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PubMed2002

Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells.

Tibolone (Org OD14) is a synthetic steroid used for post-menopausal hormone replacement therapy (HRT). Since HRT might increase breast cancer risk, it is important to determine the possible effects of tibolone on breast tissues. Tibolone and its metabolites Org 4094, Org 30126 and Org OM38 have been reported to inhibit estrone sulfatase activity in MCF-7 and T47D breast cancer cell lines, which suggest beneficial effects on hormone dependent breast cancer by reducing local production of free estrogens. Breast adipose stromal cells (ASCs) contain aromatase activity-an obligatory step in the biosynthesis of estrogens-and possibly contain sulfatase activity. We investigated the effects of tibolone, its metabolites and the pure progestin Org 2058 on PGE(2)-stimulated aromatase activity and on sulfatase activity in human ASC primary cultures and on sulfatase activity in MCF-7 and T47D cell lines. In MCF-7, tibolone and metabolites, but not Org 2058, were found to inhibit sulfatase activity. In T47D, tibolone inhibited sulfatase only at 10(-6)M, although weakly. ASC had high sulfatase activity, which was inhibited by 10(-6)M of tibolone, Org 4094 and Org 30126, but not by Org OM38 or Org 2058. Surprisingly, aromatase activity in ASC was increased by both tibolone and Org 2058 at 10(-6)M. As ligand binding assay results and immunohistochemistry indicated the absence of progesterone and estrogen receptors in ASC, these effects on aromatase and sulfatase activity in ASC likely take place by other routes. Because tibolone and its metabolites inhibit sulfatase activity, and because tibolone only increases aromatase activity at a high concentration, we conclude that effects of tibolone on the breast are probably safe.

17-Hydroxysteroid Dehydrogenases↗
PubMed2002

Letrozole for the management of breast cancer.

Letrozole, a third-generation aromatase inhibitor, has been the only aromatase inhibitor to date to show unequivocal superiority to tamoxifen as first-line treatment of metastatic postmenopausal breast cancer. The superiority of letrozole compared with tamoxifen was also reflected in the neoadjuvant setting, in both estrogen receptor-positive and estrogen receptor-unknown patients with differing HER-2 status. Currently, studies are being performed in the adjuvant setting, which will provide important data on the long-term safety of letrozole and help determine its suitability as a chemopreventive agent in healthy women at risk of developing breast cancer. Nevertheless, the superior clinical efficacy and survival data of letrozole suggest that it has the potential to displace tamoxifen as the gold standard in breast cancer treatment in the coming years.

Anastrozole↗
PubMed1987

Modulation of natural killer cell activity by tamoxifen in stage I post-menopausal breast cancer.

Tamoxifen, an antiestrogen which competes for the estrogen receptor, modulates natural killer cell activity in vivo. Seventeen post-menopausal stage I breast cancer patients received tamoxifen for 1 month and a statistically significant increase in NK activity was demonstrated (P = 0.0005). There was a small incremental shift in the number of Leu-11b positive cells. These data demonstrate that tamoxifen functions as a biological response modifier.

Aged↗
PubMed2003

Molecular assays to profile 10 estrogen receptor beta isoform mRNA copy numbers in ovary, breast, uterus, and bone tissues.

Estrogens regulate various biological processes in a diverse range of reproductive and nonreproductive tissues through two genetically distinct but structurally related high affinity nuclear receptors, the estrogen receptor alpha and beta (ERalpha and ERbeta). The physiological significance of the presence of two ERs that have redundant functions is not known. Several unique properties of ERbeta together with its distinct expression patterns are considered to be, in part, the basis for diverse functional actions of estrogens and opposing actions of selective estrogen receptor modulators (SERMs) in different tissues. To understand how relative expression levels of two ERs correlate to seemingly dissimilar actions of estrogens and SERMs, quantitative methods are required that can precisely measure the levels of every isoform. Previously, methods to quantify eight ERalpha isoforms have been described [Poola I. (2003) Anal. Biochem. 314, 217-226]. In this article, real-time PCRbased molecular assays are described that can distinguish and quantify as low as 100 copies of 10 ERbeta isoform mRNAs, the ERbeta1, ERbeta2, ERbeta4, ERbeta5, and ERbeta exon 2Delta, exon 3Delta, exon 4Delta, exon 5Delta, exon 6Delta, and exons 5-6Delta. Each isoform mRNA is quantified using a specific primer pair and a 5'FAM (carboxy-fluorescein)- and 3'TAMARA (6-carboxy tetraethyl-rhodamine)-labeled probe and in comparison with a standard curve constructed with known copy numbers of its respective reverse transcribed cRNA. The devised assays were applied to profile 10 ERbeta isoforms in four estrogen-sensitive tissues-ovary, breast, uterus, and bone. The sensitivity of detection of each isoform in these tissues varied from picograms to nanograms of reverse-transcribed total RNA depending on the isoform and the tissue. The results presented also show that each tissue has a distinct profile of 10 isoform mRNAs. Interestingly, ERalpha- negative breast cancer cell lines and tumors expressed significant amounts of ERbeta isoforms suggesting that mitogenic stimulation by estrogen exists in these tissues. Bone tissues expressed several isoforms, although wild type was not present. In addition to the assay development, evidence is presented to demonstrate for the first time that ERbeta4 and ERbeta5 are full length receptors, contrary to previous reports that they are short receptors of exon 7-8.

Base Sequence↗
PubMed2005

4-Hydroxytamoxifen inhibits proliferation of multiple myeloma cells in vitro through down-regulation of c-Myc, up-regulation of p27Kip1, and modulation of Bcl-2 family members.

PURPOSE: Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies. Our approach was to analyze the in vitro effects of a selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT), on six multiple myeloma cell lines. EXPERIMENTAL DESIGN: Cultured multiple myeloma cells were treated with various 4-OHT concentrations and the cellular response was studied: cell proliferation, cell viability, induction of apoptosis, caspase activities, and expression of signaling proteins. RESULTS: We found that pharmacologic concentrations of 4-OHT inhibit cell proliferation (4 of 6 cell lines). This inhibition is achieved by two independent events: a block at the G(1) phase of the cell cycle and the induction of apoptotic death. The cellular response to 4-OHT depends on the presence of functional estrogen receptors. 4-OHT treatment activates an intrinsic mitochondrial caspase-9-dependent pathway but not the Fas/FasL death pathway. Signaling pathways known to be involved in the survival and/or proliferation of multiple myeloma cells are not affected by 4-OHT treatment. 4-OHT-induced G(1) arrest is accompanied by the up-regulation of the cell cycle inhibitor p27(Kip1) and the down-regulation of c-Myc. Among the Bcl-2 family members tested, the proapoptotic BimS protein is induced whereas the antiapoptotic protein Mcl-1 is decreased. CONCLUSIONS: Although the effects of 4-OHT are observed at micromolar concentrations, cellular mechanisms responsible for G(1) arrest, as well as apoptosis induction, are similar to those observed in breast cancer cells. Our data support the concept that 4-OHT may represent an alternative approach to inhibit proliferation and induce apoptosis of multiple myeloma cells.

Apoptosis↗
PubMed1999

Hormone replacement therapy and cardiovascular disease.

A large amount of research continues to be conducted on the mechanisms of hormone replacement therapy (HRT) effects, and the first of the large clinical trials published its results during the past year. In addition to the well known effects on LDL-cholesterol, HDL-cholesterol, and triglycerides, recent studies confirmed that estrogen with or without a progestin lowers lipoprotein (a) concentrations in women (but not in men). In men, estrogen appears to have a similar effect on other lipids and lipoproteins and on plasminogen activator inhibitor-1 as in women. A comparison of estrogen with simvastatin indicated that simvastatin is better at lowering LDL-cholesterol while estrogen is better at raising HDL-cholesterol; when given in combination the additional effects were modest. Estrogen and simvastatin had similar beneficial effects on endothelial function. The estrogen effect on endothelial function may be blocked by medroxyprogesterone, but the data are inconsistent. These studies of intermediate outcomes were put in perspective by the results of a landmark secondary prevention trial of coronary heart disease (CHD). This randomized placebo-controlled trial (Heart and Estrogen/Progestin Replacement Study) of conjugated equine estrogens plus medroxyprogesterone failed to show the anticipated reduction in CHD, and at the same time the threefold increase in venous thromboembolism confirmed that HRT is procoagulant. Therefore, it is still not known whether HRT is a viable option for the prevention of CHD. The preliminary data on selective estrogen receptor modulators are not overly promising, but a definitive trial to test whether raloxifene will reduce CHD is ongoing.

Cardiovascular Diseases↗
PubMed2002

Anti-oestrogenic prevention of breast cancer--the make or break point.

Clinical trials have shown that giving anti-oestrogens to healthy women can reduce the early incidence of breast cancer by approximately 40%. However, the large numbers of women treated, compared with the few who get breast cancer, together with the not insignificant toxicity and the unknown long-term clinical benefits and risks, makes this strategy of prevention versus treatment precarious. So how can we improve the odds for the successful use of endocrine chemoprevention?

Antineoplastic Agents, Hormonal↗
PubMed2002

[Guidelines for drug therapy of postmenopausal osteoporosis].

Osteoporosis is known as a condition characterized by low bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and a consequent susceptibility to fracture. Osteoporosis has its highest rate of occurrence in postmenopausal women, and in Western countries it has been estimated that for white women aged fifty, the life-time risk of developing an osteoporotic fracture is nearly 40%. Given the consequences of osteoporosis, the most important goal of therapy is to prevent fractures. In Austria, several pharmacologic options for treatment of osteoporosis are available, including bisphosphonates (alendronate, etidronate, risedronate), selective estrogen receptor modulators (raloxifene), calcitonins (salm-calcitonin, elcatonin), fluorides (sodium-fluoride, monofluorophosphate), anabolic steroids (nandrolone-decanoate), steroid derivates (tibolone), estrogen and hormone replacement therapy. An evidence-based evaluation of these treatment options clearly indicates that alendronate, risedronate and raloxifene sufficiently reduce the risk of vertebral fractures. There is less evidence for reduction of vertebral fracture risk for etidronate, calcitonin, estrogen replacement therapy or hormone replacement therapy. Only alendronate and risedronate have been shown to reduce the risk of hip fractures. Calcium and vitamin D are useful adjuncts to any specific treatment for osteoporosis, particularly when Calcium and vitamin D deficiencies have been diagnosed. Also, there is good evidence that in women with Calcium and vitamin D deficiency, a combination of Calcium and vitamin D may reduce the risk of non-vertebral fractures. There is no evidence so far that a combination therapy of antiresorptive drugs would result in reduced fracture risk.

Adult↗
PubMed2002

A reactivity pattern for discrimination of ER agonism and antagonism based on 3-D molecular attributes.

Various models have been developed to predict the relative binding affinity (RBA) of chemicals to estrogen receptors (ER). These models can be used to prioritize chemicals for further tiered biological testing to assess the potential for endocrine disruption. One shortcoming of models predicting RBA has been the inability to distinguish potential receptor antagonism from agonism, and hence in vivo response. It has been suggested that steroid receptor antagonists are less compact than agonists; thus, ER binding of antagonists may prohibit proper alignment of receptor protein helices preventing subsequent transactivation. The current study tests the theory of chemical bulk as a defining parameter of antagonism by employing a 3-D structural approach for development of reactivity patterns for ER antagonists and agonists. Using a dataset of 23 potent ER ligands (16 agonists, 7 antagonists), molecular parameters previously found to be associated with ER binding affinity, namely global (E(HOMO)) and local (donor delocalizabilities and charges) electron donating ability of electronegative sites and steric distances between those sites, were found insufficient to discriminate ER antagonists from agonists. However, parameters related to molecular bulk, including solvent accessible surface and negatively charged Van der Waal's surface, provided reactivity patterns that were 100% successful in discriminating antagonists from agonists in the limited data set tested. The model also shows potential to discriminate pure antagonists from partial agonist/antagonist structures. Using this exploratory model it is possible to predict additional chemicals for their ability to bind but inactivate the ER, providing a further tool for hypothesis testing to elucidate chemical structural characteristics associated with estrogenicity and anti-estrogenicity.

Animals↗
PubMed2007

Relationship between estrogen and schizophrenia.

There is a wealth of historical and circumstantial evidence to suggest that female patients with schizophrenia may suffer from a deficit in estrogenic function. The prolactin-inducing properties of most antipsychotic drugs, and subsequent negative feedback on estrogen levels, is in keeping with this. The functions of estrogen, its complex receptor organization and its numerous actions are the focus of ongoing research activity. Of particular interest are its neuroprotective properties, particularly with regard to cognitive impairment, and its involvement with neurotransmitter systems, which are the substrate for psychotropic drugs. Estrogen has now been used as an adjunct to standard antipsychotic medication in quite a few studies of female schizophrenia patients. However, most of these are not double-blind, randomized, controlled trials. Only two relatively small double-blind, randomized clinical trials returned positive results: one long-term study that selected for hypoestrogenism reported negative findings. Furthermore, recent evidence of the risks of long-term hormone replacement therapy is of concern. The advent of specific estrogen receptor modulators, which may avoid excess risks of cancer and cardiovascular events, will have little to add to schizophrenia treatment if estrogen is, essentially, devoid of any specific antipsychotic or adjuvant mechanism of action relevant to the pathophysiology of this disorder.

Antipsychotic Agents↗
PubMed2000

Soy isoflavones: are they useful in menopause?

In October 1999, the US Food and Drug Administration authorized the use on food labels of health claims associated with soy protein and the reduced risk of coronary heart disease. Several studies have indicated that a total daily intake of 25 g of soy protein paired with a low-fat diet resulted in clinically important reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Soybeans are a rich source of isoflavones, a class of phytoestrogens found predominantly in legumes and beans. Soy isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, LDL cholesterol, and triglyceride levels. However, the soy isoflavones do not increase high-density lipoprotein cholesterol or triglyceride levels. The effects of soy protein on other target tissues reflect estrogenlike agonist and antagonist effects. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. Thus far, there is no evidence for a stimulatory effect of isoflavones on the endometrium. A few studies reveal a minimal effect of soy on hot flashes, with soy reducing hot flashes 45% and placebo causing a 30% reduction compared with an approximate 70% reduction in hot flashes with estrogen replacement therapy. Evidence from laboratory studies reveals neither a positive nor a negative effect of soy isoflavones on cognition. To date, no adverse effects of short- or long-term use of soy proteins are known in humans. The only adverse effects known are those reported in animals (infertility in sheep and quails grazing on phytoestrogen-rich pastures). In conclusion, soy isoflavones are biologically active compounds. Current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Although epidemiological and basic laboratory studies allude to the possible protective effects of soy isoflavones at specific target tissues, randomized, placebo-controlled clinical trials are necessary to address these important issues.

Animals↗
PubMed2003

Hormone therapy in menopause: the plot thickens.

The termination of one of the trials in the Women's Health Initiative (WHI) study is causing turmoil in women using hormone therapy. Practitioners and patients alike are confronted with conflicting evidence about the safety and effectiveness of both estrogen therapy (ET) and hormone (estrogen/progestin) therapy (HT). Recent investigations of the estrogen receptor, the genome, and cellular cofactors have demonstrated the heterogeneity of molecular response to hormones. This implies a heterogeneous response in the individual as well and casts doubt on the validity of prior research. Recent experiments in monkeys have provided a possible explanation for the adverse effects of HT on the cardiovascular system that were detailed by the Heart and Estrogen/Progestin Replacement Study (HERS) and WHI studies. This article explores nuances of several key studies and discusses potential therapeutic options, including use of lower-dose estrogen, transdermal estrogen, selective estrogen-receptor modulators, and diminished use of progestin.

Aged↗
PubMed2005

Pharmacologic resistance in prolactinoma patients.

Pharmacologic resistance to dopamine agonists is defined here as failure to normalize PRL levels and failure to decrease macroprolactinoma size by >or=50%. Failure to normalize PRL levels is found in about one-quarter of patients treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. The cause of dopamine resistance is primarily a decrease in D(2) receptors but the receptors have normal affinity for dopamine. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Bromocriptine↗
PubMed2006

Differential protective properties of estradiol and tamoxifen against methamphetamine-induced nigrostriatal dopaminergic toxicity in mice.

Mechanisms implicated in protective potential of estrogens are poorly understood. Tamoxifen, a selective estrogen receptor modulator (SERM), presents a neuroprotective effect against methamphetamine (MA)- and methoxy-phenyltetrahydropyridine (MPTP)-induced toxicity when used alone but abolishes estrogen's positive effects when combined with this hormone. In order to understand tamoxifen's protective properties, the present study compared it to estradiol on several markers of dopaminergic neurons to achieve a relatively comprehensive comparison between these two agents. Estradiol benzoate (E) or tamoxifen were used at different concentrations (E: 1, 10 or 40 microg; tamoxifen: 12.5, 125 or 500 microg) 24 h prior to a MA injection in ovariectomized CD-1 mice. The effects of the lesion and treatments were studied on striatal dopamine (DA) concentrations, dopamine and monoamine vesicular transporters (DAT and VMAT2), and preproenkephalin (PPE) mRNA levels. Both treatments, at all concentrations, prevented the MA-induced decrease of striatal DA concentrations and VMAT2 binding. Only E was able to prevent loss of DAT binding in the lateral striatum and to attenuate the MA-induced increase in striatal PPE mRNA levels (at 1 or 40 microg). Therefore, in this paradigm, E and tamoxifen differentially modulated MA-induced neuronal damages. While both treatments prevented the DA decrease, E protected more efficiently other dopaminergic parameters suggesting that overall E is more effective than tamoxifen as a neuroprotectant of the nigrostriatal dopaminergic system.

Animals↗
PubMedDate not supplied

Hormonal effects on the mammary gland of postmenopausal nonhuman primates.

Macaques are Old World anthropoid primates with a high degree of genetic identity to human beings and striking similarities in breast development, reproductive endocrinology, and menstrual cycle characteristics. These animals share critical pathways of hormone metabolism with humans, to a degree that is distinct from rodent models. Macaques also express estrogen receptors alpha and beta, progesterone receptors, and androgen receptors in the normal breast in patterns similar to those described for women. Spontaneously occurring hormone-dependent breast cancers occur in macaques at a similar prevalence to lower-risk populations of women, and these neoplasms exhibit similar growth patterns and key molecular changes seen in human lesions. These similarities lend support to a biomarker approach for modeling breast cancer risk. Estrogen+progestogen treatment of postmenopausal animals produces a proliferative response in the normal breast epithelium which reflects the breast cancer promoting effects of continuous combined hormone replacement therapy. Studies of novel agents such as tibolone, selective estrogen receptor modulators, and alternative progestogens in macaques have also helped to identify hormonal therapies with a more acceptable balance of benefit to risk. Future studies of novel selective estrogens, androgens, and dietary estrogens in the macaque model will further contribute to our understanding of breast cancer risk and prevention.

Animals↗
PubMed2002

Estrogen blocks 3-nitropropionic acid-induced Ca2+i increase and cell damage in cultured rat cerebral endothelial cells.

Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since the endothelial cells are important components of the BBB and the first target of a systemic intoxication, in the present study, the effect of 3-NPA on primary cultured rat brain endothelial cells (rBECs) was examined by studying intracellular Ca(2+) ([Ca(2+)](i)) response using imaging techniques with fura-2. rBECs were prepared using a method of Kis et al. [Eur. J. Pharmacol. 368 (1999) 35-42] and Szabo et al. [Neurobiology 5 (1997) 1-16]. Almost all cells were immunoreactive to antibody against the factor VIII-related antigen (von-Willebrand factor). They showed a typical dose-dependent increase of [Ca(2+)](i) in response to ATP or bradykinin. Low concentrations of 3-NPA (1.7 mM, 3.4 mM) caused no changes, and a medium concentration (6.8 mM) increased the [Ca(2+)](i) gradually and progressively, and the increase was reversed incompletely back to the resting level after washing. A high concentration (13.6 mM) increased the [Ca(2+)](i) irreversibly. These elevations of [Ca(2+)](i) were absent in a Ca(2+)-free medium. In endothelial cells treated with 17beta-estradiol (above 10(-5) M) or with a selective estrogen receptor modulator, tamoxifen (5 x 10(-7) M), no elevation of [Ca(2+)](i) was observed with 3-NPA treatment. The response to ATP was impaired after application of 3-NPA, but it was preserved by cotreatment with 17beta-estradiol or tamoxifen. An estrogen receptor antagonist ICI 182,780 inhibited these effects by 17beta-estradiol or tamoxifen. Lysosomal neutral red uptake and TUNEL experiments revealed the necrotic but not apoptotic cell death at least in this acute stage. Data indicate that a medium to high concentration of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca(2+)](i), but the damage was protected by cotreatment with 17beta-estradiol or tamoxifen, suggesting that estrogen may be protective for the brain vascular damage via estrogen receptor.

Adenosine Triphosphate↗
PubMed2005

Evaluation of estrogenic/antiestrogenic activity of ellagic acid via the estrogen receptor subtypes ERalpha and ERbeta.

Ellagic acid is a plant-derived polyphenol, possessing antioxidant, antiproliferative, and antiatherogenic properties. Whether this compound has estrogenic/antiestrogenic activity, however, remains largely unknown. To answer this question, we first investigated the ability of ellagic acid to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells. Cells co-transfected with an estrogen response element (ERE)-driven luciferase (Luc) reporter gene and an ERalpha- or ERbeta-expression vector were exposed to graded concentrations of ellagic acid. At low concentrations (10(-7) to 10(-9) M), this compound displayed a small but significant estrogenic activity via ERalpha, whereas it was a complete estrogen antagonist via ERbeta. Further evaluation revealed that ellagic acid was a potent antiestrogen in MCF-7 breast cancer-derived cells, increasing, like the pure estrogen antagonist ICI182780, IGFBP-3 levels. Moreover, ellagic acid induced nodule mineralization in an osteoblastic cell line (KS483), an effect that was abolished by the estrogen antagonist. Endometrium-derived epithelial cells (Ishikawa) showed no response to the natural compound by using a cell viability assay (MTT). These findings suggest that ellagic acid may be a natural selective estrogen receptor modulator (SERM).

Breast Neoplasms↗
PubMed2005

Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295R adrenocortical carcinoma cells.

The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 microM) compared with 8% for BPA relative to the maximum induction by 17beta-estradiol (E2, 1 microM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 microM, virtually 100% inhibition of vtg at 20 microM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 microM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 microM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 microM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 microM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 microM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 microM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At concentrations as great as 100 microM, none of the diphenylalkanes directly inhibited aromatase (CYP19) activity in H295R cells. Environmental exposure of fish to BPA and related diphenylalkanes, depending on the structure, may pose anti-estrogenic, and to a lesser extent estrogenic, risks to development and reproduction.

Adrenocortical Carcinoma↗