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PubMed2001

Differential neonatal imprinting and regulation by estrogen of estrogen receptor subtypes alpha and beta and of the truncated estrogen receptor product (TERP-1) mRNA expression in the male rat pituitary.

Two distinct nuclear estrogen receptors (ERs) have been identified, the classical one, renamed ERalpha, and the more recently cloned ERbeta. In a variety of tissues, gene expression of both receptor subtypes results in the generation of multiple transcripts encoding the full-length as well as several alternately spliced isoforms. In the rat pituitary, a truncated, tissue-specific variant of ERalpha, called TERP-1, has been identified and found able to modulate ERalpha and ERbeta activity. So far, its pattern of expression and hormonal regulation have been mostly studied in females. The present study was designed to analyze the pattern of expression of TERP-1 mRNA in the male rat pituitary at different stages of postnatal development, and to evaluate the impact of neonatal imprinting and estrogen treatment upon TERP-1 expression in the male pituitary. Assessment of TERP-1 mRNA levels by semi-quantitative RT-PCR, using a variant-specific primer pair, revealed that TERP-1 is also expressed in the male rat pituitary. Relative mRNA expression levels changed markedly during postnatal development, with moderate expression of the TERP-1 transcript at birth, barely detectable levels during the infantile-prepubertal period, and maximal values in adulthood. Expression of TERP-1 was sensitive to neonatal estrogen exposure, which resulted in a significant, persistent increase in mRNA levels from the infantile period until puberty. This phenomenon was not mimicked by neonatal blockade of endogenous GnRH. In addition, estrogen was able to acutely up-regulate pituitary TERP-1 mRNA expression levels in prepubertal (30-day-old) and adult (75-day-old) males. Interestingly, neonatal imprinting as well as acute estrogen treatment resulted in opposite effects on TERP-1 and full-length ERalpha and ERbeta transcripts, the latter being decreased under both conditions. In conclusion, our data indicate that TERP-1 mRNA is expressed in a developmentally regulated manner in the male rat pituitary, and is affected by neonatal estrogen imprinting and acute estrogen treatment. Regulation of TERP-1 expression by neonatal or acute estrogen treatment may thus represent an additional tuning mechanism for estrogen actions in the male rat pituitary.

Aging↗
PubMed2000

Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice: what their phenotypes reveal about mechanisms of estrogen action.

Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes.

Animals↗
PubMed1996

Metabolic deglucuronidation and demethylation of estrogen conjugates as a source of parent estrogens and catecholestrogen metabolites in Syrian hamster kidney, a target organ of estrogen-induced tumorigenesis.

Estrogen-induced tumors in kidneys of male Syrian hamsters have been postulated to arise from cells which are damaged by free radicals and other reactive species generated during metabolic redox cycling of catecholestrogens and which at the same time are exposed to excessive growth stimulation mediated by estrogen receptors. In this study, we have determined the rates of metabolic deconjugation of estrogen glucuronides and of catecholestrogen methyl ethers by cellular fractions from male hamster kidney and liver to evaluate the contribution of this process to renal pools of parent estrogens and of catecholestrogen metabolites. Lysosomes from male hamster kidney catalyzed the deconjugation of estradiol- and estrone-3 beta-D-glucuronides at rates of 51.7 and 64.6 pmol/mg protein/min, respectively, which were 65 and 34% higher than corresponding deconjugation rates by liver lysosomes. Treatment of hamsters with estradiol implants for 9 days increased lysosomal glucuronidase activities for these estrogen glucuronides by 15 to 25% in kidney and doubled the activities in liver, but it did not alter their corresponding Km values. Microsomal glucuronidase activities in kidney and liver were approximately 10 to 20% of lysosomal activities. Rates of demethylation of 2- and 4-methoxyestradiol by kidney microsomes were comparable (with Vmax values of 24 and 30 pmol/mg protein/min, respectively), whereas the rate of demethylation of 2-methoxyestradiol by liver microsomes was approximately fivefold higher than that of 4-methoxyestradiol. The rates of renal demethylation of methoxyestrogens were comparable with previously published rates of renal aromatic hydroxylation of estradiol, whereas rates of hepatic demethylation were about one-fifth of the corresponding hydroxylation rates. It is concluded that metabolic deconjugation is an important source of primary estrogens and of catecholestrogen metabolites in hamster kidney, a target of estrogen-induced tumorigenesis. The increased renal estrogen glucuronidase activity during prolonged estradiol treatment may also facilitate the development of estrogen-induced tumors in this target organ.

2-Methoxyestradiol↗
PubMed1988

Comparative analysis of estrogen receptors covalently labeled with an estrogen and an antiestrogen in several estrogen target cells as studied by limited proteolysis.

Estrogen receptors covalently labeled with the estrogen affinity label [3H]ketononestrol aziridine (KNA) or with the antiestrogen affinity label [3H]tamoxifen aziridine (TAZ) were subjected to limited proteolysis with trypsin, alpha-chymotrypsin, and Staphylococcus aureus V8 protease and then analyzed on 10-20% sodium dodecyl sulfate-polyacrylamide gradient gels followed by fluorography. The similar molecular weights of intact receptors (Mr 66,000 daltons) and the proteolytic digest patterns indicate extensive homology among estrogen receptors from MCF-7 human breast cancer cells, GH4 rat pituitary cells and rat uterus when liganded with estrogen or antiestrogen. Each protease generated a distinctive ladder of estrogen receptor fragments, and the fragmentation patterns were virtually identical for estrogen receptors labeled with estrogen (KNA) or antiestrogen (TAZ). Each protease yielded a relatively "resistant" receptor fragment of about 28,000-35,000 daltons. Trypsin and chymotrypsin at higher concentrations generated a much smaller 6,000-8,000 dalton digest product that still contained the [3H]KNA- or [3H]TAZ-labeled receptor binding site. Moreover, the receptor digest patterns were similar for estrogen receptors from the three different target cells. Our studies suggest considerable structural relatedness among these three estrogen receptors and also indicate that these two affinity labels bind to a similar, perhaps identical, region of the receptor molecule.

Affinity Labels↗
PubMed2001

Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation.

Elicitation of biological responses by estrogen in target tissues requires the presence of ER as well as receptor-active ligand in the local microenvironment. Though much attention has been devoted to the study of the receptor in estrogen target tissues, the concept is emerging that tissue estrogen sensitivity may also be regulated by ligand availability through metabolic transformation in situ. Here, we show that targeted disruption, in the mouse, of an estrogen metabolic enzyme, estrogen sulfotransferase (EST), causes structural and functional lesions in the male reproductive system. EST catalyzes the sulfoconjugation and inactivation of estrogen and is expressed abundantly in testicular Leydig cells. Although knockout males were fertile and phenotypically normal initially, they developed age-dependent Leydig cell hypertrophy/hyperplasia and seminiferous tubule damage. Development of these lesions in the testis could be recapitulated by exogenous E2 administration in younger knockout mice, suggesting that they arose in older knockout mice from chronic estrogen stimulation. Older knockout mice were also found to have reduced testis and epididymis weights but increased seminal vesicle/coagulating gland weight because of tissue swelling. Furthermore, total and forward sperm motility of older knockout mice was reduced by 60% and 80%, respectively, and these mice produced smaller litters compared with age-matched wild-type males. These findings establish a role for EST in the male reproductive system and indicate that intracrine and paracrine estrogen activity can be modulated by a ligand transformation enzyme under a physiological setting. Thus, inhibition of estrogen metabolic enzymes by environmental chemicals, as has been demonstrated recently for the human EST, may constitute a novel mechanism of endocrine disruption in vivo.

Aging↗
PubMed1996

[Current questions about estrogen receptor determination and hormone dependence (does estrogen receptor positivity equal estrogen dependence?)].

Exaggerated expectations were raised by estrogen and progesterone receptor determinations introduced in the 1970s for the estimation of hormone dependence. However only two thirds of estrogen and/or progesterone receptor positive cases respond to hormonal therapy. Radioligand binding immuno-assays, and immunohistochemical determinations are wide-spread, however not informative enough. The former two performed on tumor homogenate can not take into account the tissue composition, and heterogeneity of the tumor, and fail to detect receptors of the ligand-saturated forms, while the immunological methods do not give any functional information. There is increased evidence on the existence of dysfunctional estrogen receptor variants. One presents estrogen receptor negative progesterone receptor positive phenotype unable to bind its ligand but constitutively activates its specific DNA-sequence. The other most prevalent in estrogen receptor positive progesterone receptor negative tumors is a mutant "infertile" variant able to hamper normal function of the wild type estrogen receptor by heterodimerization. In order to better utilize estrogen, and progesterone receptor data, propositions are made as following: estrogen receptors from occasionally simultaneously performed biochemical and immunohistochemical determinations should be evaluated in context with other characteristics of the tumor; the detection of mutated defective estrogen receptors may suggest hormone resistance. The correct estimation of the prevalence or lack of hormone dependence is mandatory when systemic treatment-especially in the adjuvant setting is becoming more and more individualized in breast cancer.

Adult↗
PubMed1985

A monoclonal antibody to the estrogen receptor inhibits in vitro criteria of receptor activation by an estrogen and an anti-estrogen.

The effect of an IgM class monoclonal antibody (B36) (Greene, G. L., Fitch, F. W., and Jensen, E. V. (1980) Proc. Natl. Acad. Sci. U. S. A. 77, 157-161) raised against the calf uterine estrogen receptor was tested in vitro on certain parameters of estrogen receptor activation by estradiol or 4-hydroxytamoxifen, a potent anti-estrogen. The following results were obtained. The antibody prevented the decrease in the dissociation rate of the receptor-estradiol complex which results from activation of the complex, whereas it did not affect the dissociation rate of the receptor-4-hydroxytamoxifen complex, which remains unchanged upon activation. The antibody also increased the dissociation rate of the preactivated receptor-estradiol complex. The antibody protected the naked estrogen receptor against heat-inactivation. B36 partially inhibited the binding of the estradiol- and 4-hydroxy-tamoxifen-receptor complexes to DNA adsorbed onto cellulose, but did not reverse the receptor-DNA binding. This inhibition was not overcome by higher DNA concentrations and was more pronounced for the receptor interacting with estrogen than with anti-estrogen. All these effects were specific since they were related to antibody/antigen recognition and were dose-dependent. These results indicate that the binding of the antibody to the estrogen-activated receptor induces a conformational change in the receptor and that the antibody can prevent and overcome the effect of activation whatever its mechanism. They also confirm that the conformations of the estrogen receptor differ when bound to estradiol or to 4-hydroxytamoxifen.

Animals↗
PubMed1992

Estrogen platinum-diamine complexes: preparation of a non-steroidal estrogen platinum-diamine complex labeled with platinum-191 and a study of its binding to the estrogen receptor in vitro and its tissue distribution in vivo.

We have prepared in radiolabeled form (platinum-191) a non-steroidal estrogen platinum-diamine complex (Pt-diamine complex) that is reported to have selective cytostatic activity in estrogen receptor positive mouse mammary tumors. We then studied the interaction of this metal radiolabeled complex with the estrogen receptor in vitro and its distribution in immature rats in vivo. The radiolabeled complex was prepared by incubation of the non-steroidal estrogen diamine with [191Pt](II)Cl(-2)4 (t 1/2 = 2.96 days, sp. act. 7.54 Ci/mmol) in dimethylformamide (DMF)/H2O, followed by purification by HPLC. The final radiolabeled product coeluted with an authentic standard of the unlabeled Pt-diamine complex, with a retention time distinct from those of the precursor diamine and chloroplatinate. In competitive radiometric receptor binding assays with rat uterine estrogen receptor, samples of the unlabeled diamine and Pt-diamine complex have apparent binding affinities of 53 +/- 3% and 32 +/- 11%, respectively, relative to estradiol (RBA = 100% as standard). However, attempts to observe the binding of the 191Pt-diamine complex with the estrogen receptor were complicated by a very high level of non-receptor binding, an irreversible binding to proteins in the receptor preparation, and a degradation of the platinum complex that, in part, releases the diamine. As a result, it is difficult to be certain whether the binding affinity measured for the Pt-diamine complex in the competitive binding assays is due to the complex itself, or whether it arises from diamine released upon degradation of the complex. In tissue distribution studies in immature female rats, much of the 191Pt-diamine complex was deposited in the liver; there was no evidence of selective uptake of this compound by estrogen target tissues. Thus, it is not clear, from these studies, that the observed bioactivity of this complex arises from the interaction of the Pt complex or the diamine ligand with the estrogen receptor.

Animals↗
PubMed2002

Effects of estrogen receptor and estrogen on the chromatin structure in estrogen receptor stable transfectants.

The estrogen receptor (ER), a member of the nuclear hormone receptor superfamily recruits coactivators that modify local chromatin structure. Here we investigated the effect of the estrogen receptor and estrogen on the global chromatin structure and the local chromatin structure of the progesterone receptor gene during the process of transcriptional activation using Rat1+ER cells stably expressing the estrogen receptor. The total chromatin was more accessible to DNasel in Rat1+ER cells than in the parental estrogen receptor-negative Rat1 cells. After 18 h of estrogen treatment, total chromatin was more dispersed in Rat1+ER cells than in Rat1 cells. The chromatin structure of the progesterone receptor gene was more sensitive to DNasel in Rat1+ER cells than in Rat1 cells. However, the chromatin structure of the progesterone receptor gene did not change further on estrogen treatment. Our results suggest that under certain circumstances unoccupied estrogen receptors may play some role in reorganizing the repressive chromatin structure to induce gene activation.

Animals↗
PubMed2005

The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation.

Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ERalpha agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17beta-estradiol. By contrast, the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ERalpha and ERbeta. These data show that selective ERalpha but not ERbeta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.

Animals↗
PubMed2003

Estrogen, selective estrogen receptor modulators and now mechanism-specific ligands of the estrogen or androgen receptor?

Estrogen, the traditional treatment of both short- and long-term consequences of the menopause, has fallen into disfavor. Thus, selective estrogen receptor modulators (SERMs) have been used as an alternative approach to activate estrogen signaling pathways in a tissue-specific manner. In addition, recent findings indicate that some compounds might activate specific estrogen signaling pathways that are beneficial without affecting other pathways that might lead to the harmful side-effects associated with estrogen. These so-called mechanism-specific ligands of estrogen or androgen receptors hold considerable promise as novel approaches to treat (or at least ameliorate) the consequences of estrogen deficiency.

Estrogen Replacement Therapy↗
PubMed1986

Comparison of immunocytochemical estrogen receptor assay, estrogen receptor enzyme immunoassay, and radioligand-labeled estrogen receptor assay in human breast cancer and uterine tissue.

Determination of estrogen receptor content in 82 breast cancer specimens with immunocytochemical estrogen receptor assay (ER-EIA) (Abbott) was compared with our routinely used binding assay using 125I-estradiol as radioligand with Scatchard plot analysis of the binding data. Although the estrogen receptor content measured with the ER-EIA was approximately 2-fold higher compared with the binding assay, the immunochemical method proved to be a useful alternative for estrogen receptor determination. Furthermore, it is possible to detect estrogen receptors in FPLC Superose 12 (size exclusion column) eluates or in the fractions obtained after sucrose density centrifugation using the ER-EIA. Forty breast cancer samples were analyzed utilizing the immunocytochemical technique (ER-ICA) for visualization of the estrogen receptor content in frozen tumor tissues in relationship to the quantitative results obtained with the ER-EIA assay. Specific staining for estrogen receptor was confined only to the cell nucleus, was distributed irregularly among the tumor cells, and was variable in intensity. The staining intensity and the percentage of positively stained cells increased with increasing level of cytosolic estrogen receptor. In 27 of 40 cases the immunocytochemical results correlated well with the ER-EIA assay. Nine cases were ER-ICA negative with positive ER-EIA, and four were ER-ICA positive with negative ER-EIA.

Breast Neoplasms↗
PubMed1998

Expression of estrogen sulfotransferase in MCF-7 cells by cDNA transfection suppresses the estrogen response: potential role of the enzyme in regulating estrogen-dependent growth of breast epithelial cells.

Estrogen sulfotransferase (EST) is a cytosolic enzyme that catalyzes the sulfonation of estrogens at the 3-hydroxyl position by use of 3'-phosphoadenosine-5'-phosphosulfate as an activated sulfate donor. Although largely known and studied as a phase II metabolic enzyme with prominent expression in the liver, the high substrate specificity of EST (with a high Vmax/Km value for estrogen) suggests that expression of the enzyme in extrahepatic, estrogen target tissues, such as the breast epithelium, may constitute an effective mechanism for local estrogen regulation as well. In this study, we have evaluated the physiological significance of EST expression by cDNA transfection studies with use of the estrogen-dependent MCF-7 breast cancer cell line as a model system. We show that expression of EST in MCF-7 cells effectively reduces the cells' response to physiological concentrations of estradiol (10 nM) by up to 70% as determined in an estrogen-responsive reporter gene assay. In addition, we demonstrate that expression of EST similarly inhibits estrogen-stimulated DNA synthesis and cell proliferation by 21% and 46%, respectively. (The thymidine incorporation rate was measured 3 days after and the cell numbers were counted 8 days after transfection.) These results provide direct evidence for the functional significance of in situ EST expression in the breast epithelium and suggest that abnormal regulation of the enzyme may have pathological implications in the development and maintenance of hormone-dependent breast carcinomas.

Breast↗
PubMed2003

Thyroid hormone is an inhibitor of estrogen-induced degradation of estrogen receptor-alpha protein: estrogen-dependent proteolysis is not essential for receptor transactivation function in the pituitary.

Proteolysis by the 26S proteasome is an important regulatory mechanism that governs the protein stability of several steroid/nuclear receptors and that has been implicated in the control of receptor transcriptional activation function. Herein, we report that thyroid hormone can prevent estrogen-induced proteolysis of estrogen receptor-alpha (ERalpha) protein in lactotrope cells of the pituitary. The stabilization of ERalpha protein by thyroid hormone represents a selective blockade against estradiol-stimulated degradation, because thyroid hormone (but not glucocorticoid) can protect estrogen-activated ERalpha. Moreover, thyroid hormone treatment does not interfere with signal-induced proteolysis of a separate proteasome target, IkappaBalpha or ERalpha proteolysis induced by ICI182780. Using thyroid hormone as a tool to inhibit ERalpha proteolysis, we examined the effect of loss of this regulatory function on estrogen-induced transcriptional responses. Consistent with earlier reports, estrogen activation of an idealized estrogen response element reporter gene was inhibited. However, thyroid hormone did not prevent induction of prolactin gene expression or the ability of ERalpha to stimulate proliferation. These results demonstrate that estrogen-induced proteolysis of ERalpha is not a general requirement for receptor transcriptional activation function, and they demonstrate that proteolytic regulation is a means by which other endocrine factors can indirectly modulate ERalpha activity.

Blotting, Northern↗
PubMed2002

Additive estrogenic activities of the binary mixtures of four estrogenic chemicals in recombinant yeast expressing human estrogen receptor.

To evaluate the estrogenic activities of several chemicals such as 17beta-estradiol (E2), rho-nonylphenol, bisphenol A, butylparaben, and combinations of these chemicals, we used recombinant yeasts containing the human estrogen receptor [Saccharomyces cerevisiae ER + LYS 8127]. We evaluated E2 was most active in the recombinant yeast assay, followed by rho-nonylphenol, bisphenol A, butylparaben. The combinations of some concentrations of 17-estradiol as a strong estrogen and bisphenol A or butylparaben as a weak estrogen showed additive estrogenic effects. Also, the combinations of some concentrations of nonlyphenol and butylparaben and combination of butylparaben and bisphenol A showed additive effects in the estrogenic activity. Therefore, the estrogenic activities of the combinations of two chemicals were additive, not synergistic.

Benzhydryl Compounds↗
PubMed1986

Mechanisms subserving the bipotential actions of estrogen on ovarian cells: studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol.

Estrogen exerts biphasic effects on progesterone biosynthesis by swine granulosa cells, such that initial transient inhibition is followed by delayed but sustained stimulation. We have tested the functional role of the estradiol receptor in these biphasic responses by utilizing the highly selective estrogen-receptor antagonist, LY156758, and the synthetic estrogen agonist, moxestrol. The acute inhibitory action of estradiol was mimicked in a dose-dependent action by moxestrol (half-maximally inhibitory dose: 54.3 +/- 25 ng/ml), but was not antagonized by LY156758. Rather, the antiestrogen alone significantly suppressed basal progesterone synthesis, and accentuated the suppressive effect of submaximally inhibitory doses of estradiol. Inhibition was accompanied by increased pregnenolone accumulation, with a consequently augmented ratio of pregnenolone to progesterone. Moreover, in cell-free sonicates of granulosa cells, LY156758 directly inhibited 3 beta-hydroxysteroid dehydrogenase activity in a dose-dependent fashion, with half-maximal inhibition expressed at a drug concentration of 2.44 +/- 0.31 micrograms/ml compared with 85 +/- 19 ng/ml for estradiol. In addition, the combination of LY156758 and submaximally inhibitory doses of estradiol resulted in further suppression of 3 beta-hydroxysteroid dehydrogenase activity. The sustained stimulatory phase of estrogen action was also mimicked by moxestrol in a dose-dependent fashion. However, in contrast to its acute inhibitory effects, longer-term treatment with LY156758 slightly enhanced basal progesterone accumulation, and effectively antagonized estradiol's stimulatory actions. In summary, our results with moxestrol demonstrate that both the inhibitory and the stimulatory actions of estradiol are effectively mimicked by this synthetic estrogen agonist. Results with the selective anti-estrogen LY156758 indicate a small degree of intrinsic estrogen agonist activity (approx 4% that of estradiol), which is reflected by its acute and direct inhibition of 3 beta-hydroxysteroid dehydrogenase activity. However, under longer-term conditions in which estradiol's stimulation of progesterone production is expressed, LY156758 significantly antagonizes estradiol's trophic actions. Accordingly, we suggest that the acute suppressive effects of estradiol on progesterone production are mediated predominantly by direct inhibition of 3 beta-hydroxysteroid dehydrogenase activity, while delayed stimulatory effects are transduced via estrogen-receptor mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements.

Structure-dependent estrogen receptor alpha (ER alpha) agonist and antagonist activities of synthetic and natural estrogenic compounds were investigated in human HepG2, MDA-MB-231 and U2 cancer cell lines. Compounds used in this study include 4'-hydroxytamoxifen, ICI 182,780, bisphenol-A (BPA), 2',4',6'-trichloro-4-biphenylol (3Cl-PCB-OH), 2',3',4',5'-tetrachloro-4-biphenylol (4Cl-PCB-OH), p-t-octylphenol, p-nonylphenol, naringenin, kepone, resveratrol, and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). Cells were transfected with a construct (pERE(3)) containing three tandem estrogen responsive elements (EREs) and either wild-type estrogen receptor alpha (ER-wt) or variants expressing activation function-1 (ER-AF1) or AF-2 (ER-AF2). The ER agonist activities of the synthetic mono and dihydroxy aromatic compounds are comparable in all three-cell lines, whereas the activities of naringenin, kepone and resveratrol are dependent on cell context and expression of wild-type or variant forms of ER alpha. In contrast, the ER antagonist activities for these compounds were highly complex and, with the exception of 3Cl-PCB-OH, all compounds inhibited E2-induced wild-type or variant ER action. Results of this in vitro study suggest that the estrogenic and antiestrogenic activity of structurally diverse synthetic and natural estrogenic compounds is complex, and this is consistent with published data that often give contradictory results for these compounds.

Benzhydryl Compounds↗
PubMed2004

Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals.

We developed a DNA microarray to evaluate the estrogen activity of natural estrogens and industrial chemicals. Using MCF-7 cells, we conducted a comprehensive analysis of estrogen-responsive genes among approximately 20,000 human genes. On the basis of reproducible and reliable responses of the genes to estrogen, we selected 172 genes to be used for developing a customized DNA microarray. Using this DNA microarray, we examined estrogen activity among natural estrogens (17beta-estradiol, estriol, estrone, genistein), industrial chemicals (diethylstilbestrol, bisphenol A, nonylphenol, methoxychlor), and dioxin. We obtained results identical to those for other bioassays that are used for detecting estrogen activity. On the basis of statistical correlations analysis, these bioassays have shown more sensitivity for dioxin and methoxychlor.

Biological Assay↗