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1.
Dalton Trans ; 45(7): 3013-23, 2016 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-26758555

RESUMO

The silylmethylene-linked triamidophosphine P(CH2SiMe2NHPh)3 was isolated in form of its tri-lithium salt Li3[P(CH2SiMe2NPh)3]·2.5Et2O (1·2.5Et2O) and employed for the synthesis of titanium and zirconium complexes. Starting from 1·2.5Et2O, the chlorido complexes [κ(4)-N,N,N,P-PN3]MCl (4-M, M = Ti, Zr) were prepared and examined with respect to alkylation. Upon reaction of 4-Ti with (trimethylsilyl)methyl lithium, intra-ligand cyclometalation at one of the ortho-N-phenyl positions was observed and the resulting thermally stable titanazetidine [κ(5)-N,N,N,P,C-N2P(NC)]Ti (5-Ti) isolated. Similarly, the related zirconazetidine [κ(5)-N,N,N,P,C-N2P(NC)]Zr(THF) (5-Zr) was isolated upon reaction of 4-Zr with Bn2Mg(THF)2. Using LiCH2PMe2 as alkyl transfer reagent, both complexes 4-M were converted to the corresponding phosphametallacyclopropanes [κ(4)-N,N,N,P-PN3]M(κ(2)-C,P-CH2PMe2) (7-M, M = Ti, Zr). Upon gentle heating, complexes 7-M were cleanly converted to the cyclometalated species 5-M and trimethylphosphine. These results are discussed in the context of related amidophosphine and triamidoamine complexes.

2.
Rev Endocr Metab Disord ; 16(4): 341-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26847433

RESUMO

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.


Assuntos
Carcinogênese/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Reprodução/efeitos dos fármacos , Humanos , Masculino
3.
Prog Biophys Mol Biol ; 109(3): 108-14, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22796169

RESUMO

In the last century, jointly with the advent of computers, mathematical theories of information were developed. Shortly thereafter, during the ascent of molecular biology, the concept of information was rapidly transferred into biology at large. Several philosophers and biologists have argued against adopting this concept based on epistemological and ontological arguments, and also, because it encouraged genetic determinism. While the theories of elaboration and transmission of information are valid mathematical theories, their own logic and implicit causal structure make them inimical to biology, and because of it, their applications have and are hindering the development of a sound theory of organisms. Our analysis concentrates on the development of information theories in mathematics and on the differences between these theories regarding the relationship among complexity, information and entropy.


Assuntos
Biologia/métodos , Teoria da Informação , Animais , Entropia , Humanos
4.
Semin Cancer Biol ; 21(3): 165-74, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21569848

RESUMO

Erwin Schrödinger pointed out in his 1944 book "What is Life" that one defining attribute of biological systems seems to be their tendency to generate order from disorder defying the second law of thermodynamics. Almost parallel to his findings, the science of complex systems was founded based on observations on physical and chemical systems showing that inanimate matter can exhibit complex structures although their interacting parts follow simple rules. This is explained by a process known as self-organization and it is now widely accepted that multi-cellular biological organisms are themselves self-organizing complex systems in which the relations among their parts are dynamic, contextual and interdependent. In order to fully understand such systems, we are required to computationally and mathematically model their interactions as promulgated in systems biology. The preponderance of network models in the practice of systems biology inspired by a reductionist, bottom-up view, seems to neglect, however, the importance of bidirectional interactions across spatial scales and domains. This approach introduces a shortcoming that may hinder research on emergent phenomena such as those of tissue morphogenesis and related diseases, such as cancer. Another hindrance of current modeling attempts is that those systems operate in a parameter space that seems far removed from biological reality. This misperception calls for more tightly coupled mathematical and computational models to biological experiments by creating and designing biological model systems that are accessible to a wide range of experimental manipulations. In this way, a comprehensive understanding of fundamental processes in normal development or of aberrations, like cancer, will be generated.


Assuntos
Biologia de Sistemas , Animais , Humanos , Morfogênese , Dinâmica não Linear
5.
Semin Cancer Biol ; 21(3): 175-82, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21514387

RESUMO

Cancer is a highly complex disease due to the disruption of tissue architecture. Thus, tissues, and not individual cells, are the proper level of observation for the study of carcinogenesis. This paradigm shift from a reductionist approach to a systems biology approach is long overdue. Indeed, cell phenotypes are emergent modes arising through collective non-linear interactions among different cellular and microenvironmental components, generally described by "phase space diagrams", where stable states (attractors) are embedded into a landscape model. Within this framework, cell states and cell transitions are generally conceived as mainly specified by gene-regulatory networks. However, the system's dynamics is not reducible to the integrated functioning of the genome-proteome network alone; the epithelia-stroma interacting system must be taken into consideration in order to give a more comprehensive picture. Given that cell shape represents the spatial geometric configuration acquired as a result of the integrated set of cellular and environmental cues, we posit that fractal-shape parameters represent "omics" descriptors of the epithelium-stroma system. Within this framework, function appears to follow form, and not the other way around.


Assuntos
Fractais , Neoplasias/patologia , Biologia de Sistemas , Humanos
6.
Acta Biotheor ; 56(4): 257-74, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18542843

RESUMO

The dominant position in Philosophy of Science contends that downward causation is an illusion. Instead, we argue that downward causation doesn't introduce vicious circles either in physics or in biology. We also question the metaphysical claim that "physical facts fix all the facts." Downward causation does not imply any contradiction if we reject the assumption of the completeness and the causal closure of the physical world that this assertion contains. We provide an argument for rejecting this assumption. Furthermore, this allows us to reconsider the concept of diachronic emergence.


Assuntos
Causalidade , Modelos Teóricos , Neoplasias/etiologia , Humanos
8.
Biol Reprod ; 65(4): 1215-23, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11566746

RESUMO

Exposure to estrogens throughout a woman's life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 years may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that are released into the environment. Here, we investigated the effects of fetal exposure to one such chemical, bisphenol A (BPA), on development of the mammary gland. CD-1 mice were exposed in utero to low, presumably environmentally relevant doses of BPA (25 and 250 microg/kg body weight), and their mammary glands were assessed at 10 days, 1 mo, and 6 mo of age. Mammary glands of BPA-exposed mice showed differences in the rate of ductal migration into the stroma at 1 mo of age and a significant increase in the percentage of ducts, terminal ducts, terminal end buds, and alveolar buds at 6 mo of age. The percentage of cells that incorporated BrdU was significantly decreased within the epithelium at 10 days of age and increased within the stroma at 6 mo of age. These changes in histoarchitecture, coupled with an increased presence of secretory product within alveoli, resemble those of early pregnancy, and they suggest a disruption of the hypothalamic-pituitary-ovarian axis and/or misexpression of developmental genes. The altered relationship in DNA synthesis between the epithelium and stroma and the increase in terminal ducts and terminal end buds are striking, because these changes are associated with carcinogenesis in both rodents and humans.


Assuntos
Glândulas Mamárias Animais/anatomia & histologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Fenóis/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Envelhecimento , Animais , Compostos Benzidrílicos , Bromodesoxiuridina/metabolismo , DNA/biossíntese , Epitélio/metabolismo , Feminino , Glândulas Mamárias Animais/metabolismo , Camundongos , Fenóis/administração & dosagem , Gravidez
9.
Biol Reprod ; 65(4): 1271-7, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11566753

RESUMO

Environmental estrogens (xenoestrogens) are chemicals that bind to estrogen receptor, mimic estrogenic actions, and may have adverse effects on both human and wildlife health. Bisphenol A (BPA), a monomer used in the manufacture of epoxy resins and polycarbonate has estrogenic activity. In male rodents prenatal exposure to BPA resulted in modifications at the genital tract level. Our objective was to examine the effects of in utero exposure to low, environmentally relevant levels, of the xenoestrogen BPA on proliferation and differentiation of epithelial and stromal cells on the prepubertal rat ventral prostate. To characterize the periductal stromal cells phenotype the expression of vimentin and smooth muscle alpha-actin was evaluated. Androgen receptor (AR) and prostatic acid phosphatase (PAP) expression were also evaluated in epithelial and stromal compartments. Prenatal exposure to BPA increases the fibroblastic:smooth muscle cells ratio and decreases the number of AR-positive cells of periductal stroma of the ventral prostate. In contrast, no differences in AR expression were observed in epithelial cells between control and BPA-treated groups. No changes in proliferation patterns were observed in epithelial and stromal compartments; however, the expression of PAP was diminished in prostate ductal secretory cells of rats in utero exposed to BPA. Our results suggest that prenatal exposure to BPA altered the differentiation pattern of periductal stromal cells of the ventral prostate. These findings are significant in light of the data on human prostate cancers where alterations in the stroma compartment may enhance the invasive and/or malignant potential of the nascent tumor.


Assuntos
Estrogênios não Esteroides/administração & dosagem , Fenóis/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal , Próstata/citologia , Próstata/efeitos dos fármacos , Fosfatase Ácida/análise , Actinas/análise , Animais , Compostos Benzidrílicos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Epiteliais/química , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Receptor alfa de Estrogênio , Estrogênios não Esteroides/efeitos adversos , Feminino , Masculino , Fenóis/efeitos adversos , Gravidez , Próstata/fisiologia , Ratos , Ratos Wistar , Receptores Androgênicos/análise , Receptores de Estrogênio/análise , Células Estromais/química , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Vimentina/análise
11.
J Steroid Biochem Mol Biol ; 77(2-3): 97-108, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11377974

RESUMO

Estrogens control the proliferation of estrogen-target cells through a receptor mediated pathway. We have recently presented evidence that estradiol cancels the proliferative inhibition exerted by albumin on estrogen-target cells (indirect-negative hypothesis). We postulate that this mechanism requires the presence of a membrane estrogen receptor (mER)-membrane albumin receptor complex. Confirmation for mERalpha in MCF7 cells is now made using both the C542 monoclonal and ER-21 polyclonal antibodies (Ab)s specific for ERalpha. Western blot analysis of purified membrane proteins with ERalpha Abs revealed multiple high M(r) mERs (92 k, 110 k, and 130 k M(r)), as well as a 67 k M(r) mER; immunoreactive proteins were competed by inclusion of 500-fold molar excess C542 peptide. Ligand blot analysis of similar extracts with estradiol-peroxidase identified several potential mERs as well; two of these proteins were also recognized by C542 and ER-21 Abs (110 and 67 k M(r)). Fluorescence, confocal and electron microscopy of MCF7 cells fixed in 2.0% paraformaldehyde/0.1% glutaraldehyde identified specific mERalpha sites by immunocytochemistry. Specific binding of 3H-17beta-estradiol was reduced by a 200-fold molar excess of unlabeled 17beta-estradiol, but not by testosterone and progesterone. These results suggest that the ER on the plasma membrane of MCF7 cells is similar, but not identical to its intracellular counterpart. We propose that the observed mER actively participates in the estrogen-mediated proliferation of MCF7 cells.


Assuntos
Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Sequência de Aminoácidos , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Western Blotting , Divisão Celular/fisiologia , Membrana Celular/metabolismo , Receptor alfa de Estrogênio , Estrogênios/fisiologia , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Receptores de Estrogênio/imunologia , Células Tumorais Cultivadas
12.
Environ Health Perspect ; 109(1): 55-60, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11171525

RESUMO

The prevalence of synthetic chemicals in our environment that are capable of mimicking the female hormone estrogen is a growing concern. One such chemical, bisphenol A (BPA), has been shown to leach from a variety of resin-based and plastic products, including dental sealants and food and beverage containers, in concentrations that are sufficient to induce cell proliferation in vitro. The response to BPA in vivo has been varied; thus the aims of this study were to investigate a) whether BPA has an estrogenic effect in CD-1 mice, a strain that is useful for developmental studies; and b) whether the uterotrophic assay is a valid means of determining the estrogenicity of BPA by comparing it with other end points measured in the uterus. Immature female CD-1 mice were exposed to BPA in concentrations ranging from 0.1 to 100 mg/kg body weight for 3 days. Results showed that BPA induced a significant increase in the height of luminal epithelial cells within the uterus at concentrations of 5, 75, and 100 mg/kg and that BPA induced lactoferrin at concentrations of 75 and 100 mg/kg. A uterotrophic response (increase in uterine wet weight) was induced by 100 mg/kg BPA only. Further, the proportion of mice showing vaginal opening was greater after exposure to 0.1 and 100 mg/kg BPA, relative to the control animals and those receiving intermediate doses of BPA. These results demonstrate that BPA induces changes in the mouse uterus that differ depending on the exposure dose and the end point measured, and reveal that certain tissue effects show a nonmonotonic relationship with dose. These data also demonstrate that BPA induces estrogenic changes in the uterus of the CD-1 mouse, and highlight the need to reevaluate the validity of the mouse uterotrophic assay as an end point for determining the estrogenicity of suspected environmental estrogens.


Assuntos
Divisão Celular/efeitos dos fármacos , Estrogênios não Esteroides/toxicidade , Fenóis/toxicidade , Útero/efeitos dos fármacos , Útero/patologia , Animais , Compostos Benzidrílicos , Bioensaio/normas , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Feminino , Hipertrofia , Camundongos , Camundongos Endogâmicos , Sensibilidade e Especificidade , Testes de Toxicidade/normas
13.
Proc Natl Acad Sci U S A ; 97(18): 10185-90, 2000 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-10963680

RESUMO

In the prostate gland of adult mammals, most epithelial cells are in a state of proliferative quiescence. Androgens regulate this effect by inducing cell cycle arrest in the G(0)/G(1) phase. Potential mediators of this androgen-induced proliferative shutoff were identified by means of subtracted cDNA libraries. The expression pattern of one of these sequences, AS3, strongly correlated with the expression of the androgen-induced proliferative shutoff both temporally and dosewise. The AS3 gene is located on chromosome 13 q12.3, in close proximity to the BRCA2 gene. The loss of chromosomal regions where AS3 alleles are located correlates with various human cancers, including prostate. The biological effect of AS3 was tested in two stable cell lines, one expressing sense and another expressing antisense AS3 constructs, both under tetracycline regulation. S9 cells were obtained by retroviral infection with virions containing a tetracycline-regulated sense AS3 construct. In these cells, sense AS3 was negatively regulated by tetracycline. Tetracycline withdrawal increased the expression of AS3 mRNA and protein. The expression of tetracycline-regulated AS3 resulted in inhibition of cell proliferation. A4 cells were obtained by retroviral infection with virions containing a tetracycline-regulated antisense AS3 construct. Vector-driven expression of antisense-AS3 blocked the induction of androgen-induced endogenous AS3 mRNA and blocked the inhibitory effect of androgens on cell proliferation. Tetracycline-regulated expression of the empty vector control had no effect on cell proliferation. These experiments strongly suggest that AS3 is a mediator of the androgen-induced proliferative shutoff.


Assuntos
Androgênios/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Próstata/patologia , Fatores de Transcrição , Sequência de Aminoácidos , Núcleo Celular/efeitos dos fármacos , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , DNA Antissenso , DNA Complementar , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Biblioteca Gênica , Humanos , Masculino , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas Repressoras/metabolismo , Tetraciclina/farmacologia , Transativadores/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transfecção , Células Tumorais Cultivadas
14.
J Steroid Biochem Mol Biol ; 72(3-4): 89-102, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10775800

RESUMO

Hormone manipulation has been used for several decades with the purpose of inducing breast cancer regression. On the one hand, hormone ablation and antiestrogen administration were used on the rationale that estrogens induce proliferation of their target cells. Before the advent of the antiestrogen tamoxifen, on the other hand, the estrogen agonist DES was used to obtain clinical remissions. The rationale for the use of diethylstilbestrol (DES) was totally empirical. In fact, the efficacy of both treatments was comparable. A mechanistic explanation for estrogen-induced regression is urgently needed in order to provide a rationale for its use in therapeutic fields, and to develop markers to identify this phenotype in order to recognize responsive tumors. In this report, we use E8CASS cells (a MCF7 variant) as a model to study estrogen-mediated regression. The proliferation rate of E8CASS cells is decreased by estrogens. In order to isolate mRNA sequences induced by estradiol, a subtracted library was prepared from E8CASS cells grown in the presence and absence of estrogens. Twenty nine differentially expressed unique sequences were found. Seven of them were homologous to known genes, 12 of them were homologous to expressed sequence tags (EST), and 10 sequences had no homologues in the databases. The two sequences showing the highest induction by estradiol (E9 and E43) were chosen for further analysis. The sequence of the E43 coding region has 96% homology to the bovine actin2 gene and 100% identity to bovine actin2 protein, and it is homologous to the human actin-related protein 3 (Arp3). It has been suggested that Arp3 is involved in actin nucleation. The phenotype of E8CASS cells is clearly affected by estrogen treatment. It is likely that E43 may be involved in these morphological changes. The E9 cDNA is a putative zinc-finger protein of the PHD family of transcriptional transactivators. A member of this family, Requiem, is involved in apoptosis. The E9 mRNA is highly expressed in E8CASS cells treated with estrogens, a treatment which results in decreased proliferation rate and increased DNA degradation. This correlation suggests that E9 may be a mediator of estrogen-induced regression of breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estradiol/farmacologia , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Actinas/genética , Sequência de Aminoácidos , Animais , Apoptose/genética , Sequência de Bases , Neoplasias da Mama/metabolismo , Bovinos , Divisão Celular/efeitos dos fármacos , Primers do DNA/genética , DNA Complementar/genética , DNA de Neoplasias/genética , Feminino , Expressão Gênica , Biblioteca Gênica , Humanos , Dados de Sequência Molecular , Neoplasias Hormônio-Dependentes/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Homologia de Sequência de Aminoácidos , Células Tumorais Cultivadas
15.
Mol Carcinog ; 29(4): 205-11, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11170258

RESUMO

The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century. In brief, it proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are that (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence. These two premises have recently been contradicted by evidence. Supporters of the theory have dealt with these lacks of fit by incorporating ad hoc explanations similar to the use of epicycles in pre-Copernican astronomy. We propose the adoption of an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are that (1) proliferation is the default state of all cells and (2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens would act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the "morphogenetic fields" of developing organisms). Stroma appears as the primary target of carcinogens. Carcinogenesis and neoplasia occur entirely through emergent (supracellular) phenomena. Neoplastic cells may be reprogrammed to behave like "normal" cells within normal tissues. We argue that it is necessary to abandon the somatic mutation theory. Researchers will then become free to adopt alternative reliable premises to build a theory that explains carcinogenesis as another outcome, aberrant as it may be, of biological organization.


Assuntos
Mutação , Neoplasias/genética , Animais , Carcinógenos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Humanos , Mutagênicos/farmacologia , Neoplasias/etiologia , Neoplasias/patologia , Fenótipo , Teratogênicos/farmacologia
16.
Environ Health Perspect ; 107 Suppl 1: 89-108, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10229711

RESUMO

The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds--tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p'-DDT, p,p'-DDE, endosulfan, chlomequat chloride, and ethanol--varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods.


Assuntos
Poluentes Ambientais/toxicidade , Estrogênios/toxicidade , DDT/toxicidade , Estradiol/análogos & derivados , Estradiol/farmacologia , Estrogênios/metabolismo , Etanol/toxicidade , Fulvestranto , Humanos , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Células Tumorais Cultivadas , Vitelogeninas/biossíntese
17.
J Steroid Biochem Mol Biol ; 68(1-2): 41-50, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10215036

RESUMO

In the prostate gland cell numbers are regulated by androgens through three separate pathways: (a) inhibition of cell death (apoptosis), (b) induction of cell proliferation (step 1), and (c) inhibition of cell proliferation (step 2, proliferative shutoff). The precise regulation of these control pathways is still elusive. The human prostate carcinoma LNCaP cell line variants express a subset of proliferative pathways comparable to those present in normal prostate cells (LNCaP-FGC expresses both steps, LNCaP-LNO expresses step 2, LNCaP-TAC expresses step 1, LNCaP-TJA expresses neither). The purpose of the present work is to identify the genes involved in the androgen-induced proliferative arrest of these cells. Using a Wang-Brown subtracted library, a set of shutoff specific genes has been isolated. One of these new genes, AS3, shows high expression in the early regulatory phase of androgen-induced proliferative shutoff in the cell variants and in the prostates of castrated rats. The putative 1391-residue polypeptide has the molecular size of about 186 kDa. It has coiled-coil structures that usually participate in protein-protein interactions, a perfect leucine-zipper that suggests DNA binding, nuclear localization motifs, proline- and serinerich domains, unique C-terminal acidic-basic repeats, and ATP- and DNA-binding motifs. The transcript has 34 exons in a 200,000 bp region on chromosome 13q12-q13, downstream of the breast cancer susceptibility gene BRCA2, and centromeric to the retinoblastoma (Rb1) locus. This area is subject to frequent allelic losses in cancers, and is believed to carry a number of cryptic suppressor genes. The AS3 gene seems to be a novel candidate in the regulation of androgen-induced proliferative arrest of human prostate cells.


Assuntos
Androgênios/farmacologia , Genes Supressores de Tumor , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Sequência de Aminoácidos , Animais , Proteína BRCA2 , Sequência de Bases , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 13/genética , DNA Complementar/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes do Retinoblastoma , Humanos , Masculino , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/patologia , Ratos , Sequências Repetitivas de Aminoácidos , Fatores de Transcrição/genética , Células Tumorais Cultivadas
18.
J Med Food ; 2(3-4): 139-42, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-19281365
19.
J Steroid Biochem Mol Biol ; 65(1-6): 143-50, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9699867

RESUMO

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 microg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.


Assuntos
Androgênios , Poluentes Ambientais , Estrogênios , Antagonistas de Hormônios , Mimetismo Molecular , Antagonistas de Androgênios , Antagonistas de Estrogênios , Feminino , Humanos , Masculino
20.
Adv Exp Med Biol ; 444: 9-23; discussion 23-8, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-10026930

RESUMO

Substantial evidence has surfaced on the hormone-like effects of many xenobiotics in fish, wildlife and humans (Colborn et al., 1993). The endocrine and reproductive effects of xenobiotics are believed to be due to their 1) mimicking the effects of endogenous hormones such as estrogens and androgens, 2) antagonizing the effects of normal, endogenous hormones, 3) altering the pattern of synthesis and metabolism of natural hormones, and 4) modifying the hormone receptor levels. Estrogen mimics (xenoestrogens) are among the environmental chemicals found to cause reproductive impairment in wildlife and humans. All of these compounds were found to be estrogenic long after they had been released into the environment. A single causal agent can be identified in cases in which humans have had occupational exposures, whereas in cases where wildlife have shown signs of reproductive damage the exposure is usually a combination of endocrine disruptors that may have acted cumulatively. It has been hypothesized that environmental estrogens may play a role in the decrease of human semen quantity and quality of human semen during the last 50 years. They may also be partly responsible for the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. Testing this hypothesis will require: 1) the identification of xenoestrogens among the chemicals present in the environment, 2) the development of a methodology to assess the interactions among mixtures of xenoestrogens to which humans are exposed, and 3) the discovery of markers of estrogen exposure. The development of fast and sensitive bioassays is central to the achievement of these three goals.


Assuntos
Antagonistas de Androgênios/análise , Androgênios/análise , Antagonistas de Estrogênios/análise , Estrogênios/análise , Animais , Bioensaio , Divisão Celular , Humanos , Ensaio Radioligante , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo
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