| 1. |
- Antonson, P., et al.
(författare)
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aP2-Cre-Mediated Inactivation of Estrogen Receptor Alpha Causes Hydrometra
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- In this study we describe the reproductive phenotypes of a novel mouse model in which Cre-mediated deletion of ER alpha is regulated by the aP2 (fatty acid binding protein 4) promoter. ER alpha-floxed mice were crossed with transgenic mice expressing Cre-recombinase under the control of the aP2 promoter to generate aP2-Cre/ER alpha(flox/flox) mice. As expected, ER alpha mRNA levels were reduced in adipose tissue, but in addition we also detected an 80% reduction of ER alpha levels in the hypothalamus of aP2-Cre/ER alpha(flox/flox) mice. Phenotypic analysis revealed that aP2-Cre/ER alpha(flox/flox) female mice were infertile. In line with this, aP2-Cre/ER alpha(flox/flox) female mice did not cycle and presented 3.8-fold elevated estrogen levels. That elevated estrogen levels were associated with increased estrogen signaling was evidenced by increased mRNA levels of the estrogen-regulated genes lactoferrin and aquaporin 5 in the uterus. Furthermore, aP2-Cre/ER alpha(flox/flox) female mice showed an accumulation of intra-uterine fluid, hydrometra, without overt indications for causative anatomical anomalies. However, the vagina and cervix displayed advanced keratosis with abnormal quantities of accumulating squamous epithelial cells suggesting functional obstruction by keratin plugs. Importantly, treatment of aP2-Cre/ER alpha(flox/flox) mice with the aromatase inhibitor Letrozole caused regression of the hydrometra phenotype linking increased estrogen levels to the observed phenotype. We propose that in aP2-Cre/ER alpha(flox/flox) mice, increased serum estrogen levels cause over-stimulation in the uterus and genital tracts resulting in hydrometra and vaginal obstruction.
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| 2. |
- Antonson, P., et al.
(författare)
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Generation of an all-exon Esr2 deleted mouse line: Effects on fertility
- 2020
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 529:2, s. 231-237
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor beta (ER beta), encoded by the Esr2 gene, is one of two nuclear receptors that mediate the functions of the steroid hormone estradiol. The binding of estradiol to the receptor results in enhanced transcription of many genes that have estrogen response elements in promoter or enhancer regions. Several genetically modified mouse lines with mutations or deletions of exons in the Esr2 gene have been developed and results from analysis of these are not completely consistent, especially regarding ER beta's role in fertility. To address these controversies, we have used the CRISPR/Cas9 genome editing system to make a deletion of the entire Esr2 gene in the mouse genome and determined the effect of this mutation on fertility. We show that female Esr2 deleted mice, Esr2(Delta E1-10), are subfertile at young age, with fewer litters and smaller litter size, and that they become infertile/have severely reduced fertility at around six months of age, while the male Esr2(Delta E1-10) mice are fertile. Ovaries from Esr2(Delta E1-10) mice are smaller than those from wild-type littermates and the morphology of the ovary displays very few corpora lutea, indicating a defect in ovulation. We also show that the estradiol levels are reduced at diestrus, the phase in the estrous cycle when levels are expected to start to increase before ovulation. Our results verify that ER beta has an important function in female reproduction, likely as a regulator of serum estradiol levels, and that its loss does not affect male reproductive function. (C) 2020 The Authors. Published by Elsevier Inc.
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| 3. |
- Antonson, P., et al.
(författare)
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Identification of proteins highly expressed in uterine fluid from mice with hydrometra
- 2015
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 466:4, s. 650-655
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ER alpha) is an important regulator of the estrous cycle and mice with global ER alpha deletion, as well as some conditional knockout mouse lines, have an interruption in the estrous cycle. In this study we observed that conditional ERa knockout mice where the Cre gene is regulated by the rat insulin promoter (RIP), RIP-Cre/ER alpha(KO) mice, have a 3.7-fold increase in serum 17 beta-estradiol levels, blocked estrous cycle, and develop a fluid-filled uterus (hydrometra). Using a proteomics approach, we identified three proteins, lactoferrin, complement C3 and chitinase 3-like protein 1 (CHI3L1), as highly expressed proteins in hydrometra fluid. The mRNA levels of the corresponding genes were more than 50-fold higher in RIP-Cre/ER alpha(KO) uterus compared to controls. High expression of CHI3L1 in the uterine fluid was not reflected as elevated levels in the serum. The high expression of lactoferrin, complement C3 and CHI3L1 in the uterine fluid, in association with elevated estrogen levels, prompted us to address if the expression of these genes is related to reproduction. However, gonadotropin treatment of mice reduced the uterine expression of these genes in a model of in vitro fertilization. Our findings identify lactoferrin, complement C3 and CHI3L1 as highly expressed proteins in hydrometra fluid in association with chronically elevated serum estradiol levels. (C) 2015 Elsevier Inc. All rights reserved.
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| 4. |
- Chagin, A S, et al.
(författare)
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Estrogen receptor-beta inhibits skeletal growth and has the capacity to mediate growth plate fusion in female mice.
- 2004
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431 .- 1523-4681. ; 19:1, s. 72-7
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Tidskriftsartikel (refereegranskat)abstract
- To determine the long-term role of ER beta in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. Our results show that ER beta inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates. INTRODUCTION: Estrogen affects skeletal growth and promotes growth plate fusion in humans. In rodents, the growth plates do not fuse after sexual maturation, but prolonged treatment with supraphysiological levels of estradiol has the capacity to fuse the growth plates. It should be emphasized that the estrogen receptor (ER) alpha-/- and the ER alpha-/- beta-/-, but not the ER beta-/-, mouse models have clearly increased serum levels of estradiol. MATERIALS AND METHODS: The skeletal growth was monitored by X-ray and dynamic histomorphometry, and the growth plates were analyzed by quantitative histology, calcein double labeling, bromodeoxyuridine (BrdU) incorporation, and TUNEL assay in 4- and 18-month-old female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. RESULTS: Young adult (4-month-old) ER beta-/- mice demonstrated an increased axial- and appendicular-skeletal growth, supporting the notion that ER beta inhibits skeletal growth in young adult female mice. Interestingly, the growth plates were consistently fused in the appendicular skeleton of 18-month-old female ER alpha-/- mice. This fusion of growth plates, caused by a prolonged exposure to supraphysiological levels of estradiol in female ER alpha-/- mice, must be mediated through ER beta because old ER alpah-/- beta-/- mice displayed unchanged, unfused growth plates. CONCLUSIONS: Our results confirm that ER beta is a physiological inhibitor of appendicular- and axial-skeletal growth in young adult female mice. Furthermore, we made the novel observation that ER beta, after prolonged supraphysiological estradiol exposure, has the capacity to mediate growth plate fusion in old female mice.
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| 5. |
- Erlandsson, M C, et al.
(författare)
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Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus.
- 2001
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 103:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- Oestrogens affect the development and regulation of the immune system. To determine the role of oestrogen receptors alpha (ER-alpha) and beta (ER-beta) on the development of the immune system, male ER-alpha (ERKO) and ER-beta (BERKO) mice, as well as alphabeta-double knockout (DERKO) mice, were studied. Deletion of ER-alpha led to hypoplasia of both thymus and spleen. Interestingly, a higher frequency of immature double CD4+ CD8+ thymocytes was found in ER-alpha(-) mice compared with ER-alpha(+) mice. Female oophorectomized BERKO mice given oestradiol (E2) displayed a similar degree of thymic atrophy compared with the wild-type strain but showed only limited involution of thymus cortex and no alteration of thymic CD4/CD8 phenotype expression. Our data demonstrate that expression of ER-alpha, but not ER-beta, is mandatory in males for development of full-size thymus and spleen, whereas expression of ER-beta is required for E2-mediated thymic cortex atrophy and thymocyte phenotype shift in females. A potential background for the above findings may be down-regulated activity in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in males lacking ER-alpha and suppressed sensitivity of females lacking ER-beta to E2-mediated suppression of IGF-1.
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| 6. |
- Gustafsson, Karin L., 1987, et al.
(författare)
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The role of membrane ER alpha signaling in bone and other major estrogen responsive tissues
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor a (ER alpha) signaling leads to cellular responses in several tissues and in addition to nuclear ER alpha-mediated effects, membrane ER alpha (mER alpha) signaling may be of importance. To elucidate the significance, in vivo, of mER alpha signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ER alpha to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mER alpha signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mER alpha (<35% reduction in estrogen response in NOER mice). In conclusion, mER alpha signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ER alpha actions may provide means to develop new selective estrogen receptor modulators with improved profiles.
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| 7. |
- Islander, Ulrika, 1975, et al.
(författare)
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Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent
- 2005
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Ingår i: Clin Exp Immunol. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 139:2, s. 210-5
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen has extensive effects on the immune system. The aim of the present experiments was to compare the effects of 17beta-estradiol (E2) and 4-estren-3alpha,17beta-diol (estren) on T lymphopoiesis and T cell-dependent inflammation. In order to investigate the role of estrogen receptors (ER) in the effects of E2 and estren on the immune system, ER knock-out mice lacking both ERalpha and ERbeta (DERKO) were used. T lymphopoiesis and T cell-dependent inflammation were studied by investigating thymus cellularity, the delayed-type hypersensitivity (DTH) reaction, CD4(+) T cells in spleen and serum levels of interleukin (IL)-6. As expected, the presence of ERs was mandatory for all the effects of E2. In contrast, treatment with estren reduced thymus cellularity in ER knock-out mice, indicating an effect through ER-independent pathways. Interestingly, estren suppressed only DTH, the frequency of CD4(+) T cells in spleen and serum levels of IL-6 in wild-type (WT) mice, but not in mice lacking ERs. Thus, our study is the first to show that estren inhibits T lymphopoiesis via ER-independent pathways, whereas its suppressive effects on inflammation are ER-dependent.
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| 8. |
- Islander, Ulrika, 1975, et al.
(författare)
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Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands
- 2005
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Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Estrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3alpha,17beta-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT), respectively. Estrogen receptors (ERs) were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used. RESULTS: As expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs. CONCLUSION: Our study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor.
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| 9. |
- Islander, Ulrika, 1975, et al.
(författare)
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Influence of oestrogen receptor alpha and beta on the immune system in aged female mice.
- 2003
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 110:1, s. 149-57
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Tidskriftsartikel (refereegranskat)abstract
- Oestrogen has a dichotomous effect on the immune system. T and B lymphopoiesis in thymus and bone marrow is suppressed, whereas antibody production is stimulated by oestrogen. In this study the importance of the oestrogen receptors (ER) ER-alpha and ER-beta in the aged immune system was investigated in 18 months old-wild type (WT), ER-alpha (ERKO), ER-beta (BERKO) and double ER-alpha and ER-beta (DERKO) knock-out mice, and compared with 4 months old WT mice. Cell phenotypes in bone marrow, spleen and thymus, and the frequency of immunoglobulin (Ig) spot forming cells (SFC) were determined. We show here that the 17-beta-oestradiol (E2)-induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER-alpha and ER-beta. However, only ER-alpha is required for the age-related increased frequency of immunoglobulin M (IgM) SFC in the bone marrow, as well as for the increased production of interleukin-10 (IL-10) from cultured splenocytes in aged mice. Furthermore, increased age in WT mice resulted in lower levels of both pro- and pre-B cells but increased frequency of IgM SFC in the bone marrow, as well as increased frequency of both IgM and IgA SFC in the spleen. Results from this study provide valuable information regarding the specific functions of ER-alpha and ER-beta in the aged immune system.
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| 10. |
- Karas, R H, et al.
(författare)
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Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice.
- 2001
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Ingår i: Circulation research. - : Ovid Technologies (Wolters Kluwer Health). - 1524-4571 .- 0009-7330. ; 89:6, s. 534-9
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Tidskriftsartikel (refereegranskat)abstract
- The two known estrogen receptors, ERalpha and ERbeta, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ERalpha knockout (ERalphaKO(CH)), and ERbeta knockout (ERbetaKO(CH)) mice. We generated mice harboring disruptions of both ERalpha and ERbeta genes (ERalpha,betaKO(CH)) by breeding and studied the effect of 17beta-estradiol (E2) on vascular injury responses in ovariectomized female ERalpha,betaKO(CH) mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ERalpha,betaKO(CH) mice, demonstrating for the first time that the two known estrogen receptors are necessary and sufficient to mediate estrogen inhibition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibited vascular smooth muscle cell (VSMC) proliferation following injury in the ERalpha,betaKO(CH) mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ERalpha,betaKO(CH) mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ERalpha,betaKO(CH) mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ERalpha splice variant reported previously in the parental ERalphaKO(CH) mice. These possibilities may be resolved by studies of mice in which ERalpha has been fully disrupted (ERalphaKO(St)), which are in progress.
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