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1.
Chemosphere ; 258: 127361, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947662

RESUMO

In female mammals, puberty and fertility are regulated by the synthesis of estradiol (E2) by the ovaries at the infantile stage and at the approach of puberty, a process which may be affected by endocrine disrupting chemicals (EDC)s acting through the Aryl hydrocarbon receptor (AhR). However, there is no information on AhR-mediated regulation of ovarian estrogenic activity during these developmental periods. Here, we assessed in mouse models, the intrinsic and exogenous ligand-induced AhR action on E2 synthesis at the infantile stage (14 days postnatal (dpn)) and at the approach of puberty (28 dpn). Intrinsic AhR pathway became activated in the ovary at the approach of puberty, as suggested by the decreased intra-ovarian expression in prototypical and steroidogenesis-related AhR targets and E2 contents in Ahr knockout (Ahr-/-) mice versus Ahr+/+ mice exclusively at 28 dpn. Accordingly, AhR nuclear localization in granulosa cells, reflecting its activity in cells responsible for E2 synthesis, was much lower at 14 dpn than at 28 dpn in C57BL/6 mice. However, AhR signaling could be activated by exogenous ligands at both ages, as revealed by FICZ- and TCDD-induced Ahrr and Cyp1a1 expression in C57BL/6 mice. Nevertheless, TCDD impacted ovarian estrogenic activity only at 28 dpn. This age-related AhR action may be ligand-dependent, since FICZ had no effect on E2 synthesis at 28 dpn. In conclusion, AhR would not regulate ovarian estrogenic activity before the approach of puberty. Its activation by EDCs may be more detrimental to reproductive health at this stage than during infancy.


Assuntos
Ovário/fisiologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Citocromo P-450 CYP1A1/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Estrogênios/farmacologia , Feminino , Células da Granulosa/efeitos dos fármacos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Dibenzodioxinas Policloradas/metabolismo , Maturidade Sexual/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 11(1): 4642, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934200

RESUMO

Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Glândulas Mamárias Animais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem da Célula , Metilação de DNA , Proteínas de Ligação a DNA/genética , Sistema Endócrino/metabolismo , Epigênese Genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética
3.
Ecotoxicol Environ Saf ; 205: 111338, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956867

RESUMO

Lead (Pb) is well-recognized for its great hazards to human and wildlife health. It has negative influences on multiple organs and systems of birds. Especially, lead exposure caused adverse impacts on bird reproduction. In this study, one week old female Japanese quails were randomly allocated into four groups and each group was respectively fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb in drinking water for 36 days to determine the effects of chronic lead exposure on ovarian development and function. The results showed that Pb did accumulate in the ovary and ovarian development was delayed by high dose lead exposure (500 ppm and 1000 ppm). Moreover, high Pb dosage induced ovarian histopathological damages characterized by granulosa cells disorganization, follicle atresia and interstitial cell degeneration. Meanwhile, the concentration of estradiol (E2) was significantly decreased and mRNA levels of genes involved with ovarian steroidogenesis were significantly down-regulated by high concentration Pb. In addition, Pb exposure caused increasing cell apoptosis and significant changes of the expression of genes involved with cell death in the ovary. High dose Pb exposure also inhibited thyroid hormone release and disrupted ovarian thyroid deiodination apart from causing thyroid histopathological injury such as follicular deformation and atrophy. The study indicated that Pb might cause ovarian malfunction by inducing ovary and thyroid microstructural damages, thyroid hormone and estrogen release inhibition and ovarian steroidogenesis disruption.


Assuntos
Coturnix/metabolismo , Poluentes Ambientais/toxicidade , Estradiol/metabolismo , Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Ovário/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Coturnix/genética , Coturnix/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Estradiol/genética , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/patologia , Humanos , Chumbo/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovário/patologia , Distribuição Aleatória , Reprodução/efeitos dos fármacos , Reprodução/genética , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/genética
4.
Life Sci ; 259: 118383, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896555

RESUMO

AIMS: Previous studies have shown that the widespread use of estrogen preparations can cause adverse outcomes such as thrombosis and cardiovascular disease. Autophagy is a biochemical process necessary to maintain cell homeostasis. The present study investigated whether E-2 mediates autophagy-induced endothelial cell dysfunction. The role of aspirin in this process was then studied. MAIN METHODS: Western blot, fluorescence microscopy, electron transmission microscopy, plasma construction and transfection, vasoreactivity study in wire myograph are all used in this study. KEY FINDINGS: We found that E-2 activated the PI3K/mTOR signaling pathway and inhibited the formation of the Atg14L-Beclin1-Vps34-Vps15 complex, thereby inhibiting autophagy. Aspirin promoted Beclin1 phosphorylation in autophagy initiation complexes and enhanced autophagy. Furthermore, E-2 treatment of HAECs resulted in endothelial dysfunction by inhibiting autophagy and leading to accumulation of α-smooth muscle actin (α-SMA). E-2 inhibited the activation of eNOS and reduced the expression of eNOS protein. In the mouse aortic vascular function test, E-2 disrupted endothelium-dependent vasodilation. An α-SMA-shRNA lentivirus eliminated the disruption to endothelium-dependent vasodilation by E-2. Aspirin inhibited α-SMA accumulation by enhancing autophagy, reversed endothelial functional impairment caused by E-2, and promoted endothelium-dependent vasodilation. SIGNIFICANCE: This study provides new evidence that E-2 inhibits autophagy and induces abnormal accumulation of α-SMA, resulting in endothelial cell dysfunction and affecting vasodilation. Aspirin can effectively restore the endothelial cell function disrupted E-2.


Assuntos
Actinas/metabolismo , Aspirina/farmacologia , Autofagia/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estradiol/metabolismo , Proteína VPS15 de Distribuição Vacuolar/metabolismo , Animais , Western Blotting , Células Cultivadas , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Fosforilação/efeitos dos fármacos
5.
Food Chem ; 333: 127451, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32683255

RESUMO

Castration may decrease off-odors and improve meat flavor. Meat flavor is generated through complex chemical reactions that involve hydrophilic and hydrophobic flavor precursors. In this study, we investigated the flavor precursors in psoas major muscles of castrated and intact sheep using lipidomics and targeted metabolomics. Castration decreased testosterone levels and increased intramuscular fat content. Six hundred fourteen lipid molecules confirmed showed a separation between castrated and intact sheep based on principal component analysis. Fourteen lipid species and 224 lipid molecules increased in castrated sheep. Targeted metabolomics analysis showed that 18 hydrophilic metabolites were affected by castration; however, only hypoxanthine significantly increased in the castration group. Among 45 volatiles identified, 1-octen-3-ol and hexanal were significantly higher in castrated sheep. These results revealed that lipids, hydrophilic metabolites, and volatile compounds in lamb were affected by castration, which might be beneficial in lamb quality.


Assuntos
Carne , Orquiectomia , Músculos Psoas/química , Músculos Psoas/metabolismo , Carneiro Doméstico/metabolismo , Paladar , Animais , Estradiol/metabolismo , Aromatizantes/análise , Metabolismo dos Lipídeos , Lipidômica , Lipídeos/análise , Masculino , Carne/análise , Metabolômica , Odorantes/análise , Testosterona/metabolismo , Compostos Orgânicos Voláteis/análise
6.
Am J Physiol Endocrinol Metab ; 319(3): E562-E567, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726128

RESUMO

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delaying viral clearance in men as compared with women. We propose that modulating sex hormones, either by increasing estrogen or antiandrogen, may be a therapeutic option to reduce mortality from SARS-CoV-2.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/mortalidade , Hormônios Esteroides Gonadais/fisiologia , Pneumonia Viral/mortalidade , Caracteres Sexuais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mortalidade , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Fatores Sexuais , Carga Viral/efeitos dos fármacos , Carga Viral/genética
7.
Life Sci ; 257: 118078, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663577

RESUMO

This study aimed to evaluate the modulatory role of sex-related hormone estradiol on cancer stem cells with the origin of colorectal adenocarcinoma in vitro. Cancer stem cells were incubated with 100 nM estradiol for 48 h. The cell survival rate was analyzed using the MTT assay. Immunocytochemistry staining of Ki-67 and Inhibin and Apoptosis PCR array were done to measure proliferation/apoptosis. Cell migration was monitored via the Transwell Migration assay. The expression of exosome biogenesis genes was measured using a real-time PCR assay. The fatty acid profile was monitored using gas chromatography. The level of FAK, SQSTM1, ER, and SIRT1 was examined using Western blotting. Cancer stem-endothelial cell interaction was investigated using Surface Plasmon Resonance assay. Data showed no significant differences in cancer stem cell viability and proliferation between control and estradiol-treated groups (p>0.05). PCR array highlighted the up-regulation of both pro- and anti-apoptosis effectors in the treatment group compared to the control cells (p<0.05). Cell migration capacity was increased after treatment with estradiol (p<0.001). Both exocytosis and exosome biogenesis were decreased in cancer stem cells exposed to estradiol (p<0.05). Data showed the reduction of palmitic acid, and increase of Palmitoleic and Linolenic acids in estradiol-treated cells. Estrogen induced estrogen receptor, SQSTM1 proteins and decreased SIRT1 factor after 48 h. Surface Plasmon Resonance revealed the suppression of cancer stem-endothelial cell interaction and affinity. Estradiol could change the migration, juxtacrine and paracrine activities of cancer stem cells, showing the importance of sex-related hormones in the dynamic of cancer development.


Assuntos
Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Estradiol/metabolismo , Células-Tronco Neoplásicas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Estradiol/farmacologia , Células HT29 , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Estrogênicos/metabolismo
8.
Anticancer Res ; 40(6): 3097-3108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487604

RESUMO

BACKGROUND/AIM: C-C motif chemokine ligand 18 (CCL18) is overexpressed in the microenvironment of tumors, promotes invasion and metastasis and is thus important for the therapeutic outcome of many tumor entities. The Gs-coupled seven-transmembrane receptor GPR30 is known as both a CCL18 and an estrogen receptor; its activation by estradiol leads to a transactivation of membrane-tethered pro-heparin-binding EGF-like growth factor and the MAPK/ERK pathway. We examined whether this signaling pathway remains the same under CCL18 stimulation, as opposed to estradiol stimulation. MATERIALS AND METHODS: We investigated the effects of CCL18 on the lung cancer cell line A549, that show low GPR30 expression and the breast cancer cell lines MCF-7, that has high GPR30 expression and MDA-MB-231. These cells were stimulated in different media with CCL18 and then analyzed by qPCR, In-Cell Western®, western blot and ELISA. RESULTS: Many similarities on the effect of CCL18 on the already known estradiol-activated signaling pathway via the G protein-coupled estrogen receptor GPR30 were identified. GPR30 is involved in the expression of matrix metalloproteinases (MMPs), which may play a role in the transactivation of ERK-1/-2 via the cleavage of membrane-bound HB-EGF, via Src-related tyrosine kinases and Gßγ-subunits. With increasing CCL18 concentration, the expression of MMP7 decreased in A549 cells. With decreasing estrogen content of the medium, there was an increasing effect of CCL18 on the inhibition of the relative expression of MMP7. Inhibition of GPR30 with G15 also resulted in a decrease in the relative expression of MMP7, irrespective of the subsequent stimulation with CCL18. This is a rather unexpected result, because the estrogen estradiol and CCL18 both activate GPR30. MCF-7 cells which express more GPR30 did not show any dependence of the relative MMP7 expression on CCL18 except in estrogen-free FCS medium. CCL18 induced an increased relative ERK activation in In-Cell western (ICW) at A549 cells. Stimulation with CCL18 caused decreased ERK activation with simultaneous inhibition of adenylate cyclase in MCF-7. However, stimulation with CCL18 and simultaneous inhibition of cyclooxygenase in MCF-7 resulted in increased ERK activation. In A549, stimulation with CCL18 and co-incubation with dbcAMP resulted in decreased ERK activation in both ICW and Western blot. CONCLUSION: In summary, the Gs-coupled receptor GPR30 plays an important role in the signaling pathway of CCL18. CCL18 and estradiol may not lead to the same signaling pathway after activating GPR30.


Assuntos
Quimiocinas CC/metabolismo , Estradiol/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células A549 , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiocinas CC/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Metaloproteinase 7 da Matriz/biossíntese , Metaloproteinase 7 da Matriz/genética , Fosforilação , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais
9.
PLoS Genet ; 16(6): e1008601, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555663

RESUMO

Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-"resistant" disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E2) and/or progesterone (P4), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P4, E2 extensively affected the eSF DNA methylome and transcriptome. Importantly, E2 resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E2 with P4 affected a totally different landscape than E2 or P4 alone. ii) P4 responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P4-targets, leading to question the P4-"resistant" phenotype in endometriosis. Interestingly, an aberrant E2-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E2 response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction.


Assuntos
Metilação de DNA , Endometriose/genética , Epigênese Genética , Estradiol/metabolismo , Progesterona/metabolismo , Transcriptoma , Adulto , Cromatina/genética , Cromatina/metabolismo , Ilhas de CpG , Endometriose/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Progesterona/farmacologia
10.
J Steroid Biochem Mol Biol ; 202: 105722, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32565247

RESUMO

PTX3, a member of the pentraxin protein family, plays important roles in ovulation as a marker of cumulus cell-oocyte complex expansion. However, the expression and function of PTX3 in goat ovarian GCs remain unclear. We isolated GCs from small and large follicles and found that PTX3 expression was significantly decreased and miR-29 mRNA expression was significantly increased during the growth of antral follicles. MiR-29 decreased PTX3 expression by targeting its 3' untranslated. Furthermore, miR-29 promoted GC proliferation, suppressed steroidogenesis and apoptosis by targeting PTX3 via the activation of the PI3K/AKT/mTOR and Erk1/2 signaling pathways. Treatment with inhibitors also verified these results. Meanwhile, we found that PI3K/AKT/mTOR and Erk1/2 signaling pathways had different role in secretion of E2 and P4 by regulating differently various steroidogenic enzyme (CYP19A1, CYP11A1, StAR and HSD3B) expression. These outcomes indicate the potential role of PTX3 in goat follicular growth and atresia.


Assuntos
Proteína C-Reativa/metabolismo , Células da Granulosa/metabolismo , MicroRNAs/genética , Componente Amiloide P Sérico/metabolismo , Animais , Apoptose , Proteína C-Reativa/genética , Proliferação de Células , Estradiol/metabolismo , Feminino , Cabras , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Progesterona/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Componente Amiloide P Sérico/genética , Serina-Treonina Quinases TOR/metabolismo
11.
Chemosphere ; 258: 127304, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32559490

RESUMO

Humans are exposed to numerous endocrine disruptors on a daily basis, which may interfere with endogenous estrogens, with Di-(2-ethylhexyl) phthalate (DEHP) being one of the most employed. The anterior pituitary gland is a target of 17ß-estradiol (E2) through the specific estrogen receptors (ERs) α and ß, whose expression levels fluctuate in the gland under different contexts, and the ERα/ß index is responsible for the final E2 effect. The aim of the present study was to evaluate in vivo and in vitro the DEHP effects on ERα and ß expression in the pituitary cell population, and also its impact on lactotroph and somatotroph cell growth. Our results revealed that perinatal exposure to DEHP altered the ERα and ß expression pattern in pituitary glands from prepubertal and adult female rats and increased the percentage of lactotroph cells in adulthood. In the in vitro system, DEHP down-regulated ERα and ß expression, and as a result increased the ERα/ß ratio and decreased the percentages of lactotrophs and somatotrophs expressing ERα and ß. In addition, DEHP increased the S + G2M phases, Ki67 index and cyclin D1 in vitro, leading to a rise in the lactotroph and somatotroph cell populations. These results showed that DEHP modified the pituitary ERα and ß expression in lactotrophs and somatotrophs from female rats and had an impact on the pituitary cell growth. These changes in ER expression may be a mechanism underlying DEHP exposure in the pituitary gland, leading to cell growth deregulation.


Assuntos
Dietilexilftalato/toxicidade , Ácidos Ftálicos/toxicidade , Receptores Estrogênicos/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Dietilexilftalato/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Lactotrofos/efeitos dos fármacos , Lactotrofos/metabolismo , Hipófise/efeitos dos fármacos , Ratos
12.
Chemosphere ; 256: 126946, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32445993

RESUMO

Hepatocellular fibrillar inclusions (HFI) are an unusual pathology of unknown aetiology affecting European flounder (Platichthys flesus), particularly from estuaries historically impacted by pollution. This study demonstrated that the HFI prevalence range was 6-77% at several UK estuaries, with Spearman rank correlation analysis showing a correlation between HFI prevalence and sediment concentrations of ∑PBDEs and ∑HBCDs. The data showed that males exhibit higher HFI prevalence than females, with severity being more pronounced in estuaries exhibiting higher prevalence. HFI were not age associated indicating a subacute condition. Electron microscopy confirmed that HFI were modified proliferating rough endoplasmic reticulum (RER), whilst immunohistochemistry provided evidence of VTG production in HFI of male P. flesus. Despite positive labelling of aberrant VTG production, we could not provide additional evidence of xenoestrogen exposure. Gene transcripts (VTG/CHR) and plasma VTG concentrations (>1 µg ml-1), were only considered elevated in four male fish showing no correlation with HFI severity. Further analysis revealed that reproductively mature female P. flesus i.e. >3-year-old, did not exhibit HFI, whereas males of all ages were affected. This, combined with previous reports that estradiol (E2) can impair mixed function oxygenase activity, supports a hypothesis that harmful chemical metabolites (following phase 1 metabolism of their parent compounds) are potentially responsible for HFIs observed in male and ≤ 3-year-old female fish. Consequently, HFI and xenoestrogenic induced VTG production could be independent of each other resulting from different concurrent toxicopathic mechanisms, although laboratory exposures will likely be the only way to determine the true aetiology of HFI.


Assuntos
Carcinoma Hepatocelular/veterinária , Linguado/fisiologia , Neoplasias Hepáticas/veterinária , Animais , Carcinoma Hepatocelular/patologia , Poluição Ambiental , Estradiol/metabolismo , Estrogênios/metabolismo , Estuários , Feminino , Peixes , Linguado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Reino Unido , Poluentes Químicos da Água/metabolismo
13.
Poult Sci ; 99(4): 2215-2229, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241507

RESUMO

The effect of ME intake (MEI) on the reproductive system was evaluated. Ross 308 broiler breeder pullets (n = 140) were assigned to 2 treatments from 22 to 26 wk of age: (1) Low-energy diet fed restricted (2,807 kcal/kg, low MEI) and (2) high-energy diet fed unrestricted (3,109 kcal/kg, high MEI). Daylength was increased from 8 to 14 h at 22 wk of age with a light intensity of 30 lux. Daily palpation was used to detect sexual maturity via the presence of a hard-shelled egg in the shell gland. Expression of gonadotropin releasing hormone-I (GnRH) and gonadotropin inhibitory hormone (GnIH) genes in the hypothalamus and GnRH receptor (GnRH-RI) and GnIH receptor (GnIH-R) genes in the anterior pituitary gland of each pullet was evaluated from 22 to 26 wk of age using quantitative real time-PCR. Blood samples were taken weekly and luteinizing hormone (LH), follicle stimulating-hormone (FSH), and 17-beta-estradiol (E2) determined using commercial ELISA kits. Carcass samples were used for determination of CP and fat content. Data were analyzed using the MIXED procedure in SAS, and differences were reported where P ≤ 0.05. High MEI treatment pullets had 2.3-fold higher GnRH and 1.8-fold higher GnRH-RI mRNA levels than low MEI pullets. MEI affected neither expression of GnIH and GnIH-R nor carcass protein content. For high MEI (489 kcal/D) and low MEI treatments (258 kcal/D), respectively, from 22 to 26 wk of age (P ≤ 0.05), LH concentration was 3.05 and 1.60 ng/mL; FSH concentration was 145 and 89.3 pg/mL; E2 concentration was 429 and 266 pg/mL, and carcass lipid was 13.9 and 10.3%. The onset of lay for pullets in the high MEI treatment advanced such that 100% had laid by 26 wk of age compared with 30% in the low MEI treatment. We concluded that higher MEI advanced the activation of the hypothalamic-pituitary-gonadal axis and also increased body lipid deposition, and moreover, stimulated reproductive hormone levels which overall accelerated puberty in broiler breeder pullets.


Assuntos
Proteínas Aviárias/metabolismo , Galinhas/crescimento & desenvolvimento , Ingestão de Energia , Estradiol/metabolismo , Luz , Puberdade , Animais , Galinhas/metabolismo , Feminino , Gonadotropinas Hipofisárias/metabolismo , Hormônios Hipotalâmicos/metabolismo , RNA Mensageiro/metabolismo
14.
Medicina (B Aires) ; 80(2): 157-161, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32282322

RESUMO

Female sex hormones participate in the regulation of blood pressure and renal epithelial proliferation, effects not related to their reproductive function. About one-third of the world's population has abnormally high levels of blood pressure, hypertension, which is responsible for almost 50% of deaths from stroke and coronary heart disease. Salt sensitivity is a risk factor for cardiovascular morbidity and mortality and other diseases as well. We reported a model of salt sensitive hypertension in adult ovariectomized (oVx) Wistar rats. oVx rats are normotensive under normal salt intake (NS, 0.24% NaCl), but upon a high salt intake (HS, 1% NaCl) oVx rats developed a blood pressure profile of salt-sensitive hypertension. Our studies on kidney molecules related to sodium balance found that the circuit dopamine D1-like receptor, cytochrome P450 4A and Na+, K+-ATPase is altered by the absence of ovary hormones which is accompanied by a reduced ability to excrete sodium. In oVx rats HS intake also promotes changes in the expression of proteins related to sodium transport in peripheral blood mononuclear cells, mainly peripheral lymphocytes. Therefore, sodium transport is modified at several levels of normal physiology. Lately, we described that estradiol increases the rate of renal epithelial cell proliferation in primary cultures developed from human renal cortex. Thus, salt sensitivity, adaptive immunity, blood pressure and renal cell proliferation are complex biological responses regulated by female sex hormones.


Assuntos
Estradiol/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Cloreto de Sódio/metabolismo , Animais , Pressão Sanguínea , Proliferação de Células , Feminino , Humanos , Hipertensão/fisiopatologia , Ratos , Ratos Wistar , Cloreto de Sódio/efeitos adversos , ATPase Trocadora de Sódio-Potássio
15.
Life Sci ; 253: 117673, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32311377

RESUMO

Aging effects in energy balance in all tissues and organs, including the cardiovascular. The risk of cardiovascular disease is drastically higher in postmenopausal women than in premenopausal women. Estrogen plays an important role in the cardiac function and body's metabolism. The aim of this study was to determine whether 17ß-estradiol (E2) has beneficial effects on insulin resistance and some key stages of the insulin signalling pathway in the aged hearts. Young and aged female Wistar rats were ovariectomized and were randomly divided into three groups: young (YS) and aged (AS) sham, young (YV) and aged (AV) vehicle, and young (YE2) and aged (AE2) E2 treatment groups. E2 (1 mg/kg) was administrated every four days for four weeks. Results showed that ovariectomy increased fasting blood glucose, insulin, and HOMAIR in young, while none of these parameters was affected in aged animals. On the other hand, aging itself increased these variables. Furthermore, E2 therapy alleviated these changes in both young and aged animals. Moreover, aging also decreased the p-IRS1, p-Akt level, and translocation of GLUT4 to the plasma membrane. E2 reduced the negative impact of menopause and aging on insulin sensitivity by favoring increase in the level of IL-10 and decrease in the levels of TNF-α and IL-1ß. Our results indicated that the heart response to E2 depended on age, and E2 increased insulin sensitivity in the heart of both young and aged animals by altering inflammatory conditions. Determining the exact mechanism of this action is suggested in future studies.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Insulina/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Menopausa/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar , Transdução de Sinais
16.
Metabolism ; 107: 154241, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32304754

RESUMO

BACKGROUND: Hyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown. METHODS: Steriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion. RESULTS: The decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression. CONCLUSION: High serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.


Assuntos
MicroRNAs/genética , Folículo Ovariano/metabolismo , Esteroides/biossíntese , Androgênios/biossíntese , Androgênios/genética , Animais , Estradiol/metabolismo , Estrogênios/biossíntese , Estrogênios/genética , Feminino , Regulação da Expressão Gênica/genética , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/metabolismo , Letrozol , Hormônio Luteinizante/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
17.
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
18.
J Steroid Biochem Mol Biol ; 201: 105671, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32289430

RESUMO

The estrogen receptor (ER) plays a role in the progression of hormone-dependent breast cancer and is a hormone therapy target. Estrogen acts as a transcription factor (genomic action) and also produces a quick non-genomic reaction through intracellular signaling pathways. The membrane associated ER (mER) may regulate both these signals and hormone therapy resistance. However, the details remain unclear because a reliable method to distinguish the signals induced by the estradiol (E2)-mER and E2-nuclear ER complex has not been established. In the present study, we prepared the novel ligand Qdot-6-E2, selective for mER, by coupling E2 with insoluble quantum dot nano-beads. We investigated the characteristics of mER signaling pathways and its contribution to hormone therapy resistance using different cell lines including estrogen depletion resistant (EDR) cells with different mechanisms. Qdot-6-E2 stimulated proliferation of nuclear ER-positive cells, but nuclear ER-negative cells showed no response. In addition, Qdot-6-E2 indirectly activated nuclear ER and increased mRNA expression of target genes. We confirmed that E2 was not dissociated from Qdot-6-E2 using a mammalian one-hybrid assay. We visually demonstrated that Qdot-6-E2 acts from the outside of cells. The gene expression profile induced by Qdot-6-E2-mER was different from that induced by E2-nuclear ER. The effect of anti-ER antibody, the GFP-ER fusion protein localization, and the effect of palmitoyl acyltransferase inhibitor also indicated the existence of mER. Regarding intracellular phosphorylation signaling pathways, the MAPK (Erk 1/2) and the PI3K/Akt pathways were both activated by Qdot-6-E2. In EDR cells, only nuclear ER-positive cells showed increased cell proliferation with increased localization of ERα to the membrane fraction. These findings suggested that Qdot-6-E2 reacts with ERα surrounding the cell membrane and that mER signals help the cells to survive under estrogen-depleted conditions by re-localizing the ER to use trace amounts of E2 more effectively. We expect that Qdot-6-E2 is a useful tool for studying the mER.


Assuntos
Neoplasias da Mama/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Pontos Quânticos/metabolismo , Receptores Estrogênicos/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Transcriptoma
19.
Am J Physiol Endocrinol Metab ; 318(6): E901-E919, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32286880

RESUMO

Lack of GABAB receptors in GABAB1 knockout mice decreases neonatal ARC kisspeptin 1 (Kiss1) expression in the arcuate nucleus of the hypothalamus (ARC) in females, which show impaired reproduction as adults. Our aim was to selectively impair GABAB signaling during a short postnatal period to evaluate its impact on the reproductive system. Neonatal male and female mice were injected with the GABAB antagonist CGP 55845 (CGP, 1 mg/kg body wt sc) or saline from postnatal day 2 (PND2) to PND6, three times per day (8 AM, 1 PM, and 6 PM). One group was killed on PND6 for collection of blood samples (hormones by radioimmunoassay), brains for gene expression in the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN), and ARC micropunches [quantitative PCR (qPCR)] and gonads for qPCR, hormone contents, and histology. A second group of mice was injected with CGP (1 mg/kg body wt sc) or saline from PND2 to PND6, three times per day (8 AM, 1 PM, and 6 PM), and left to grow to adulthood. We measured body weight during development and parameters of sexual differentiation, puberty onset, and estrous cycles. Adult mice were killed, and trunk blood (hormones), brains for qPCR, and gonads for qPCR and hormone contents were obtained. Our most important findings on PND6 include the CGP-induced decrease in ARC Kiss1 and increase in neurokinin B (Tac2) in both sexes; the decrease in AVPV/PeN tyrosine hydroxylase (Th) only in females; the increase in gonad estradiol content in both sexes; and the increase in primordial follicles and decrease in primary and secondary follicles. Neonatally CGP-treated adults showed decreased ARC Kiss1 and ARC gonadotropin-releasing hormone (Gnrh1) and increased ARC glutamic acid decarboxylase 67 (Gad1) only in males; increased ARC GABAB receptor subunit 1 (Gabbr1) in both sexes; and decreased AVPV/PeN Th only in females. We demonstrate that ARC Kiss1 expression is chronically downregulated in males and that the normal sex difference in AVPV/PeN Th expression is abolished. In conclusion, neonatal GABAergic input through GABAB receptors shapes gene expression of factors critical to reproduction.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipotálamo Anterior/metabolismo , Receptores de GABA-B/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Antagonistas de Receptores de GABA-B/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo Anterior/efeitos dos fármacos , Kisspeptinas/genética , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ácidos Fosfínicos/farmacologia , Propanolaminas/farmacologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Puberdade/efeitos dos fármacos , Puberdade/genética , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de GABA-B/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Reprodução/efeitos dos fármacos , Reprodução/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/genética , Taquicininas/genética , Taquicininas/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
20.
Sci Rep ; 10(1): 4227, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144339

RESUMO

Laryngeal squamous cell carcinoma (LSCC) responds to 17ß-estradiol via estrogen-receptor (ER, transcribed from ESR1) dependent mechanisms, but is not recognized as a hormonally responsive cancer. 17ß-estradiol production by LSCC cell lines UM-SCC-11A and UM-SCC-12 was examined. Wild type (WT) and ESR1-silenced LSCC cultures and xenografts were examined for 17ß-estradiol responsiveness in vivo. 14 LSCC and surrounding epithelial samples at various pathological stages were obtained from patients; ERα and ERß expression were verified using data from the total cancer genome atlas. UM-SCC-11A and UM-SCC-12 both produce 17ß-estradiol, but only UM-SCC-12, not UM-SCC-11A, xenograft tumors grow larger in vivo in response to systemic 17ß-estradiol treatments. ERα66 and ERα36 expression inversely correlated with clinical cancer stage and tumor burden. LSCC ERα66 expression was higher compared to surrounding epithelia in indolent samples but lower in aggressive LSCC. ERß expression was highly variable. High ESR1 expression correlated with improved survival in LSCC. Loss of ERα66 expression inversely correlated with prognosis in LSCC. ERα66 may be a histopathological marker of aggression in LSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Estradiol/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/antagonistas & inibidores , Neoplasias Laríngeas/patologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Células Tumorais Cultivadas
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