptor α/β Activity of (Iso)flavonoids: Importance of Prenylation, C-Ring (Un)Saturation, and Hydroxyl Substituents. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:10651-10663. [PMID: 32945668 PMCID: PMC8294944 DOI: 10.1021/acs.jafc.0c03526] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Many botanicals used for women's health contain estrogenic (iso)flavonoids. The literature suggests that estrogen receptor beta (ERβ) activity can counterbalance estrogen receptor alpha (ERα)-mediated proliferation, thus providing a better safety profile. A structure-activity relationship study of (iso)flavonoids was conducted to identify ERβ-preferential structures, overall estrogenic activity, and ER subtype estrogenic activity of botanicals containing these (iso)flavonoids. Results showed that flavonoids with prenylation on C8 position increased estrogenic activity. C8-prenylated flavonoids with C2-C3 unsaturation resulted in increased ERβ potency and selectivity [e.g., 8-prenylapigenin (8-PA), EC50 (ERβ): 0.0035 ± 0.00040 μM], whereas 4'-methoxy or C3 hydroxy groups reduced activity [e.g., icaritin, EC50 (ERβ): 1.7 ± 0.70 μM]. However, nonprenylated and C2-C3 unsaturated isoflavonoids showed increased ERβ estrogenic activity [e.g., genistein, EC50 (ERβ): 0.0022 ± 0.0004 μM]. Licorice (Glycyrrhiza inflata, [EC50 (ERα): 1.1 ± 0.20; (ERβ): 0.60 ± 0.20 μg/mL], containing 8-PA, and red clover [EC50 (ERα): 1.8 ± 0.20; (ERβ): 0.45 ± 0.10 μg/mL], with genistein, showed ERβ-preferential activity as opposed to hops [EC50 (ERα): 0.030 ± 0.010; (ERβ): 0.50 ± 0.050 μg/mL] and Epimedium sagittatum [EC50 (ERα): 3.2 ± 0.20; (ERβ): 2.5 ± 0.090 μg/mL], containing 8-prenylnaringenin and icaritin, respectively. Botanicals with ERβ-preferential flavonoids could plausibly contribute to ERβ-protective benefits in menopausal women.
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Affiliation(s)
- Obinna C. Mbachu
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Caitlin Howell
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Charlotte Simmler
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Center for Natural Product Technologies (CENAPT), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Gonzalo R. Malca Garcia
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Kornelia J. Skowron
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Huali Dong
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Sarah G. Ellis
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Ryan T. Hitzman
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Atieh Hajirahimkhan
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Shao-Nong Chen
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Center for Natural Product Technologies (CENAPT), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Dejan Nikolic
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Terry W. Moore
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- University of Illinois Cancer Center, 1801 W Taylor St., Chicago, Illinois 60612-7231, United States
| | - Günter Vollmer
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Molecular Cell Physiology and Endocrinology, Faculty of Biology, Dresden University of Technology, 01217 Dresden, Germany
| | - Guido F. Pauli
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Center for Natural Product Technologies (CENAPT), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Judy L. Bolton
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
| | - Birgit M. Dietz
- UIC/NIH Center for Botanical Dietary Supplements Research, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
- Department of Pharmaceutical Sciences, College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231
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Abstract
Kv7 channels (Kv7.1-7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1-5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2-7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2-7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.
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Affiliation(s)
- Emely Thompson
- Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
| | - Jodene Eldstrom
- Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
| | - David Fedida
- Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
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Böckers M, Paul NW, Efferth T. Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor α. Toxicol Appl Pharmacol 2020; 399:115030. [DOI: 10.1016/j.taap.2020.115030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/21/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
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Yang Y, Yang T, Liu S, Cao Z, Zhao Y, Su X, Liao Z, Teng X, Hua J. Concentrated ambient PM 2.5 exposure affects mice sperm quality and testosterone biosynthesis. PeerJ 2019; 7:e8109. [PMID: 31799077 PMCID: PMC6885350 DOI: 10.7717/peerj.8109] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 10/28/2019] [Indexed: 12/18/2022] Open
Abstract
Background Studies suggested that PM2.5 exposure could lead to adverse reproductive effects on male animals. However, the underlying mechanism is still not clear. Besides, animals in the majority of previous studies were exposed to PM2.5 through intratracheal instillation which should be improved. In addition, limited amount of research has been conducted in China where the PM2.5 concentration is higher and the PM2.5 components are different. The aim of this work is to explore the effects of concentrated ambient PM2.5 (CAP) on mice sperm quality and testosterone biosynthesis. Methods A total of 12 male C57BL/6 mice were exposed to filtered air (FA) or CAP for 125 days using the Shanghai Meteorological and Environmental Animal Exposure System. The mice sperm concentration, sperm motility, DNA fragmentation index, high DNA stainability and plasma testosterone were analyzed. Testicular histology and sperm morphology were observed through optical microscope. Testosterone biosynthesis related gene expressions were analyzed using real-time PCR, including cytochrome P450 CHOL side-chain cleavage enzyme (P450scc), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β HSD), 17β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase (P450arom), estrogen receptor (ER), androgen receptor (AR) and follicle stimulating hormone receptor (FSHR). Results Exposure to CAP resulted in disturbance of various stages of spermatogenesis and significant higher percentage of abnormal sperm (FA vs. CAP: 24.37% vs. 44.83%) in mice testis. CAP exposure significantly decreased sperm concentration (43.00 × 106 vs. 25.33 × 106) and motility (PR: 63.58% vs. 55.15%; PR + NP: 84.00% vs. 77.08%) in epididymis. Plasma testosterone concentration were significantly declined (0.28 ng/ml vs. 0.69 ng/ml) under CAP exposure. Notably, the levels of testosterone biosynthesis related genes, StAR, P450scc, P450arom, ER and FSHR were significantly decreased with CAP exposure. Conclusion Concentrated ambient PM2.5 exposure altered mice sperm concentration, motility and morphology, which might be mediated primarily by the decline in testosterone concentration and testosterone biosynthesis process.
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Affiliation(s)
- Yingying Yang
- Department of Women and Children's Health Care, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Tingting Yang
- Department of Social Medicine, School of Public Health, Fudan University, Shanghai, China
| | - Shengxin Liu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Zhijuan Cao
- Department of Women and Children's Health Care, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yan Zhao
- Department of Women and Children's Health Care, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiujuan Su
- Department of Women and Children's Health Care, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Xiaoming Teng
- Department of Assisted Reproductive Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jing Hua
- Department of Women and Children's Health Care, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
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15
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16
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Frump AL, Selej M, Wood JA, Albrecht M, Yakubov B, Petrache I, Lahm T. Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner. Am J Respir Cell Mol Biol 2019; 59:114-126. [PMID: 29394091 DOI: 10.1165/rcmb.2017-0167oc] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
17β-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague-Dawley rats and ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs). Hypoxia increased expression of ERβ, but not ERα, in lungs from HPH rats as well as in rat and human PAECs. ERβ mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1α/HIF-2α stabilization increased PAEC ERβ, whereas HIF-1α knockdown decreased ERβ abundance in hypoxic PAECs. In turn, ERβ knockdown in hypoxic PAECs increased HIF-2α expression, suggesting a hypoxia-sensitive feedback mechanism. ERβ knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERβ activation increased PHD2 and decreased both HIF-1α and HIF-2α, suggesting that ERβ regulates the PHD2/HIF-1α/HIF-2α axis during hypoxia. Whereas hypoxic wild-type or ERα knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1α after hypoxia compared with untreated hypoxic mice, ERβ knockout mice exhibited increased HIF-2α and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1α, increases ERβ expression and the E2-ERβ axis targets PHD2, HIF-1α, and HIF-2α to attenuate HPH development.
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Affiliation(s)
- Andrea L Frump
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine
| | - Mona Selej
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine
| | - Jordan A Wood
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine
| | - Marjorie Albrecht
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine
| | - Bakhtiyor Yakubov
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine
| | - Irina Petrache
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine.,2 Richard L. Roudebush VA Medical Center, and
| | - Tim Lahm
- 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine.,2 Richard L. Roudebush VA Medical Center, and.,3 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
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17
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Binding Constants of Maackia Amurensis Whole Extract and its Separate Flavanoids to Estradiol Receptors. Pharm Chem J 2019. [DOI: 10.1007/s11094-019-1914-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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18
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Kim JG, Leem YE, Kwon I, Kang JS, Bae YM, Cho H. Estrogen modulates serotonin effects on vasoconstriction through Src inhibition. Exp Mol Med 2018; 50:1-9. [PMID: 30559345 PMCID: PMC6297153 DOI: 10.1038/s12276-018-0193-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/18/2018] [Accepted: 10/01/2018] [Indexed: 12/25/2022] Open
Abstract
Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin.
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Affiliation(s)
- Jae Gon Kim
- Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Korea
| | - Young-Eun Leem
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ilmin Kwon
- Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Jong-Sun Kang
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Young Min Bae
- Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Korea.
| | - Hana Cho
- Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea. .,Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea.
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19
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Facial Sadness Recognition is Modulated by Estrogen Receptor Gene Polymorphisms in Healthy Females. Brain Sci 2018; 8:brainsci8120219. [PMID: 30544539 PMCID: PMC6315436 DOI: 10.3390/brainsci8120219] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 02/06/2023] Open
Abstract
Polymorphisms of the estrogen receptor ESR1 and ESR2 genes have been linked with cognitive deficits and affective disorders. The effects of these genetic variants on emotional processing in females with low estrogen levels are not well known. The aim was to explore the impact of the ESR1 and ESR2 genes on the responses to the facial emotion recognition task in females. Postmenopausal healthy female volunteers were genotyped for the polymorphisms Xbal and PvuII of ESR1 and the polymorphism rs1256030 of ESR2. The effect of these polymorphisms on the response to the facial emotion recognition of the emotions happiness, sadness, disgust, anger, surprise, and fear was analyzed. Females carrying the P allele of the PvuII polymorphism or the X allele of the Xbal polymorphism of ESR1 easily recognized facial expressions of sadness that were more difficult for the women carrying the p allele or the x allele. They displayed higher accuracy, fast response time, more correct responses, and fewer omissions to complete the task, with a large effect size. Women carrying the ESR2 C allele of ESR2 showed a faster response time for recognizing facial expressions of anger. These findings link ESR1 and ESR2 polymorphisms in facial emotion recognition of negative emotions.
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20
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Zhang R, Zhang Y, Wu M, Yan P, Izaz A, Wang R, Zhu H, Zhou Y, Wu X. Molecular cloning of androgen receptor and gene expression of sex steroid hormone receptors in the brain of newborn Chinese alligator (Alligator sinensis). Gene 2018; 674:178-187. [DOI: 10.1016/j.gene.2018.06.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 05/29/2018] [Accepted: 06/11/2018] [Indexed: 12/16/2022]
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21
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Sehl ME, Ganz PA. Potential Mechanisms of Age Acceleration Caused by Estrogen Deprivation: Do Endocrine Therapies Carry the Same Risks? JNCI Cancer Spectr 2018; 2:pky035. [PMID: 31360862 PMCID: PMC6649786 DOI: 10.1093/jncics/pky035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/30/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023] Open
Abstract
Longer duration of endocrine therapy decreases breast cancer recurrence and mortality, but these benefits need to be weighed against potential risks to overall health. Notable side effects of endocrine therapy include cataracts, uterine cancer, thromboembolic events, osteoporosis and fracture risk, chronic musculoskeletal complaints, as well as vaginal dryness and discharge, and vasomotor symptoms. Estrogen deprivation in healthy women younger than 50 years undergoing bilateral oophorectomy has been shown to accelerate the development of diseases related to aging, including coronary artery disease, cardiac arrhythmias, stroke, dementia, and osteoporosis, raising concern that even less dramatic modulation of estrogen homeostasis may adversely affect health outcomes. Diminished available estrogen at the cellular and molecular level may facilitate mechanisms that underlie the aging process, often termed the hallmarks of aging. In this review, we describe estrogen's role in normal physiology across tissues, review the effects of estrogen deprivation on health outcomes in the setting of both surgical and natural menopause, and examine the hallmarks of aging with attention to the effects of estrogen and estrogen blockade on each molecular mechanism underlying the aging process.
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Affiliation(s)
- Mary E Sehl
- Medicine, Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.,Biomathematics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Patricia A Ganz
- Medicine, Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.,Health Policy and Management, School of Public Health, University of California Los Angeles, Los Angeles, CA
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22
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Matsuda KI, Hashimoto T, Kawata M. Intranuclear Mobility of Estrogen Receptor: Implication for Transcriptional Regulation. Acta Histochem Cytochem 2018; 51:129-136. [PMID: 30279614 PMCID: PMC6160615 DOI: 10.1267/ahc.18023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/31/2018] [Indexed: 11/22/2022] Open
Abstract
The estrogen receptor (ER) is a ligand-dependent transcription factor that has two subtypes: ERα and ERβ. ERs regulate transcription of estrogen-responsive genes through interactions with multiple intranuclear components, such as cofactors and the nuclear matrix. Live cell imaging using fluorescent protein-labeled ERs has revealed that ligand-activated ERs are highly mobile in the nucleus, with transient association with the DNA and nuclear matrix. Scaffold attachment factor B (SAFB) 1 and its paralogue, SAFB2, are nuclear matrix-binding proteins that negatively modulate ERα-mediated transcription. Expression of SAFB1 and SAFB2 reduces the mobility of ERα in the presence of ligand. This regulatory machinery is emerging as an epigenetic-like mechanism that alters transcriptional activity through control of intranuclear molecular mobility.
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Affiliation(s)
- Ken Ichi Matsuda
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
| | - Takashi Hashimoto
- Division of Anatomy and Neuroscience, Department of Morphological and Physiological Sciences, University of Fukui Faculty of Medical Sciences
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23
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Wu S, Hu G, Zhao X, Wang Q, Jiang J. Synergistic potential of fenvalerate and triadimefon on endocrine disruption and oxidative stress during rare minnow embryo development. ENVIRONMENTAL TOXICOLOGY 2018; 33:759-769. [PMID: 29683247 DOI: 10.1002/tox.22563] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 03/28/2018] [Accepted: 04/01/2018] [Indexed: 06/08/2023]
Abstract
Pyrethroids have been reported to interact synergistically when co-exposed with azoles fungicides in different organisms. In the present study, we investigated the mixture toxicity of fenvalerate (FEN) and triadimefon (TDF) toward embryos of Gobiocypris rarus after 96 h exposure. Results demonstrated that TDF enhanced the acute toxicity of FEN. Exposure to binary mixtures of FEN and TDF resulted in synergistic responses of endocrine disruption by inducing the transcripts of several genes including vtg, erα, erβ1, erβ2, cyp19a, cyp1a, cyp4, cyp11a, gnrh3, gnrhr1a, star, and dmrt1. Furthermore, FEN and TDF mixture increased the VTG level and aromatase activity in rare minnow embryos. FEN and TDF co-exposure also regulated the mRNA of vezf, hsp70, p53, gadd45α, induced the synthesis of ROS and activity of GST, suggesting the synergistic potential of oxidative stress induced by FEN and TDF co-exposure. The results indicated that binary mixtures of FEN and TDF could simultaneously induce endocrine disruption and oxidative stress in a synergistic manner during rare minnow embryo development.
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Affiliation(s)
- Shenggan Wu
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Gaojie Hu
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Xueping Zhao
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Qiang Wang
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Jinhua Jiang
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
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24
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Khillare GS, Sastry KVH, Agrawal R, Saxena R, Mohan J, Singh RP. Expression of gonadotropin and sex steroid hormone receptor mRNA in the utero-vaginal junction containing sperm storage tubules of oviduct during sexual maturation in Japanese quail. Gen Comp Endocrinol 2018; 259:141-146. [PMID: 29174868 DOI: 10.1016/j.ygcen.2017.11.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 11/06/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
Sex steroid hormones play an important role in reproductive tissue development of avian species. However, their role in Japanese quail is yet to be established. To understand the physiological role of hormones involved in the development of sperm storage tubules (SSTs) in quail, we investigated expression profiles of gonadotropin (LH-R and FSH-R) and sex steroid hormone (PR-R, ER-α and ER-β) receptors in the uterovaginal junction (UVJ) containing SSTs before and during sexual maturation i.e. four to eight weeks. Every week four birds were sacrificed to collect blood and UVJ for sex steroid hormone (progesterone and estrogen) estimation and gene expression profiling of sex steroid hormone (PR-R, ER-α and ER-β) and gonadotropin receptors (LH-R and FSH-R) using qRT-PCR. Receptor expression results showed that the expression of sex steroid receptor (PR-R, ER-α and ER-β) genes were upregulated significantly (P < .05) in SSTs with the advancement of age. The expression of gonadotropin receptors (LH-R and FSH-R) was only high at week 5 and 6 respectively. Serum hormone analysis indicated a significant (P < .05) rise in estradiol till 7th week and progesterone from 7th week onwards. These results suggest that the gonadotropin and sex steroid hormone receptors may have the role in the development and maintenance of UVJ that contains predominantly SSTs during sexual maturation.
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Affiliation(s)
- Gautam Sudamrao Khillare
- Molecular Physiology Laboratory, Division of Avian Physiology and Reproduction, ICAR-Central Avian Research Institute, Izatnagar, 243122, India
| | - Kochiganti Venkata Hanumat Sastry
- Molecular Physiology Laboratory, Division of Avian Physiology and Reproduction, ICAR-Central Avian Research Institute, Izatnagar, 243122, India
| | - Radha Agrawal
- Molecular Physiology Laboratory, Division of Avian Physiology and Reproduction, ICAR-Central Avian Research Institute, Izatnagar, 243122, India
| | - Ritu Saxena
- Molecular Physiology Laboratory, Division of Avian Physiology and Reproduction, ICAR-Central Avian Research Institute, Izatnagar, 243122, India
| | - Jag Mohan
- Molecular Physiology Laboratory, Division of Avian Physiology and Reproduction, ICAR-Central Avian Research Institute, Izatnagar, 243122, India
| | - Ram Pratap Singh
- Sálim Ali Centre for Ornithology and Natural History, Anaikatty, Coimbatore 641108, India.
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25
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Fujimura T, Takayama K, Takahashi S, Inoue S. Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine. Cancers (Basel) 2018; 10:cancers10020029. [PMID: 29360794 PMCID: PMC5836061 DOI: 10.3390/cancers10020029] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022] Open
Abstract
Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. Therefore, new therapeutic strategies are required in clinical practice. In addition, ARs; estrogen receptors (ERs; ERα and ERβ); and estrogen-related receptors (ERRs; ERRα, ERRβ, and ERRγ) have been reported to be involved in the development or regulation of PC. Recent investigations have revealed the role of associated molecules, such as KLF5, FOXO1, PDGFA, VEGF-A, WNT5A, TGFβ1, and micro-RNA 135a of PC, via ERs and ERRs. Selective ER modulators (SERMs) have been developed. Recently, estrogen and androgen blockade (EAB) using a combination of toremifene and ADT has been demonstrated to improve biochemical recurrence rate in treatment-naïve bone metastatic PC. In the future, the suitability of ADT alone or EAB for individuals may be evaluated by making clinical decisions on the basis of information obtained from RT-PCR, gene-panel, or liquid biopsy to create a “personalized medicine” or “precision medicine”. In this review, we summarize ER and ERR signaling pathways, molecular diagnosis, and SERMs as candidates for advanced PC treatment.
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Affiliation(s)
- Tetsuya Fujimura
- Department of Urology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
| | - Kenichi Takayama
- Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
| | - Satoru Takahashi
- Department of Urology, Nihon University School of Medicine, Tokyo 173-8610, Japan.
| | - Satoshi Inoue
- Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
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26
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Mackeh R, Marr AK, Dargham SR, Syed N, Fakhro KA, Kino T. Single-Nucleotide Variations of the Human Nuclear Hormone Receptor Genes in 60,000 Individuals. J Endocr Soc 2018; 2:77-90. [PMID: 29379896 PMCID: PMC5779106 DOI: 10.1210/js.2017-00406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 11/28/2017] [Indexed: 01/15/2023] Open
Abstract
Nuclear hormone receptors (NRs) mediate biologic actions of lipophilic molecules to gene transcription and are phylogenetically and functionally categorized into seven subfamilies and three groups, respectively. Single-nucleotide variations (SNVs) or polymorphisms are genetic changes influencing individual response to environmental factors and susceptibility to various disorders, and are part of the genetic diversification and basis for evolution. We sorted out SNVs of the human NR genes from 60,706 individuals, calculated three parameters (percentage of all variants, percentage of loss-of-function variants, and ratio of nonsynonymous/synonymous variants in their full protein-coding or major domain-coding sequences), and compared them with several valuables. Comparison of these parameters between NRs and control groups identified that NRs form a highly conserved gene family. The three parameters for the full coding sequence are positively correlated with each other, whereas four NR genes are distinct from the others with much higher tolerance to protein sequence-changing variants. DNA-binding domain and N-terminal domain are respectively those bearing the least and the most variation. NR subfamilies based on their phylogenetic proximity or functionality as well as diversity of tissue distribution and numbers of partner molecules are all not correlated with the variation parameters, whereas their gene age demonstrates an association. Our results suggest that the natural selection driving the NR family evolution still operates in humans. Gene age and probably the potential to adapt to various new ligands, but not current functional diversity, are major determinants for SNVs of the human NR genes.
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Affiliation(s)
- Rafah Mackeh
- Department of Human Genetics, Division of Translational Medicine, Sidra Medical and Research Center, Doha 26999, Qatar
| | - Alexandra K. Marr
- Department of Human Genetics, Division of Translational Medicine, Sidra Medical and Research Center, Doha 26999, Qatar
| | - Soha R. Dargham
- Biostatistics, Epidemiology and Biomathematics Research Core, Weill Cornell Medicine in Qatar, Doha 24811, Qatar
| | - Najeeb Syed
- Division of Biomedical Informatics, Sidra Medical and Research Center, Doha 26999, Qatar
| | - Khalid A. Fakhro
- Department of Human Genetics, Division of Translational Medicine, Sidra Medical and Research Center, Doha 26999, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine in Qatar, Doha 24144, Qatar
| | - Tomoshige Kino
- Department of Human Genetics, Division of Translational Medicine, Sidra Medical and Research Center, Doha 26999, Qatar
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27
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Jiang J, Hu G, Zhang C, Zhao X, Wang Q, Chen L. Toxicological analysis of triadimefon on endocrine disruption and oxidative stress during rare minnow (Gobiocypris rarus) larvae development. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2017; 24:26681-26691. [PMID: 28956230 DOI: 10.1007/s11356-017-0317-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 09/22/2017] [Indexed: 06/07/2023]
Abstract
Triadimefon (TDF) is a systemic wide-spectrum antifungal compound that is widely used in agriculture to inhibit fungal growth on various crops. Since previous studies focused on the embryo and adult life stages in the investigation of ecological impact, here we investigated the long-term effects of TDF (1, 10, 100 μg/L) on rare minnow during its larvae development. TDF caused an anti-estrogenic effect by decreasing vitellogenin (VTG) and CYP19a mRNA level, and inhibiting the aromatase activity and VTG levels after a 3, 6, 10, or 14-day exposure in rare minnow larvae. TDF also disturbed the endocrine disruption by regulating the transcription of estrogen receptors ERα, ERβ1 and ERβ2, CYP1a, CYP11, CYP17, steroidogenic acute regulator (STAR), doublesex and mab-3 related transcription factor (DMRT1), gonadotropin-releasing hormone (GnRH2), GnRH3, GnRHR1A, and GnRHR1B. Furthermore, TDF induced the accumulation of reactive oxygen species (ROS) and the activity of antioxidant proteins glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT), and significantly increased the transcriptions of stress response genes P53, growth arrest and DNA damage-inducible 45 alpha (Gadd45α), and COX1, suggested that TDF might cause oxidative stress during larvae development. The changes in transcript and biological levels represented the potential adaptive or compensatory responses to impaired oxidative stress and endocrine system after TDF exposure in rare minnow during its larvae development.
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Affiliation(s)
- Jinhua Jiang
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Gaojie Hu
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Changpeng Zhang
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Xueping Zhao
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Qiang Wang
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China
| | - Liezhong Chen
- State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Quality and Standard for Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China.
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Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW. Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 2017; 157:188-211. [PMID: 26891883 PMCID: PMC4985492 DOI: 10.1016/j.pneurobio.2015.12.008] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/06/2015] [Accepted: 12/10/2015] [Indexed: 12/30/2022]
Abstract
There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging and brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations in the context of aging, cognition, stroke, and traumatic brain injury. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.
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Affiliation(s)
- E B Engler-Chiurazzi
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
| | - C M Brown
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV 26506, United States.
| | - J M Povroznik
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Pediatrics, West Virginia University, Morgantown, WV 26506, United States.
| | - J W Simpkins
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
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Asokan Shibu M, Kuo WW, Kuo CH, Day CH, Shen CY, Chung LC, Lai CH, Pan LF, Vijaya Padma V, Huang CY. Potential phytoestrogen alternatives exert cardio-protective mechanisms via estrogen receptors. Biomedicine (Taipei) 2017; 7:11. [PMID: 28612709 PMCID: PMC5479424 DOI: 10.1051/bmdcn/2017070204] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 02/10/2017] [Indexed: 12/19/2022] Open
Abstract
The 17 beta-estradiol (E2) is a sex hormone that is most abundant and most active estrogen in premenopausal women. The importance of E2 in providing cardioprotection and reducing the occurrence of heart disease in women of reproductive age has been well recognized. There are three subtype of estrogen receptors (ERs), including ERα, ERβ and GPR30 have been identified and accumulating evidence reveal their roles on E2-mediated genomic and nongenomic pathway in cardiomyocytes against various cardiac insults. In this review, we focus on the estrogen and ERs mediated signaling pathways in cardiomyocytes that determines cardio-protection against various stresses and further discuss the clinical implication of ERs and phytoestrogens. Further we provide some insights on phytoeostrogens which may play as alternatives in estrogen replacement therapies.
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Affiliation(s)
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, Department of Sports Sciences, University of Taipei, Taipei 100, Taiwan
| | | | - Chia-Yao Shen
- Department of Nursing, Meiho University, Pingtung 912,Taiwan
| | - Li-Chin Chung
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy & Science, Tainan 717, Taiwan
| | - Chao-Hung Lai
- Division of Cardiology, Department of Internal Medicine, Armed-Force, Taichung General Hospital, Taichung 411, Taiwan
| | - Lung-Fa Pan
- Division of Cardiology, Department of Internal Medicine, Armed-Force, Taichung General Hospital, Taichung 411, Taiwan
| | - V Vijaya Padma
- Department of Biotechnology, Bharathiyar University, Coimbatore, Tamil Nadu 641046, India
| | - Chih-Yang Huang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan - School of Chinese Medicine, China Medical University, Taichung 404, Taiwan - Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan
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30
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Thivyah Prabha A, Sekar D. Deciphering the molecular signaling pathways in breast cancer pathogenesis and their role in diagnostic and treatment modalities. GENE REPORTS 2017; 7:1-17. [DOI: 10.1016/j.genrep.2017.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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31
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Yang X, Guo Y, He J, Zhang F, Sun X, Yang S, Dong H. Estrogen and estrogen receptors in the modulation of gastrointestinal epithelial secretion. Oncotarget 2017; 8:97683-97692. [PMID: 29228643 PMCID: PMC5722595 DOI: 10.18632/oncotarget.18313] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 05/22/2017] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) epithelial ion transport is physiologically important in many aspects of humans, such as in maintaining fluid balance of whole body, and also plays a role in the development and progression of common GI disease. Estrogen and estrogen receptors have been shown to modulate the activity of epithelial ion secretion in GI tract. This review aims to address the current state of knowledge about the role of estrogen and estrogen receptors in modulation of GI epithelial secretion and to elucidate the underlying mechanisms. We highlight the recent findings regarding the importance of estrogen and estrogen receptors in GI epithelia protection and body fluid balance by modulation of gastrointestinal epithelial HCO3- and Cl- secretion, especially current information about the regulatory mechanisms of duodenal HCO3- secretion based on our study in this field. Since there are no reviews on this topic but only few papers to address the main issues, we hope to timely provide new perspectives for the association between estrogen and GI disease.
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Affiliation(s)
- Xin Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Yanjun Guo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Jialin He
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Fenglian Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Xuemei Sun
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.,Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, California, USA
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32
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Berkane N, Liere P, Oudinet JP, Hertig A, Lefèvre G, Pluchino N, Schumacher M, Chabbert-Buffet N. From Pregnancy to Preeclampsia: A Key Role for Estrogens. Endocr Rev 2017; 38:123-144. [PMID: 28323944 DOI: 10.1210/er.2016-1065] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 02/28/2017] [Indexed: 02/08/2023]
Abstract
Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.
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Affiliation(s)
- Nadia Berkane
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland.,U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Philippe Liere
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Jean-Paul Oudinet
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Alexandre Hertig
- Department of Nephrology, Tenon Hospital, APHP, 75020 Paris, France.,University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Unité Mixte de Recherche Scientifique 1155, F-75020 Paris, France
| | - Guillaume Lefèvre
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Biochemistry and Hormonology, Tenon Hospital, APHP, F-75020 Paris, France
| | - Nicola Pluchino
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland
| | | | - Nathalie Chabbert-Buffet
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Obstetrics, Gynecology and Reproductive Medicine, Tenon Hospital, APHP, F-75020 Paris, France.,INSERM, UMR-S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France
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33
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Qi X, Zhou W, Wang Q, Guo L, Lu D, Lin H. Gonadotropin-Inhibitory Hormone, the Piscine Ortholog of LPXRFa, Participates in 17β-Estradiol Feedback in Female Goldfish Reproduction. Endocrinology 2017; 158:860-873. [PMID: 28324026 DOI: 10.1210/en.2016-1550] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/27/2016] [Indexed: 02/08/2023]
Abstract
Gonadotropin-inhibitory hormone (GnIH) plays a critical role in regulating gonadotropin-releasing hormone, gonadotropin hormone, and steroidogenesis in teleosts. In the present study, we sought to determine whether 17β-estradiol (E2) acts directly on GnIH neurons to regulate reproduction in goldfish, a seasonal breeder, and we investigated the role of estrogen receptors (ERs) in mediating this process. We found that GnIH neurons coexpress three types of ERs. Ovariectomy and letrozole implantation into female goldfish at the vitellogenic stage elicited a substantial decrease in the expression of GnIH messenger RNA (mRNA), and E2 supplementation abolished this effect. In primary cultured hypothalamus cells, E2 increased GnIH mRNA levels; surprisingly, selective ERα and ERβ agonists showed opposite effects in regulating GnIH mRNA levels. Using genome walking, we isolated a 2329-bp section of the GnIH promoter sequence, and 7 half-estrogen response elements (EREs) were found in the promoter region. Luciferase assays and electrophoretic mobility shift assay results show that the half-ERE element at -2203 is the key site for competitive binding between ERα and ERβ. Ovariectomy and letrozole implantation into female goldfish in the maturating stage did not change the GnIH mRNA expression levels. Taken together, these findings suggest that E2 binds to multiple types of ERs, which competitively bind to the same half-ERE binding site of the GnIH promoter to achieve both positive and negative feedback in response to estrogen to regulate goldfish reproduction at different stages of ovarian development.
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Affiliation(s)
- Xin Qi
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Wenyi Zhou
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Qingqing Wang
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Liang Guo
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Danqi Lu
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Haoran Lin
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
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34
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Kwakowsky A, Milne MR, Waldvogel HJ, Faull RL. Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease. Int J Mol Sci 2016; 17:E2122. [PMID: 27999310 PMCID: PMC5187922 DOI: 10.3390/ijms17122122] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 12/05/2016] [Accepted: 12/12/2016] [Indexed: 02/06/2023] Open
Abstract
The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.
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Affiliation(s)
- Andrea Kwakowsky
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
| | - Michael R Milne
- School of Biomedical Sciences, Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane 4072, QLD, Australia.
| | - Henry J Waldvogel
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
| | - Richard L Faull
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
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35
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Harris DM, Besselink E, Henning SM, Go VLW, Heber D. Phytoestrogens Induce Differential Estrogen Receptor Alpha- or Beta-Mediated Responses in Transfected Breast Cancer Cells. Exp Biol Med (Maywood) 2016; 230:558-68. [PMID: 16118406 DOI: 10.1177/153537020523000807] [Citation(s) in RCA: 171] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor a (ERα) and human estrogen receptor β (ERβ). Nine phytoestrogens were tested for their ability to transactivate ERα or ERβ at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERα or ERβ, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17β-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERα- and ERβ-induced transcription, with an up to 100-fold stronger activation of ERβ. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17β-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERα and ERβ by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.
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Affiliation(s)
- D M Harris
- The UCLA Center for Human Nutrition, 13-145 Warren Hall, 900 Veteran Avenue, Los Angeles, CA 90095-1742, USA.
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36
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Quadalti C, Galli C, Lazzari G. Development of an in vitro test battery for the screening of the receptor-mediated mechanism and the spindle-poison mode of action of estrogenic compounds. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 48:245-252. [PMID: 27846407 DOI: 10.1016/j.etap.2016.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 10/24/2016] [Accepted: 11/08/2016] [Indexed: 06/06/2023]
Abstract
The implementation of the REACH regulation has imposed the urgent need of developing alternative testing methods to screen large number of compounds more quickly and at lower costs. In this study, a battery of tests, suitable for reproductive toxicology testing, was developed with the objective of detecting the mechanism of action of estrogenic and xenoestrogenic compounds. With this aim, two compounds known for their estrogenic activity, diethylstilbestrol and 17β-estradiol, were used to set up four different in vitro tests: 1) bovine oocyte in vitro maturation assay, 2) bovine preimplantation embryo in vitro culture assay and 3) MCF-7 and 4) BALB/3T3 cell lines proliferation and cytotoxicity assay, respectively. The results show that this battery of tests allows to identify and to distinguish between two major mechanisms of action of (xeno)estrogenic compounds: the receptor-mediated mechanism and the spindle-poison effect on microtubules polimerization.
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Affiliation(s)
- Corinne Quadalti
- Avantea, Laboratory of Reproductive Technologies, Via Porcellasco 7/f, Cremona, 26100, Italy; Dept. of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, 40064, Ozzano dell'Emilia (BO), Italy.
| | - Cesare Galli
- Avantea, Laboratory of Reproductive Technologies, Via Porcellasco 7/f, Cremona, 26100, Italy; Dept. of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, 40064, Ozzano dell'Emilia (BO), Italy; Fondazione Avantea, Cremona, Italy.
| | - Giovanna Lazzari
- Avantea, Laboratory of Reproductive Technologies, Via Porcellasco 7/f, Cremona, 26100, Italy; Fondazione Avantea, Cremona, Italy.
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37
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Zhang R, Hu Y, Wang H, Yan P, Zhou Y, Wu R, Wu X. Molecular cloning, characterization, tissue distribution and mRNA expression changes during the hibernation and reproductive periods of estrogen receptor alpha (ESR1) in Chinese alligator, Alligator sinensis. Comp Biochem Physiol B Biochem Mol Biol 2016; 200:28-35. [PMID: 27212643 DOI: 10.1016/j.cbpb.2016.05.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/16/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023]
Abstract
Chinese alligator, Alligator sinensis, is a critically endangered reptile species unique to China. Little is known about the mechanism of growth- and reproduction-related hormones gene expression in Chinese alligator. Estrogens play important roles in regulating multiple reproduction- and non-reproduction-related functions by binding to their corresponding receptors. Here, the full-length cDNA of estrogen receptor alpha (ERα/ESR1) was cloned and sequenced from Chinese alligator for the first time, which comprises 1764bp nucleotides and encodes a predicted protein of 587 amino acids. Phylogenetic analysis of ESR1 showed that crocodilians and turtles were the sister-group of birds. The results of real-time quantitative PCR indicated that the ESR1 mRNA was widely expressed in the brain and peripheral tissues. In the brain and pituitary gland, ESR1 was most highly transcribed in the cerebellum. But in other peripheral tissues, ESR1 mRNA expression level was the highest in the ovary. Compared with hibernation period, ESR1 mRNA expression levels were increased significantly in the reproductive period (P<0.05) in cerebellum, pituitary gland, liver, spleen, lung, kidney and ovary, while no significant change in other examined tissues (P>0.05). The ESR1 mRNA expression levels changes during the two periods of different tissues suggested that ESR1 might play an important role in mediation of estrogenic multiple reproductive effects in Chinese alligator. Furthermore, it was the first time to quantify ESR1 mRNA level in the brain of crocodilians, and the distribution and expression of ESR1 mRNA in the midbrain, cerebellum and medulla oblongata was also reported for the first time in reptiles.
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Affiliation(s)
- Ruidong Zhang
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui 241000, People's Republic of China
| | - Yuehong Hu
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui 241000, People's Republic of China
| | - Huan Wang
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui 241000, People's Republic of China
| | - Peng Yan
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui 241000, People's Republic of China
| | - Yongkang Zhou
- Alligator Research Center of Anhui Province, Xuanzhou 242000, People's Republic of China
| | - Rong Wu
- Alligator Research Center of Anhui Province, Xuanzhou 242000, People's Republic of China
| | - Xiaobing Wu
- Key Laboratory for Conservation and Use of Important Biological Resources of Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui 241000, People's Republic of China.
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38
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Clemons KV, Shankar J, Stevens DA. Mycologic Endocrinology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 874:337-63. [PMID: 26589227 DOI: 10.1007/978-3-319-20215-0_16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
The interactions of fungi and chemical messenger molecules, hormones or pheromones, are addressed in this chapter. These interactions include mammalian fungal pathogens, also plant pathogens, or non-pathogenic fungi, which can result in functional responses in receptor- or non-receptor-mediated fashions. Endogenous ligands in the fungi have been demonstrated to be important for mating in a number of systems. Mammalian hormones have been demonstrated to have stimulatory or inhibitory effects on growth for organisms such as Candida albicans, Paracoccidioides brasiliensis, Saccharomyces cerevisiae, Rhizopus nigricans, Aspergillus fumigatus, Coccidioides, and dermatophytic fungi. A number of fungi have been shown to have specific binding proteins for corticosteroid, estrogen and progesterone that are stereo-specific and high affinity. In some instances, the interactions of a mammalian hormone with the organism, in vivo, affects pathogenesis. Genome expression profiles of C. albicans in the presence of estradiol or progesterone, and S. cerevisiae with progesterone, indicate major up-regulation of various drug resistance pumps, like CDR1, and CDR2, can affect antifungal susceptibility. Azole antifungal interactions occur with fungal hormone binding proteins. Azoles also can block mammalian steroidogenesis. The finding of interactions of mammalian hormones with fungi and subsequent functional responses by the fungi, suggest that hormonal interactions with fungal systems has been conserved throughout evolution and have an important role in fungal pathogenesis, as well as in the overall biology of the organisms.
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Affiliation(s)
- Karl V Clemons
- California Institute for Medical Research, San Jose, CA, USA. .,Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
| | - Jata Shankar
- California Institute for Medical Research, San Jose, CA, USA. .,Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
| | - David A Stevens
- California Institute for Medical Research, San Jose, CA, USA. .,Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
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Seeger B, Klawonn F, Nguema Bekale B, Steinberg P. Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β. PLoS One 2016; 11:e0147490. [PMID: 26812056 PMCID: PMC4728068 DOI: 10.1371/journal.pone.0147490] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 01/05/2016] [Indexed: 11/18/2022] Open
Abstract
Consumers of fruits and vegetables are frequently exposed to small amounts of hormonally active pesticides, some of them sharing a common mode of action such as the activation of the human estrogen receptor α (hERα) or β (hERβ). Therefore, it is of particular importance to evaluate risks emanating from chemical mixtures, in which the individual pesticides are present at human-relevant concentrations, below their corresponding maximum residue levels. Binary and ternary iso-effective mixtures of estrogenic pesticides at effect concentrations eliciting a 1 or 10% effect in the presence or absence of 17β-estradiol were tested experimentally at the hERα in the yeast-based estrogen screen (YES) assay as well as in the human U2-OS cell-based ERα chemical-activated luciferase gene expression (ERα CALUX) assay and at the hERβ in the ERβ CALUX assay. The outcome was then compared to predictions calculated by means of concentration addition. In most cases, additive effects were observed with the tested combinations in all three test systems, an observation that supports the need to expand the risk assessment of pesticides and consider cumulative risk assessment. An additional testing of mixture effects at the hERβ showed that most test substances being active at the hERα could also elicit additive effects at the hERβ, but the hERβ was less sensitive. In conclusion, effects of the same ligands at the hERα and the hERβ could influence the estrogenic outcome under physiological conditions.
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Affiliation(s)
- Bettina Seeger
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Frank Klawonn
- Biostatistics Group, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124, Braunschweig, Germany
- Department of Computer Science, Ostfalia University of Applied Sciences, Salzdahlumerstr. 46/48, 38302, Wolfenbüttel, Germany
| | - Boris Nguema Bekale
- Department of Computer Science, Ostfalia University of Applied Sciences, Salzdahlumerstr. 46/48, 38302, Wolfenbüttel, Germany
| | - Pablo Steinberg
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173, Hannover, Germany
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Locatelli M, Sciascia F, Cifelli R, Malatesta L, Bruni P, Croce F. Analytical methods for the endocrine disruptor compounds determination in environmental water samples. J Chromatogr A 2016; 1434:1-18. [PMID: 26805600 DOI: 10.1016/j.chroma.2016.01.034] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 01/11/2016] [Accepted: 01/13/2016] [Indexed: 10/22/2022]
Abstract
The potential risk of exposure to different xenobiotics, which can modulate the endocrine system and represent a treat for the wellness of an increasing number of people, has recently drawn the attention of international environmental and health agencies. Several agents, characterized by structural diversity, may interfer with the normal endocrine functions that regulate cell growth, homeostasis and development. Substances such as pesticides, herbicides, plasticizers, metals, etc. having endocrine activity (EDCs) are used in agriculture and industry and are also used as drugs for humans and animals. A difficulty in the analytical determination of these substances is the complexity of the matrix in which they are present. In fact, the samples most frequently analyzed consist of groundwater and surface water, including influent and effluent of wastewater treatment plants and drinking water. In this review, several sample pretreatment protocols, assays and different instrumental techniques recently used in the EDCs determination have been considered. This review concludes with a paragraph in which the most recent hyphenated-instrument techniques are treated, highlighting their sensitivity and selectivity for the analyses of environmental water samples.
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Affiliation(s)
- Marcello Locatelli
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy; Interuniversity Consortium of Structural and Systems Biology INBB, Viale Medaglie d'oro 305, 00136 Roma, Italy.
| | - Francesco Sciascia
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy
| | - Roberta Cifelli
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy
| | - Luciano Malatesta
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy
| | - Pantaleone Bruni
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy
| | - Fausto Croce
- University "G. d'Annunzio" of Chieti-Pescara, Department of Pharmacy, via dei Vestini 31, 66100 Chieti (CH), Italy
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Islam MA, Patel DA, Rathod SG, Chunarkar P, Pillay TS. Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy. Med Chem Res 2016. [DOI: 10.1007/s00044-015-1496-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a. J Neurosci 2015; 35:13110-23. [PMID: 26400941 DOI: 10.1523/jneurosci.2056-15.2015] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. Significance statement: The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute intracerebroventricular injections of specific agonists and antagonists following blockade of brain aromatase, we show here that brain-derived estrogens acutely facilitate male sexual motivation through the activation of estrogen receptor β interacting with the metabotropic glutamate receptor 1a. This behavioral effect occurring within minutes provides a mechanistic explanation of how an estrogen receptor not intrinsically coupled to intracellular effectors can signal from the membrane to govern behavior in a very rapid fashion. It suggests that different subtypes of estrogen receptors could regulate the motivation versus performance aspects of behavior.
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Jiang J, Wu S, Wang Y, An X, Cai L, Zhao X, Wu C. Carbendazim has the potential to induce oxidative stress, apoptosis, immunotoxicity and endocrine disruption during zebrafish larvae development. Toxicol In Vitro 2015; 29:1473-81. [DOI: 10.1016/j.tiv.2015.06.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 04/16/2015] [Accepted: 06/04/2015] [Indexed: 12/26/2022]
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Vannuccini ML, Grassi G, Leaver MJ, Corsi I. Combination effects of nano-TiO2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on biotransformation gene expression in the liver of European sea bass Dicentrarchus labrax. Comp Biochem Physiol C Toxicol Pharmacol 2015; 176-177:71-8. [PMID: 26235595 DOI: 10.1016/j.cbpc.2015.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/15/2015] [Accepted: 07/23/2015] [Indexed: 01/09/2023]
Abstract
The aim of present study was to investigate the influence of titanium dioxide nanoparticles (nano-TiO2, Aeroxide® P25) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dependent biotransformation gene expression in liver of juvenile European sea bass Dicentrarchus labrax. An in vivo 7day waterborne exposure was performed with nano-TiO2 (1mg/L) and 2,3,7,8-TCDD (46pg/L), singly and in combination. The mRNA expression of aryl hydrocarbon receptor repressor (Ahrr), estrogen receptor (erβ2), ABC transport proteins as Abcb1, Abcc1-c2-g2, cytochrome P450 (cyp1a), glutathione-s-transferase (gsta), glutathione reductase (gr) and engulfment and motility (ELMO) domain-containing protein 2 (elmod2) was investigated. Ahrr, erβ2, abcc1 and abcg2 resulted down-regulated with respect to controls in all experimental groups. Co-exposure to nano-TiO2 and 2,3,7,8-TCDD caused a further significant down regulation of ahrr, erβ2, Abcb1 and Abcc2 compared to single chemical exposure (nano-TiO2 or 2,3,7,8-TCDD alone). No effects were observed for 2,3,7,8-TCDD and nano-TiO2 alone in abcb1 gene, while abcc2 was down-regulated by nano-TiO2 alone. Cyp1a, gst and elmod2 genes were up-regulated by 2,3,7,8-TCDD and to a similar extent after co-exposure. Overall the results indicate that nano-TiO2 is unlikely to interfere with 2,3,7,8-TCDD-dependent biotransformation gene expression in the liver of European sea bass, although the effects of co-exposure observed in ABC transport mRNAs might suggest an impact on xenobiotic metabolite disposition and transport in European sea bass liver.
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Affiliation(s)
- Maria Luisa Vannuccini
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, Italy
| | - Giacomo Grassi
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, Italy
| | - Michael J Leaver
- Institute of Aquaculture, University of Stirling, Stirling, United Kingdom
| | - Ilaria Corsi
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, Italy.
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Patel S, Kilburn B, Imudia A, Armant DR, Skafar DF. Estradiol Elicits Proapoptotic and Antiproliferative Effects in Human Trophoblast Cells. Biol Reprod 2015; 93:74. [PMID: 26246219 DOI: 10.1095/biolreprod.115.129114] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 07/31/2015] [Indexed: 12/29/2022] Open
Abstract
During the first trimester of pregnancy, appropriate regulation of estradiol (E2) is essential for normal placental development. Previous studies demonstrate that premature elevation in E2 concentrations can lead to abnormal placentation, but have not fully elaborated the mechanism of this effect in the first-trimester trophoblast. Our aim was to determine whether E2 elicits trophoblast cell death or inhibits proliferation. The first-trimester human cytotrophoblast cell line HTR-8/SVneo was cultured in phenol red-free medium containing charcoal-stripped serum and treated with 17beta-E2 at concentrations between 0 and 100 nM. TUNEL and invasion assays indicated that E2 significantly increased cell death and reduced cell invasion at 10 nM, and nuclear Ki67 expression revealed that it decreased cell proliferation at 1 nM. A similar effect on cell death was observed in first-trimester placental explants. The E2 antagonist fulvestrant blocked all effects of E2. Immunohistochemistry showed that protein expression of proapoptotic caspases 3, 8, and 9 increased at E2 concentrations of 25 nM and greater, whereas expression of antiapoptotic BCL2-alpha decreased at E2 concentrations of 10 nM and greater. Additionally, treatments with estrogen receptor (ER) alpha-specific and ERbeta-specific agonists at concentrations between 0 and 1000 nM indicated that only ERalpha mediates E2's effects, although immunohistochemistry and Western immunoblotting showed that HTR-8/SVneo cells and placental explants express both ERalpha and ERbeta. Taken together, these findings reveal the interplay between elevated serum E2 and apoptosis in the first trimester of pregnancy. These factors could be associated with pregnancy complications including infertility and uteroplacental insufficiency.
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Affiliation(s)
- Shivali Patel
- Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan
| | - Brian Kilburn
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan
| | - Anthony Imudia
- Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida
| | - D Randall Armant
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, Maryland
| | - Debra F Skafar
- Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan
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Hara Y, Waters EM, McEwen BS, Morrison JH. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev 2015; 95:785-807. [PMID: 26109339 PMCID: PMC4491541 DOI: 10.1152/physrev.00036.2014] [Citation(s) in RCA: 284] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
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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Affiliation(s)
- Yuko Hara
- Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute, Department of Geriatrics and Palliative Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; and Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York
| | - Elizabeth M Waters
- Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute, Department of Geriatrics and Palliative Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; and Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York
| | - Bruce S McEwen
- Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute, Department of Geriatrics and Palliative Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; and Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York
| | - John H Morrison
- Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute, Department of Geriatrics and Palliative Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; and Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York
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Jochmanová I, Lazúrová Z, Rudnay M, Bačová I, Mareková M, Lazúrová I. Environmental estrogen bisphenol A and autoimmunity. Lupus 2015; 24:392-399. [PMID: 25801882 DOI: 10.1177/0961203314560205] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over the past few years, there has been evidence of the increasing prevalence of autoimmune diseases. Autoimmune diseases consist of many complex disorders of unknown etiology resulting in immune responses to self-antigens. The immune system, and its function, is under complex and integrated control and its disruption can be triggered by multiple factors. Autoimmunity development is influenced by multiple factors and is thought to be a result of interactions between genetic and environmental factors. Here, we review the role of a specific environmental factor, bisphenol A (BPA), in the pathogenesis of autoimmune diseases. BPA belongs to the group of environmental estrogens that have been identified as risk factors involved in the development of autoimmune diseases.
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Affiliation(s)
- I Jochmanová
- 1st Department of Internal Medicine, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Z Lazúrová
- 1st Department of Internal Medicine, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - M Rudnay
- 1st Department of Internal Medicine, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - I Bačová
- Department of Medical Physiology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - M Mareková
- Department of Medical and Clinical Biochemistry and LABMED, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - I Lazúrová
- 1st Department of Internal Medicine, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
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Tandrasasmita OM, Sutanto AM, Arifin PF, Tjandrawinata RR. Anti-inflammatory, antiangiogenic, and apoptosis-inducing activity of DLBS1442, a bioactive fraction of Phaleria macrocarpa, in a RL95-2 cell line as a molecular model of endometriosis. Int J Womens Health 2015; 7:161-9. [PMID: 25678821 PMCID: PMC4322889 DOI: 10.2147/ijwh.s74552] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
DLBS1442 is a bioactive fraction extracted from the fruit of the native Indonesian plant, Phaleria macrocarpa (Scheff.) Boerl (Thymelaceae). This bioactive fraction is a potential treatment for dysmenorrhea and endometriosis. The present study investigated the pharmacological action of DLBS1442 in endometrial cells. The effect of various doses of DLBS1442 (0–200 μg/mL) over 24 hours was studied using the human endometrial RL95-2 cell line to observe its effect on angiogenesis, cell migration, estrogen and progesterone receptor levels, the eicosanoid pathway, cell viability, and apoptosis. The impact of DLBS1442 on nuclear factor kappa B (NFκB) and the eicosanoid pathway was also studied through its marker gene expression using a quantitative real-time polymerase chain reaction method. DLBS1442 showed an ability to inhibit angiogenesis and cell migration in a dose-dependent manner. At a dose of 100 μg/mL, DLBS1442 increased the cell population in sub-G1 phase from 7% to 34%. DLBS1442 also significantly downregulated the estrogen receptor level and upregulated the progesterone receptor level. Further, it inhibited the eicosanoid signaling pathway by reducing the NFκB transcription level and subsequent reduction of inducible nitric oxide synthase. A dose-dependent decrease in viability and increased apoptosis in RL95-2 cells were also evident after exposure to DLBS1442, where the IC50 was obtained at around 100 μg/mL. In conclusion, DLBS1442 is a potential agent for alleviating symptoms of endometriosis via its antiangiogenic, anti-inflammatory, and proapoptotic activity.
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Affiliation(s)
- Olivia M Tandrasasmita
- Section of Molecular Pharmacology, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, West Java, Indonesia
| | - Adeline M Sutanto
- Section of Molecular Pharmacology, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, West Java, Indonesia
| | - Poppy F Arifin
- Section of Molecular Pharmacology, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, West Java, Indonesia
| | - Raymond R Tjandrawinata
- Section of Molecular Pharmacology, Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, PT Dexa Medica, Cikarang, West Java, Indonesia
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Nikoleris L, Hansson MC. Unraveling the estrogen receptor (er) genes in Atlantic salmon (Salmo salar) reveals expression differences between the two adult life stages but little impact from polychlorinated biphenyl (PCB) load. Mol Cell Endocrinol 2015; 400:10-20. [PMID: 25451980 DOI: 10.1016/j.mce.2014.11.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 11/13/2014] [Accepted: 11/14/2014] [Indexed: 11/30/2022]
Abstract
Estrogen receptors (ers) not only are activated by hormones but also interact with many human-derived environmental contaminants. Here, we present evidence for four expressed er genes in Atlantic salmon cDNA - two more ers (erα2 and erβ2) than previously published. To determine if er gene expression differs between two adult life-stages we sampled 20 adult salmon from the feeding phase in the Baltic Sea and during migration in the River Mörrum, Sweden. Results show that all four er genes are present in the investigated tissues, except for erα2 not appearing in the spleen. Overall, a profile analysis reveals the erα1 gene to be the most highly expressed er gene in both female and male Baltic Sea salmon tissues, and also in female River Mörrum salmon. In contrast, this gene has the lowest gene expression level of the four er genes in male salmon from the River Mörrum. The erα2 gene is expressed at the lowest levels in both female/male Baltic Sea salmon and in female River Mörrum salmon. Statistical analyses indicate a significant and complex interaction where both sex and adult life stage can impact er gene expression. Regression analyses did not demonstrate any significant relationship between polychlorinated biphenyl (PCB) body burden and er gene expression level, suggesting that accumulated pollutants from the Baltic Sea may be deactivated inside the salmon's lipid tissues and have limited impact on er activity. This study is the first comprehensive analysis of four er gene expression levels in two wild salmon populations from two different adult life stages where information about PCB load is also available.
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Affiliation(s)
- Lina Nikoleris
- Department of Biology, Lund University, Ecology Building, SE-223 62 Lund, Sweden; Center for Environmental and Climate Research (CEC), Lund University, SE-223 62 Lund, Sweden.
| | - Maria C Hansson
- Center for Environmental and Climate Research (CEC), Lund University, SE-223 62 Lund, Sweden
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Hsu HH, Kuo WW, Ju DT, Yeh YL, Tu CC, Tsai YL, Shen CY, Chang SH, Chung LC, Huang CY. Estradiol agonists inhibit human LoVo colorectal-cancer cell proliferation and migration through p53. World J Gastroenterol 2014; 20:16665-16673. [PMID: 25469035 PMCID: PMC4248210 DOI: 10.3748/wjg.v20.i44.16665] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 04/10/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of 17β-estradiol via estrogen receptors (ER) or direct administration of ER agonists on human colorectal cancer.
METHODS: LoVo cells were established from the Bioresource Collection and Research Center and cultured in phenol red-free DMEM (Sigma, United States). To investigate the effects of E2 and/or ER selective agonists on cellular proliferation, LoVo colorectal cells were treated with E2 or ER-selective agonists for 24 h and 48 h and subjected to the MTT (Sigma) assay to find the concentration. And investigate the effects of E2 and/or ER selective agonists on cell used western immunoblotting to find out the diversification of signaling pathways. In order to observe motility and migration the wound healing assay and a transwell chamber (Neuro Probe) plate were tased. For a quantitative measure, we counted the number of migrating cells to the wound area post-wounding for 24 h. We further examined the cellular migration-regulating factors urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and matrix metalloproteinase (MMP)-9 in human LoVo cells so gelatin zymography that we used and gelatinolytic activity was visualized by Coomassie blue staining. And these results are presented as means ± SE, and statistical comparisons were made using Student’s t-test.
RESULTS: The structure was first compared with E2 and ER agonists. We then treated the LoVo cells with E2 and ER agonists (10-8 mol/L) for 24 h and 48 h and subsequently measured the cell viability using MTT assay. Our results showed that treatment with 17β-estradiol and/or ER agonists in human LoVo colorectal cancer cells activated p53 and then up-regulated p21 and p27 protein levels, subsequently inhibiting the downstream target gene, cyclin D1, which regulates cell proliferation. Taken together, our findings demonstrate the anti-tumorigenesis effects of 17β-estradiol and/or ER agonists and suggest that these compounds may prove to be a potential alternative therapy in the treatment of human colorectal cancer. These results demonstrate that 17β-estradiol and/or ER agonists downregulate migration-related proteins through the p53 signaling pathway in human LoVo colorectal cancer cells. These findings suggest that p53 plays a critical role in the 17β-estradiol and/or ER agonist-mediated protective activity against colorectal cancer progression. In addition, 17β-estradiol and/or ER agonists dramatically inhibited cell migration and reduced the expression of u-PA, t-PA and MMP-9 as well as MMP-2/9 activity in LoVo cells, which regulate cell metastasis. Moreover, we observed that pretreatment with a p53 inhibitor significantly blocked the anti-migration effects of E2 and/or ER agonists on LoVo cells. That E2 and/or ER agonists may impair LoVo cell migration by modulating migration-related factors via the p53 tumor suppressor gene.
CONCLUSION: Direct ER treatment may prove to be an attractive alternative therapy in the treatment of human colorectal tumors in the future.
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