Am J Physiol Renal Physiol. 2002 Jan;282(1):F164-9.
Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2.
Guccione M, Silbiger S, Lei J, Neugarten J.
Division of Nephrology, Department of Medicine, Montefiore Medical Center, and the Albert Einstein College of Medicine, Bronx, New York 10467, USA.
The accumulation of extracellular matrix in the glomerular mesangium reflects the net balance between the synthesis and degradation of matrix components. We have shown that estradiol suppresses the synthesis of types I and IV collagen by cultured mesangial cells (Kwan G, Neugarten J, Sherman M, Ding Q, Fotadar U, Lei J, and Silbiger S. Kidney Int 50: 1173-1179, 1996; Neugarten J, Acharya A, Lei J, and Silbiger S. Am J Physiol Renal Physiol 279: F309-F318, 2000; Neugarten J, Medve I, Lei J, and Silbiger SR. Am J Physiol Renal Physiol 277: F1-F8, 1999; Neugarten J and Silbiger S. Am J Kidney Dis 26: 147-151, 1995; Silbiger S, Lei J, and Neugarten J. Kidney Int 55: 1268-1276, 1998; Silbiger S, Lei J, Ziyadeh FN, and Neugarten J. Am J Physiol Renal Physiol 274: F1113-F1118, 1998). In the present study, we evaluated the effects of sex hormones on the activity of matrix metalloproteinase-2 (MMP-2) in murine mesangial cells, the synthesis of which is regulated by the transcription factor activator protein-2 (AP-2). Estradiol stimulated MMP-2 activity by increasing MMP-2 protein levels in a dose-dependent manner. These effects occurred at physiological concentrations of estradiol and were receptor mediated. Estradiol also increased AP-2 protein levels and increased binding of mesangial cell nuclear extracts to an AP-2 consensus binding sequence oligonucleotide. The ability of estradiol to increase AP-2 protein expression, AP-2/DNA binding activity, MMP-2 protein expression, and metalloproteinase activity was reversed by PD-98059, a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade. We conclude that estradiol u
Endocr Pathol. 2001 Fall;12(3):315-27.
Testosterone and estradiol have specific differential modulatory effect on the proliferation of human thyroid papillary and follicular carcinoma cell lines independent of TSH action.
Banu KS, Govindarajulu P, Aruldhas MM.
Department of Endocrinology, Dr. Alm P.G. Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, India.
Differential effects of testosterone and estradiol on the proliferation of human thyroid papillary (NPA-87-1) and follicular (WRO-82-1) carcinoma cell lines were assessed by [(3)H]-thymidine incorporation and the cell number. Cells (2.5 x 10(5)) plated in 24-well culture plates in 400 microL RPMI-1640 medium/well, under 5% CO(2) and 95= air, at 37 degrees C were exposed to exponential concentrations of human thyroid-stimulating hormone (hTSH) (1.25-640 ng/mL), testosterone (1.25-640 ng/mL), or estradiol (1.25-640 pg/mL) for 24 h. Testosterone and estradiol increased the proliferation of NPA cell line in a dose-dependent manner; flutamide (an anti-androgen) and tamoxifen (an anti-estrogen) (10(-8), 10(-7), 10(-6), and 10(-5) mol/L) effectively inhibited the testosterone and estradiol-induced cell proliferation, respectively. While flutamide inhibited the stimulatory effect of testosterone on the WRO cell line, tamoxifen augmented the inhibitory effect of estradiol. TSH did not have any effect on the proliferation of NPA or WRO cell lines, and testosterone-estradiol had no impact on TSH binding to these cells. N-ethylmalemide (5alpha-reductase inhibitor) (10(-8)-10(-5) mol/L) did not modulate basal and testosterone-induced cell proliferation, indicating the direct effect of testosterone without getting converted into dihydrotestosterone (DHT). Both the cell lines tested positive for androgen and estrogen receptors and were up-regulated by the respective ligands. It is concluded that testosterone and estradiol modify the proliferation of thyroid cancer cells through homologous up-regulation of their own receptor
Acta Pharmacol Sin. 2001 Feb;22(2):148-54.
Role of cytochrome P450 in estradiol metabolism in vitro.
Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH.
Pharmacogenetics Research Institute, Hunan Medical University, Changsha 410 078, China.
AIM: Catechol estrogens and 16alpha-hydroxy estrogen are important metabolites that cause carcinogenesis. This study was aimed to stud y the role of cytochrome P450 in estradiol metabolism. METHODS: The estradiol metabolites were determined with HPLC-ECD. Correlation of estradiol metabolites production between cytochrome P450 activity, the inhibitory effect of specific inhibitors and enzyme catalyzing kinetics were studied in cDNA-expressed P450 or human liver microsomes. RESULT: CYP1A2, CYP3A4, and CYP2C9 catalyze the estradiol 2-hydroxylation. CYP2C9, CYP2C19, and CYP2C8 have high activity in catalyzing 17beta-hydroxy dehydrogenation in cDNA expressed P450, but CYP1A2 is the most important enzyme in catalyzing estradiol 2-hydroxylation. Using furafyllin and troleandomycin to inhibit CYP1A2 and CYP3A4 in liver microsomes, it was found that the 2-hydroxylation had been inhibited about the same amount. This result suggests that in human liver microsomes CYP1A2 and CYP3A4 play an important role in 2-hydroxy estradiol formation. At low substrate concentration, 17beta -hydroxy dehydrogenation dominated the estradiol metabolism, but at high substrate concentration, 2-hydroxylation exceeded 17beta-hydroxy dehydrogenation to become the important mechanism. CONCLUSION: CYP1A2 and CYP3A4 are two important enzymes catalyzing the main estradiol 2-hydroxylation metabolism pathway at high substrate concentrations. 17beta-hydroxy dehydrogenation is the main metabolism pathway at low concentrations, and CYP2C9, CYP2C19, and CYP2C8 may have high catalyzing activity.
Int J Oncol. 2002 Jan;20(1):117-20.
Up-regulation of Frizzled-10 (FZD10) by beta-estradiol in MCF-7 cells and by retinoic acid in NT2 cells.
Saitoh T, Mine T, Katoh M.
Genetics and Cell Biology Section, Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Frizzled (FZD) genes encode receptors for WNTs, which play key roles in carcinogenesis and embryogenesis. We have previously cloned the FZD10 gene, and demonstrated up-regulation of FZD10 mRNA in the cervical cancer cell line HeLa S3, gastric cancer cell lines TMK1 and MKN74, and 4 cases out of 10 cases of primary gastric cancer. Here, effects of beta-estradiol, retinoic acid, and inflammatory cytokines on expression of FZD10 mRNA in human cancer cell lines were investigated. FZD10 mRNA was undetectable in MCF-7 cells derived from breast cancer, and was significantly up-regulated by beta-estradiol in MCF-7 cells with a peak at 24 h after treatment. FZD10 mRNA was expressed in NT2 cells, which are reported to differentiate into neuronal cells after exposure to retinoic acid. Although expression level of FZD10 mRNA was unchanged until 36 h after retinoic-acid treatment, FZD10 mRNA was up-regulated at 48 and 72 h after retinoic-acid treatment in NT2 cells. Effects of inflammatory cytokines on FZD10 mRNA expression in a gastric cancer cell line MKN45 was next investigated. FZD10 mRNA was undetectable in MKN45 cells, and was not up-regulated by IFNgamma and TNFalpha in MKN45 cells. Because we have previously demonstrated up-regulation of WNT2 mRNA by beta-estradiol in MCF-7 cells, FZD10 and WNT2 mRNAs were found to be up-regulated together by beta-estradiol in MCF-7 cells with the same time course. Synchronous up-regulation of FZD10 and WNT2 mRNAs might lead to activation of the WNT signaling pathway in human breast cancer.
J Pediatr Orthop. 2002 Jan-Feb;22(1):88-91.
Serum 17 beta-estradiol in newborn and neonatal hip instability.
Andersson JE, Vogel I, Uldbjerg N.
Department of Pediatrics, Blekingesjukhuset, Barn-och Ungdomskliniken, 371 85 Karlskrona, Denmark. john.anderssotblekinge.se
This study evaluates the association between the level of 17 beta-estradiol in the umbilical cord blood and neonatal hip instability (NHI) in a population-based prospective case-control study comprising 2,185 consecutively newborns. beta-Estradiol levels were measured with a standard fluoroimmunoassay kit. Neonatal hip instability was determined by the anterior dynamic ultrasound method. An increased risk of NHI was found after breech malposition and in girls. Levels of beta-estradiol were higher in boys without NHI than in girls. A negative association between beta-estradiol level and parity was found. A significant association between beta-estradiol level and NHI was shown in boys with low serum concentrations. High levels of beta-estradiol tended to be associated with an increased risk of NHI in girls. An association was found between gender, parity, and beta-estradiol level in cord blood. No firm conclusion on the association between NHI and beta-estradiol level can be made; the possible association may be gender-dependent.
J Comp Neurol. 2001 Dec 3;441(1):1-8.
Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus.
Liu Z, Gastard M, Verina T, Bora S, Mouton PR, Koliatsos VE.
Department of Pathology (Division of Neuropathology), The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Estrogens are known to have broad effects on neuronal plasticity, but their specific role in neuronal cell death has not been determined. In the present study, we investigated the effects of beta-estradiol on an experimental model of apoptosis of granule cells of the dentate gyrus, i.e., apoptosis induced by intraventricular injection of the microtubule polymerization inhibitor colchicine. Cell death was characterized with multiple methods, including TUNEL and DNA electrophoresis. Nonrandom digestion of DNA was observed within 8-10 hours after colchicine injection, followed by condensation and fragmentation of granule cell nuclei and extensive anterograde degeneration of mossy fibers/terminals in 2 days. We compared the outcomes of the above-described manipulation in ovariectomized or sham-operated rats and animals treated daily with beta-estradiol or vehicle. Animals were lesioned with colchicine or vehicle 2 weeks after ovariectomy or sham operation. Beta-estradiol or vehicle was administered for 1 week prior to lesion and was continued for a further 2 weeks. Total numbers and densities of granule cells in different animal groups were counted by stereology in various anteroposterior levels of the hippocampus. Our results show that ovariectomy intensifies colchicine-induced granule cell apoptosis, which is ameliorated by exogenous beta-estradiol. In doses that ameliorate the adverse effect of ovariectomy, exogenous beta-estradiol appears to have no effect of preventing granule cell death in animals with intact ovaries; i.e., an estrogen excess is not more neuroprotective than physiological levels of these hormones. Taken together, our results indicate that est
J Neurosci Res. 2001 Nov 1;66(3):475-81.
Nongenomic mechanism mediates estradiol stimulation of axon growth in male rat hypothalamic neurons in vitro.
Cambiasso MJ, Carrer HF.
Instituto de Investigacion Medica Mercedes y Martin Ferreyra, INIMEC-CONICET, Cordoba, Argentina.
The purpose of the present work was to investigate the participation of estradiol receptors (ER) in estrogen-induced axon growth in vitro. Hypothalamic neurons from 16 day (E16) male rat fetuses were cultured with or without 17-beta-estradiol at 1 x 10(-7) M in basal medium or medium conditioned by astroglia derived from ventral mesencephalon (CM). After 48 hr in vitro, neurite outgrowth was quantified by morphometric analysis. An axogenic effect could be demonstrated for estradiol added to CM. With RT-PCR, the mRNA transcript for ERalpha was found in the donor tissues as well as in the neuron cultures. In this model two specific nuclear ER blockers (tamoxifen and ICI 182,780) were ineffective in blocking the neuritogenic effect, and a membrane-impermeable estrogen-albumin construct (E2-BSA) was as effective as estradiol. These results indicate that the axogenic effect of estradiol at E16 is not exerted through the classical intracellular receptor signal transduction system and suggest the possibility of a membrane-mediated mechanism. The data are discussed in light of our previous findings pointing to the interdependent activation of the estrogenic and the trophic factor signaling pathways that mediate stimulated axon growth. Copyright 2001 Wiley-Liss, Inc.
Toxicology. 2002 Jan 15;170(1-2):21-30.
Comparison of reporter gene assay and immature rat uterotrophic assay of twenty-three chemicals.
Yamasaki K, Takeyoshi M, Yakabe Y, Sawaki M, Imatanaka N, Takatsuki M.
Chemicals Assessment Center, Chemicals Evaluation and Research Institute, 3-822, Ishii, Hita, 877-0061, Oita, Japan. yamasaki-kanjeri.jp
We performed a reporter gene assay for ERalpha-mediated transcriptional activation and an immature rat uterotrophic assay of 23 chemicals, to study the relationship between these two assays and to examine the usefulness of the reporter gene assay. The chemicals analyzed in the study were as follows: benzophenone, bisphenol A, bisphenol B, bisphenol F, p-cumyl phenol, dibutyl phthalate, dicyclohexylphthalate, dihydrotestosterone, equilin, 17alpha-estradiol, estrone, ethynyl estradiol, genistein, hematoxylin, nonylphenol mixture, 4-n-nonylphenol, norethindrone, norgestrel, octachlorostyrene, 4-n-octylphenol, 4-tert-octylphenol, tributyltin-chloride and zearalenone. To perform the reporter gene assay, HeLa cells were transfected with a rat ERalpha expression construct and an estrogen-regulated luciferase reporter construct. The transcriptional activities of each chemical were tested over concentrations ranging from 10 pM to 10 microM and the EC50, PC50 and PC10 values were calculated. In the immature rat uterotrophic assay, the doses of 21 chemicals, with the exception of dibutyl phthalate and ethynyl estradiol, were 0, 2, 20 and 200 mg/kg; each group consisted of six rats. The doses of dibutyl phthalate and ethynyl estradiol were 0, 40, 200 and 1000 mg/kg per day and 0, 0.2, 2 and 20 microg/kg per day, respectively. In the reporter gene assay, the PC10 values were calculated for 15 chemicals: bisphenol A, bisphenol B, bisphenol F, p-cumyl phenol, dihydrotestosterone, equilin, 17alpha-estradiol, estrone, ethynyl estradiol, genistein, nonylphenol mixture, norethindrone, norgestrel, 4-tert-octylphenol and zearalenone. These chemicals corresponded to the
Neuropsychopharmacology. 2001 Dec;25(6):881-91.
Effects of estrogen antagonists and agonists on the ACTH response to restraint stress in female rats.
Young EA, Altemus M, Parkison V, Shastry S.
Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109-0729, USA. eayounmich.edu
Previous studies have found that female rats are less sensitive than males to hypothalamic-pituitary-adrenal axis feedback inhibition by exogenous glucocorticoid administration. To determine whether estrogen contributes to this sex difference, we examined the effects of the estrogen antagonists tamoxifen and C1628 on the ACTH and corticosterone responses to restraint stress. CI628 increased both the ACTH and corticosterone response to restraint stress, and tamoxifen increased the ACTH response to restraint. Using overiectomized female rats, we also examined the effects of seven days of estradiol and/or progesterone replacement. Low dose estradiol decreased the ACTH but not the corticosterone response to restraint stress while progesterone had no effect on ACTH or corticosterone responses. The combination of estradiol and progesterone also decreased the ACTH response to stress, and the magnitude of the effect did not differ from that found with estradiol treatment alone. These data suggest that in the physiological range estradiol is an important inhibitory factor in the hypothalamic-pituitary-adrenal stress response of females.
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