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1.
Aquat Toxicol ; 227: 105586, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882451

RESUMO

Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.


Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Estrogênios/metabolismo , Hepatócitos/efeitos dos fármacos , Testosterona/toxicidade , Truta/metabolismo , Poluentes Químicos da Água/toxicidade , Androgênios/metabolismo , Animais , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/genética , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Cultura Primária de Células , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Poluentes Químicos da Água/metabolismo
2.
Ecotoxicol Environ Saf ; 204: 111068, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32745784

RESUMO

Herein, eight common endocrine disrupting chemicals (EDCs) were exposed to zebrafish (Danio rerio) to investigate the relationship between different EDCs and their activated estrogen receptors. Under acute exposure, we identified five major malformation types whose incidence and deformity modes differed among EDCs. Luciferase analysis divided the EDC receptors into four categories: (i) triclosan (TCS), 17ß-estradiol (E2) and estriol (E3) mainly activated GPER expression; (ii) bisphenol A (BPA), p-(tert-octyl) phenol (POP), 17α-ethynylestradiol (EE2), E2 and E3 activated ERß expression; (iii) E2 and E3 acted on both GPER and ERß; and (iv) estrone (E1) and 9,9-bis(4-hydroxyphenyl)fluorene (BHPF) had little effect on the two receptors. In vivo immunofluorescence experiments on 96-hpf larvae provided evidence that TCS and POP acted on GPER and ERß, respectively, while E2 acted on the two receptors simultaneously. Luciferase activities in the promoter regions of gper (-986 to -488) and erß (-1998 to -1496) were higher than those in other regions, identifying these key regions as targets for transcription activity. TCS promoted GPER expression by acting on the JUND transcription factor, while POP promoted ERß expression by activating the Foxl1 transcription factor. In contrast, E2 mainly regulated transcription of GPER and ERß by Arid3a. These findings provide compelling evidence that different EDCs possess varying estrogen receptors, leading to differential regulatory pathways and abnormality symptoms. These results offer an experimental strategy and fundamental information to assess the molecular mechanisms of EDC-induced estrogen effects.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Receptor beta de Estrogênio/metabolismo , Fenóis/toxicidade , Receptores Acoplados a Proteínas-G/metabolismo , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Compostos Benzidrílicos/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Disruptores Endócrinos/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Fenóis/metabolismo , Poluentes Químicos da Água/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(29): 17166-17176, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632016

RESUMO

Signaling of 17ß-estradiol (estrogen) through its two nuclear receptors, α and ß (ERα, ERß), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERß-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERß-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERß-specific signaling in TGF-ß-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERß, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERß was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERß normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.


Assuntos
Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Inflamação/imunologia , Intestinos/imunologia , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Animais , Doença de Crohn/imunologia , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Glucocorticoides/metabolismo , Humanos , Ileíte/patologia , Doenças Inflamatórias Intestinais/imunologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
4.
Arch Biochem Biophys ; 689: 108458, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524997

RESUMO

Our previous studies showed that silibinin promoted activation of caspases to induce apoptosis in human breast cancer MCF-7 cells by down-regulating the protein expression level of estrogen receptor (ER) α and up-regulating ERß. Recently, it has been reported that silibinin-induced apoptosis also involved nuclear translocation of apoptosis-inducing factor (AIF). Here we report that silibinin induces nuclear translocation of AIF through the down-regulation of ERα and up-regulation of ERß in a concentration dependent manner in MCF-7 cells. AIF knockdown with siRNA significantly reverses silibinin-induced apoptosis. The nuclear translocation of AIF is enhanced by treatment with MPP, an ERα antagonist, and blocked with PPT, an ERα agonist. In contrast to ERα activity, the nuclear AIF is increased with an ERß agonist, DPN and blocked with an ERß antagonist, PHTPP. Autophagy, negatively regulated by ERα, positively controls AIF-mediated apoptosis, as evidenced by the preventive effect of autophagy inhibitor 3-MA and siRNA targeting LC3, on the nuclear translocation of AIF and cell death induced by silibinin co-treatment with or without MPP. In sum we conclude that AIF in nuclei is involved in silibinin-induced apoptosis, and the nuclear translocation of AIF is increased by down-regulated ERα pathway and/or up-regulated ERß pathway in MCF-7 cells, accompanying up-regulation of autophagy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fator de Indução de Apoptose/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Silibina/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Feminino , Humanos , Células MCF-7
5.
Am J Physiol Endocrinol Metab ; 319(1): E81-E90, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396496

RESUMO

We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17ß-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERß, inhibited Efna5 and gonadotropin-releasing hormone 1 (Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.


Assuntos
Efrina-A5/metabolismo , Receptor alfa de Estrogênio/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Hormônio Luteinizante/metabolismo , Precursores de Proteínas/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Efrina-A5/efeitos dos fármacos , Efrina-A5/genética , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Feminino , Hormônio Liberador de Gonadotropina/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hormônio Luteinizante/efeitos dos fármacos , Oligopeptídeos/farmacologia , Ovariectomia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Precursores de Proteínas/efeitos dos fármacos , Ratos , Receptor EphA7/genética , Receptor EphA7/metabolismo , Receptor EphA7/farmacologia , Proteínas Recombinantes
6.
PLoS One ; 15(5): e0226057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413024

RESUMO

Estrogen receptor ß (ERß) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERß, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERß is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERß and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERß. Transcriptomic analysis indicated relatively few changes in gene expression with ERß overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERß activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERß. These findings suggest that ERß-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERß in PCa.


Assuntos
Receptor beta de Estrogênio/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Benzopiranos/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/agonistas , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Masculino , Receptores Androgênicos/genética , Transdução de Sinais , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo
7.
Chemosphere ; 254: 126819, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32334263

RESUMO

Bisphenol A (BPA) is a synthetic xenoestrogen diffused worldwide. Humans are chronically exposed to low doses of BPA from food and drinks, thus BPA accumulates in tissues posing human health risk. In this study, we investigated the effects of BPA on peripheral blood mononuclear cells (PBMC) from human healthy donors, and in glia and microglia of rat offspring at postnatal day 17 (17PND) from pregnant females who received BPA soon after coupling and during lactation and weaning. Results indicated that BPA affected Phytoemagglutinin (PHA) stimulated PBMC proliferation causing an S-phase cell cycle accumulation at nanomolar concentrations while BPA was almost ineffective in resting PBMC. Furthermore, BPA induced chromosome aberrations and the appearance of shattered cells characterized by high number of fragmented and pulverized chromosomes, suggesting that the compound could cause a massive genomic rearrangement by inducing catastrophic events. The BPA-induced DNA damage was observed mainly in TCD4+ and TCD8+ subsets of T lymphocytes and was mediated by the increase of ERK1/2 phosphorylation, p21/Waf1 and PARP1 protein expression. Intriguingly, we observed for the first time that BPA-induced effects were associated to a sex specific modulation of ERα and ERß in human PBMC. Immunofluorescence analysis of rat hippocampus corroborated in vitro findings showing that BPA induced É£H2AX phosphorylation in microglia and astrocytosis by decreasing ERα expression within the dentate gyrus. Overall these results suggest that BPA can alter immune surveillance functions at both peripheral and central level with a potential risk for cancer, neuroinflammation and neurodegeneration.


Assuntos
Compostos Benzidrílicos/toxicidade , Dano ao DNA , Fenóis/toxicidade , Animais , Ciclo Celular , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Proteína Quinase 3 Ativada por Mitógeno , Fosforilação , Gravidez , Ratos
8.
Orv Hetil ; 161(14): 532-543, 2020 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-32223415

RESUMO

Colorectal cancer (CRC) is one of the most common types of cancers worldwide. The incidence of sporadic CRC is lower in individuals below 50 years and increases with age, furthermore, it shows typical clinical, macroscopic and molecular differences between females and males. According to the results of epidemiological and molecular biology studies, the estradiol-regulating signaling pathway plays an important role in the development and prognosis of CRC, predominantly through estrogen receptor beta (ERß), which is dominant in the colonic epithelium. Estradiol has multiple gastrointestinal effects, which were confirmed by in vitro and in vivo studies on histologically intact and cancerous cells as well. In contrast to estrogen receptor alpha (ERα), the activation of ERß inhibits cell proliferation and enhances apoptosis, nevertheless, the expression of estrogen receptor beta can change both during physiological ageing and in colorectal disorders. The ERß-mediated antitumour effects of estradiol may be exerted through inhibition of cell proliferation, stimulation of apoptosis, inhibition of metastasis formation and its anti-inflammatory activity. Based on the results of cell culture and animal studies, selective modulators of estrogen receptor beta (selective estrogen receptor modulator [SERM]) and phytoestrogens can be new, additional therapeutic options in the treatment of colorectal diseases characterized by chronic inflammation and uncontrolled cell proliferation. Orv Hetil. 2020; 161(14): 532-543.


Assuntos
Neoplasias Colorretais/metabolismo , Estrogênios/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32141511

RESUMO

Over the entire reproductive lifespan in mammals, a fixed number of primordial follicles serve as the source of mature oocytes. Uncontrolled and excessive activation of primordial follicles can lead to depletion of the ovarian reserve. We observed that disruption of estrogen receptor ß (ESR2) signaling results in increased activation of primordial follicles in Esr2-null (Esr2-/-) rats. However, follicle assembly was unaffected, and the total number of follicles remained comparable between neonatal wild-type and Esr2-/- ovaries. While the activated follicle counts were increased in Esr2-/- ovary, the number of primordial follicles were markedly decreased. Excessive recruitment of primordial follicles led to premature ovarian senescence in Esr2-/- rats and was associated with reduced levels of serum AMH and estradiol. Disruption of ESR2 signaling through administration of a selective antagonist (PHTPP) increased the number of activated follicles in wildtype rats, whereas a selective agonist (DPN) decreased follicle activation. In contrast, primordial follicle activation was not increased in the absence of ESR1, indicating that the regulation of primordial follicle activation is ESR2 specific. Follicle activation was also increased in Esr2 mutants lacking the DNA binding domain, suggesting a role for the canonical transcriptional activation function. Both primordial and activated follicles express ESR2, suggesting a direct regulatory role for ESR2 within these follicles. We also detected that loss of ESR2 augmented the activation of AKT, ERK, and mTOR pathways. Our results indicate that the lack of ESR2 upregulated both granulosa and oocyte factors, which can facilitate AKT and mTOR activation in Esr2-/- ovaries leading to increased activation of primordial follicles.


Assuntos
Hormônio Antimülleriano/sangue , Estradiol/sangue , Receptor beta de Estrogênio/genética , Folículo Ovariano/metabolismo , Reserva Ovariana/fisiologia , Animais , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Alvo Mecanístico do Complexo 1 de Rapamicina , Nitrilos/farmacologia , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Transdução de Sinais/efeitos dos fármacos
10.
Toxicology ; 436: 152428, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32151602

RESUMO

The increase in human infertility prevalence due to male reproductive disorders has been associated with extensive endocrine-disrupting chemical (EDC) exposure. Acrylamide (AA) is a compound formed spontaneously during heat processing of some foods that are mainly consumed by children and adolescents. In this study, we evaluated the prepubertal AA exposure effects on male adult reproductive physiology using a prepubertal experimental model to analyze the pubertal development, spermatogenesis hormones levels and genes expression involved in male reproductive function. This study is the first one to use the validated protocol to correlate the AA exposure with puberty development, as well as the AA-induced endocrine disrupting effects on reproductive axis. AA did not affect the age at puberty, the reproductive organ's weight and serum hormonal levels. AA reduces spermatogenesis, induces morphological and functional defects on sperm and alters transcript expression of sexual hormone receptors (Ar and Esr2), the transcript expression of Tnf, Egr2, Rhcg and Lrrc34. These findings suggest that excessive AA consumption may impair their reproductive capacity at adulthood, despite no changes in hormonal profile being observed.


Assuntos
Acrilamida/toxicidade , Disruptores Endócrinos/toxicidade , Contaminação de Alimentos , Infertilidade Masculina/induzido quimicamente , Desenvolvimento Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Fatores Etários , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Relação Dose-Resposta a Droga , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Medição de Risco , Espermatozoides/metabolismo , Espermatozoides/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Cardiovasc Drugs Ther ; 34(2): 165-178, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157565

RESUMO

PURPOSE: Oestrogen receptor ß is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor ß activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway. METHODS: Male C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor ß and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function. RESULTS: DPN-mediated oestrogen receptor ß activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor ß activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor ß activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor ß activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered. CONCLUSIONS: All of these new findings indicate that oestrogen receptor ß activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.


Assuntos
Receptor beta de Estrogênio/agonistas , Estrogênios/farmacologia , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Nitrilos/farmacologia , Receptor Notch1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Receptor beta de Estrogênio/metabolismo , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
12.
Arch Esp Urol ; 73(2): 119-125, 2020 Mar.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32124842

RESUMO

OBJECTIVES: This prospective study aimed to investigate the expression of the androgen receptor(AR) and the estrogen receptor-ß (ER-ß) in foreskint issues in boys with and without distal hypospadias. METHODS: Thirty boys with distal hypospadias were evaluated. Fifteen boys who under went elective circumcision over a period of 18 months served as the control group. The presence of AR and ER-ß in foresk in tissues was investigated immunohistochemically. RESULTS: The percentages of AR in epithelial cells were18.9 ± 27.3% in the hypospadias group and 3.3 ±5.3% in the circumcision group, and the difference betweent he groups was significant (p=0.034). Of the stromal cells, 19.5 ± 26.8% in the hypospadias group and2.6 ± 4.4% in the circumcision group were positive lystained for AR (p=0.004). In the hypospadias group,significantly higher stromal cell percentage of ER-ß was found compared to that in the control group (24± 24.5% and 1.3 ± 1.1%, respectively, p<0.001). Moreover, epithelial cell percentage of ER-ß was higher in the hypospadias group than that in the control group,and the respective values were 6.8 ± 10.1% and 0.9± 1.3% (p<0.0001)CONCLUSION: The percent of AR and ER-ß expression were higher in hypospadias-affected foresk in than in the normal foreskin. Whether the normal function of these receptors reveals, there is a need for more detailed studies.


Assuntos
Receptor beta de Estrogênio , Prepúcio do Pênis , Hipospadia , Receptores Androgênicos , Receptor beta de Estrogênio/metabolismo , Prepúcio do Pênis/metabolismo , Humanos , Hipospadia/metabolismo , Masculino , Estudos Prospectivos , Receptores Androgênicos/metabolismo , Receptores Estrogênicos
13.
Gene ; 740: 144535, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32156529

RESUMO

Many human epidemiology and animal model studies have reported that bisphenol A (BPA) exerts adverse effects on reproduction through different regulatory mechanisms and signaling pathways in adults. In recent years, the exposure risk has increased for the general population, and little is known about how BPA affects ovarian development in adolescent animals and humans. In the present study, we aimed to investigate the effects of BPA exposure on ovarian development and the transcriptome in adolescent mice. Four-week-old ICR female mice were randomly divided into two groups and orally administered BPA (200 ng/kg/day) by gavage for 4 weeks. The BPA and estrogen (E2) levels in sera from the two groups were subsequently determined by using enzyme-linked immunosorbent assays (ELISAs). An immunohistochemical study showed that several obvious ovarian structural and developmental abnormalities were observed in the treatment group with changes in the E2 receptor gene and protein expression levels. A total of 4266 differentially expressed genes (DEGs) were identified, and the possible functions of these DEGs were explored by bioinformatics analyses based on the RNA-Seq data. The two most significant expression profiles were identified by Short Time-series Expression Miner (STEM) software, and the genes in these two profiles were enriched in actin filament-based processes, behaviour and membrane potential regulation according to Gene Ontology (GO) enrichment analysis. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEGs are particularly involved in the endocrine system, the calcium and cAMP signaling pathways.


Assuntos
Compostos Benzidrílicos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Fenóis , Maturidade Sexual/efeitos dos fármacos , Animais , Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/toxicidade , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/sangue , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Camundongos , Ovário/ultraestrutura , Fenóis/sangue , Fenóis/metabolismo , Fenóis/toxicidade
14.
Arch. esp. urol. (Ed. impr.) ; 73(2): 119-125, mar. 2020. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-192906

RESUMO

OBJECTIVES: This prospective study aimed to investigate the expression of the androgen receptor(AR) and the estrogen receptor-β (ER-β) in foreskint issues in boys with and without distal hypospadias. METHODS: Thirty boys with distal hypospadias were evaluated. Fifteen boys who under went elective circumcision over a period of 18 months served as the control group. The presence of AR and ER-Beta in foresk in tissues was investigated immunohistochemically. RESULTS: The percentages of AR in epithelial cells were18.9 ± 27.3% in the hypospadias group and 3.3 ±5.3% in the circumcision group, and the difference betweent he groups was significant (p = 0.034). Of the stromal cells, 19.5 ± 26.8% in the hypospadias group and2.6 ± 4.4% in the circumcision group were positive lystained for AR (p = 0.004). In the hypospadias group,significantly higher stromal cell percentage of ER-β was found compared to that in the control group (24 ± 24.5% and 1.3 ± 1.1%, respectively, p < 0.001). Moreover, epithelial cell percentage of ER-β was higher in the hypospadias group than that in the control group,and the respective values were 6.8 ± 10.1% and 0.9 ± 1.3% (p < 0.0001). CONCLUSION: The percent of AR and ER-Beta expression were higher in hypospadias-affected foresk in than in the normal foreskin. Whether the normal function of these receptors reveals, there is a need for more detailed studies


OBJETIVO: Este estudio prospectivo que pretende investigar la expresión del receptor androgénicoy estrogénico en la piel prepucial en niños con y sin hipospadias distal. MÉTODOS: Treinta niños con hipospadias distal fueron evaluados. 15 niños recibieron una circuncisión electiva en un periodo de 18 meses y sirvieron de grupo control.La presencia de RA y RE-Beta en la piel prepucial se investigó por immunohistoquimica. RESULTADOS: El porcentaje de expresión del receptor androgenico en células epiteliales fue de 18,9 +/- 27,3% en el grupo hipospadias y 3,3 +/- 5,3% en el grupo de circuncisión. La diferencia entre ambos grupos fue significativo (p = 0,034). En las células estromales,19,5 +/- 26,8% en el grupo hipospadias y 2,6+/-4,4% en el grupo circuncisión fueron positivos para el RA (p = 0,004). En el grupo de hipospadias, un porcentaje más elevdo de expresión de RE-b β se evidencio en comparación al grupo control (24 +/- 24,5%y 1,3 +/- 1,1, respectivamente, pel porcentaje de células epiteliales con RE-Beta fue superior en el grupo hipospadias que en el grupo control; los valores respectivos fueron 6,8 +/- 10,1% y 0,9 +/- 1,3%(p < 0,0001). CONCLUSIÓN: En este estudio se sugiere que la expresiónde RA y RE fueron superiores en el grupo conhipospadias que en piel prepucial normal. Se requierenmas estudios para determinar el significado de esta expresión


Assuntos
Humanos , Masculino , Receptor beta de Estrogênio/metabolismo , Hipospadia/metabolismo , Receptores Androgênicos/metabolismo , Prepúcio do Pênis/metabolismo , Estudos Prospectivos , Receptores Estrogênicos
15.
Breast Cancer Res ; 22(1): 23, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075687

RESUMO

BACKGROUND: Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7-alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERß) may impact the association between 27HC and breast cancer risk. METHODS: We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-ß, and ERß and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography-mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1-negative cases, whereas a higher proportion of ERß-positive cases were Bcl-2 low, relative to ERß-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-ß, and ERß, with the exception of statistically significant heterogeneity by LXR-ß status in the subgroup of women perimenopausal at blood collection (p = 0.02). CONCLUSION: This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-ß, or ERß.


Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Hidroxicolesteróis/sangue , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Colestanotriol 26-Mono-Oxigenase/metabolismo , Família 7 do Citocromo P450/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Alemanha/epidemiologia , Humanos , Receptores X do Fígado/metabolismo , Pessoa de Meia-Idade , Tipagem Molecular/métodos , Gradação de Tumores , Avaliação Nutricional , Estudos Prospectivos , Fatores de Risco , Esteroide Hidroxilases/metabolismo
16.
FASEB J ; 34(2): 3069-3090, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908053

RESUMO

Intestinal epithelial barrier dysfunction is deeply involved in the pathogenesis of inflammatory bowel diseases (IBD). Arctigenin, the main active constituent in Fructus Arctii (a traditional Chinese medicine), has previously been found to attenuate colitis induced by dextran sulfate sodium (DSS) in mice. The present study investigated whether and how arctigenin protects against the disruption of the intestinal epithelial barrier in IBD. Arctigenin maintained the intestinal epithelial barrier function of mice with DSS- and TNBS-induced colitis. In Caco-2 and HT-29 cells, arctigenin lowered the monolayer permeability, increased TEER, reversed the abnormal expression of tight junction proteins, and restored the altered localization of F-actin induced by TNF-α and IL-1ß. The specific antagonist PHTPP or shRNA of ERß largely weakened the protective effect of arctigenin on the epithelial barrier function of Caco-2 and HT-29 cells. Molecular docking demonstrated that arctigenin had high affinity for ERß mainly through hydrogen bonds as well as hydrophobic effects, and the protective effect of arctigenin on the intestinal barrier function was largely diminished in ERß-mutated (ARG346 and/or GLU305) Caco-2 cells. Moreover, arctigenin-blocked TNF-α induced increase of the monolayer permeability in Caco-2 and HT-29 cells and the activation of myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway in an ERß-dependent manner. ERß deletion in colons of mice with DSS-induced colitis resulted in a significant attenuation of the protective effect of arctigenin on the barrier integrity and colon inflammation. Arctigenin maintained the integrity of the intestinal epithelial barrier under IBD by upregulating the expression of tight junction proteins through the ERß-MLCK/MLC pathway.


Assuntos
Receptor beta de Estrogênio/agonistas , Furanos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Lignanas/farmacologia , Animais , Células CACO-2 , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mutação de Sentido Incorreto , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Am J Physiol Lung Cell Mol Physiol ; 318(1): L112-L124, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617730

RESUMO

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERß, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]i regulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα agonist (PPT) increased [Ca2+]i response to histamine, whereas ERß activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERß activation was more effective than 17ß-estradiol in reducing [Ca2+]i responses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERß were mediated partially via L-type calcium channel inhibition and increased Ca2+ sequestration by sarcoplasmic reticulum. Overall, these data highlight the differential signaling of ERα and ERß in ASM during inflammation. Specific ERß activation reduces [Ca2+]i in the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.


Assuntos
Asma/metabolismo , Cálcio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Miócitos de Músculo Liso/metabolismo , Broncoconstrição/fisiologia , Linhagem Celular , Estradiol/metabolismo , Estrogênios/metabolismo , Humanos , Interleucina-13/metabolismo , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Sistema Respiratório/metabolismo , Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
18.
Mol Cell Biochem ; 463(1-2): 161-173, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31595422

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia, which characterized by toxic senile plaques is composed of amyloid-ß (Aß). ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting protease in Aß generation. Therefore, pharmacology BACE1 inhibition is one of the prime targets for potential treatment of AD. Curcumin, a yellow polyphenol derived from the rhizomes of the plant Curcuma longa Linn, has been reported to cross the blood-brain barrier and prevent Aß aggregation in AD models. However, its neuroprotective mechanism is still unclear. In the present study, we find that curcumin markedly reduces Aß levels in HEK293-APPswe cells. Our results show that curcumin inhibits BACE1 gene expression in SH-SY5Y cells at transcriptional and translational levels. Furthermore, we reveal that nuclear factor kappa B (NFκB) signaling is involved in the regulation of curcumin on BACE1. Interestingly, the estrogenicity of curcumin is found to partially contribute to its protective action. Our data show that curcumin activates estrogen receptor ß (ERß) selectively and the activation of ERß directly effects on the upstream factors of the NFκB signaling pathway. The above results indicate that curcumin reduces BACE1 expression through ERß and NFκB pathway, providing a novel mechanism for curcumin as a candidate for AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Curcumina/farmacologia , Receptor beta de Estrogênio/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , Linhagem Celular Tumoral , Receptor beta de Estrogênio/genética , Células HEK293 , Humanos , NF-kappa B/genética , Transdução de Sinais/genética
19.
Eur J Pharmacol ; 869: 172887, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31877277

RESUMO

Pseudoprotodioscin (PPD), a phytoestrogen isolated from Dioscorea nipponica Makino, is recognized to possess anti-inflammatory and antiadipogenic capacities. However, little is known about the antiatherosclerotic effects of PPD and the underlying mechanisms. Here, the contribution of estrogen receptors (ERs) and inflammation to PPD-mediated amelioration of endothelial dysfunction has been fully assessed. PPD administration alleviated atherosclerotic lesions by lowering total cholesterol in ovariectomized apoE-/- mice fed a high-cholesterol diet. Molecular docking analysis suggested a selective interaction of PPD with ERα. Upon PPD treatment, ERα and endothelial nitric oxide synthase (eNOS) protein levels were increased, whereas cell adhesion molecule and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were suppressed in human umbilical vein endothelial cells (HUVECs) after injury caused by oxidized low-density lipoprotein (ox-LDL). These effects could be abolished by an ERα antagonist or a NOS inhibitor. Whereas, PPD can ERα-independently suppress TNFα expression in peritoneal macrophages upon LPS induction. Estrogen deficiency induced inflammatory phenotypes in perivascular adipose tissue (PAT), which could be partially attenuated by PPD. The increased release of adiponectin in PAT after PPD treatment is in accordance with previous reported data showing that adiponectin exerts anti-inflammatory effects in multiple cell types. ERα-dependent antiadipogenic effects of PPD were also detected in PAT-derived stromal cells. The present study reveals a novel mechanism through which PPD exerts estrogenic and anti-inflammatory properties in atherosclerosis-prone mice. Thus, PPD is a promising compound which has potential therapeutic effects on atherosclerotic cardiovascular diseases in postmenopausal women.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Diosgenina/análogos & derivados , Estrogênios/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Apoptose/efeitos dos fármacos , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Células Cultivadas , Quimiocina CCL2/genética , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Malondialdeído/metabolismo , Camundongos Knockout para ApoE , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo III/metabolismo , Pós-Menopausa , Fator de Necrose Tumoral alfa/metabolismo
20.
Ecotoxicol Environ Saf ; 188: 109918, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31753310

RESUMO

Hormonal regulation controls mammary gland (MG) development. Therefore some hormone-related factors can disrupt the early phases of MGs development, making the gland more susceptible to long term modifications in its response to circulating hormones. Endocrine disruptors, such as bisphenol A (BPA), are able to cause alterations in hormone receptor expression, leading to changes in the cell proliferation index, which may expose the tissue to neoplastic alterations. Thus, we evaluated the variations in hormone receptor expression in the MG of 6-month old Mongolian gerbils exposed to BPA and 17ß estradiol during the perinatal period. Receptors for estrogen alpha (ERα), beta (ERß), progesterone (PGR), prolactin (PRL-R), and co-localization of connexin 43 (Cx43) and ERα in gerbils were analyzed, and serum concentrations of estradiol and progesterone were assessed. No alterations in body, liver, and ovary-uterus complex weights were observed. However, there was an increase in epithelial ERα expression in the 17ß estradiol (E2) group and in PGR in the BPA group. Although immunohistochemistry did not show alterations in ERß expression, western blotting revealed a decrease in this protein in the BPA group. PRL-R was more present in epithelial cells in the vehicle control (VC), E2, and BPA groups in comparison to the intact control group. Cx43 was more frequent in E2 and BPA groups, suggesting a protective response from the gland against possible malignancy. Serum concentration of estradiol reduced in VC, E2, and BPA groups, confirming that alterations also impacts steroid levels. Consequently, perinatal exposure to BPA and the reference endogenous estrogen, 17ß estradiol, are able to increase the tendency of endocrine disruption in MG in a long term manner, since repercussions are observed even 6 months after exposure.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estradiol/toxicidade , Glândulas Mamárias Animais/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Gerbillinae , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
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