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1.
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
2.
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
3.
Nat Commun ; 11(1): 4755, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958772

RESUMO

We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.


Assuntos
Homeostase , Oxigênio/metabolismo , RNA Longo não Codificante/fisiologia , Esteróis/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Colesterol/metabolismo , Estrogênios/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Humanos , Células MCF-7 , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
4.
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
5.
Food Chem ; 333: 127529, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679419

RESUMO

A solid-phase extraction (SPE) method for enriching and purifying estrogenic disrupting compounds (EDCs) based on the estrogen response element was established. The estrogen receptor was used for molecular recognition, as it specifically binds EDCs. An estrogen response element was used to maintain the activity of the estrogen receptor. High-performance liquid chromatography (HPLC) was used to quantify the EDCs. This method combined with HPLC was applied to detect three kinds of EDCs, such as bisphenol A (BPA), 17ß-estradiol, and diethylstilbestrol in a liquid milk matrix, with recoveries of 84.1 ± 8.2% to 113.6 ± 2.9%. The limits of detection and quantification of the established method were 1 × 10-6 mg·mL-1 and 5 × 10-6 mg·mL-1. The method was further applied to analyze market samples, including liquid milk, fermented milk, and milk powder. Only BPA was detected from one brand of liquid milk and it was below the regulatory level.


Assuntos
Disruptores Endócrinos/isolamento & purificação , Estrogênios/metabolismo , Elementos de Resposta , Extração em Fase Sólida/métodos , Animais , Cromatografia Líquida de Alta Pressão , Disruptores Endócrinos/análise , Leite/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/isolamento & purificação
7.
Proc Natl Acad Sci U S A ; 117(32): 19566-19577, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719118

RESUMO

The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.


Assuntos
Glicemia/metabolismo , Estrogênios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Metabolismo Energético , Feminino , Glutamato Descarboxilase/metabolismo , Homeostase , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Mutantes , Rede Nervosa , Inibição Neural , Neurônios/metabolismo , Neurônios/fisiologia , Receptor de Glutamato Metabotrópico 5/genética , Receptores Estrogênicos/metabolismo , Fatores Sexuais , Transdução de Sinais , Fator Esteroidogênico 1/metabolismo , Sistema Nervoso Simpático/metabolismo , Transmissão Sináptica , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo
8.
Aquat Toxicol ; 225: 105553, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32622090

RESUMO

Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 µg/L) or EE2 (0.01 µg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.


Assuntos
Compostos Benzidrílicos/toxicidade , Etinilestradiol/toxicidade , Oryzias/fisiologia , Fenóis/toxicidade , Testículo/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Disruptores Endócrinos/metabolismo , Estrogênios/metabolismo , Etinilestradiol/metabolismo , Feminino , Perfilação da Expressão Gênica , Larva/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos
10.
Life Sci ; 256: 117921, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32526288

RESUMO

Estrogen is a hormone responsible for modulating several physiological processes such as immune response and bone homeostasis. Physiological fluctuations of estrogen concentration are one of the defining principles behind its mechanism. In cases of estrogen deficiency, such as in menopausal women, a more intense bone resorption may occur due to an increase in osteoclast activity. One of the main factors that influence osteoclast formation and response is the immune system, mainly through cytokines secreted by B and T cells. The purpose of this review is to highlight how estrogen can modulate the secretion of cytokines that can alter bone physiology, thereby establishing an axis between estrogen, immune cells, and osteoclastogenesis.


Assuntos
Linfócitos B/metabolismo , Citocinas/metabolismo , Estrogênios/metabolismo , Osteogênese/fisiologia , Linfócitos T/metabolismo , Animais , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Diferenciação Celular , Citocinas/genética , Moduladores de Receptor Estrogênico/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Menopausa/metabolismo , Osteoclastos/metabolismo
11.
PLoS One ; 15(6): e0234427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511270

RESUMO

MicroRNAs (miRNAs) play an important role in regulating mammary gland development and lactation. We previously analyzed miRNA expression profiles in Laoshan dairy goat mammary glands at the early (20 d postpartum), peak (90 d postpartum) and late lactation (210 d postpartum) stages. To further enrich and clarify the miRNA expression profiles during the lactation physiological cycle, we sequenced miRNAs in the mammary gland tissues of Laoshan dairy goats at three newly selected stages: the late lactation (240 d postpartum), dry period (300 d postpartum) and late gestation (140 d after mating) stages. We obtained 4038 miRNAs and 385 important miRNA families, including mir-10, let-7 and mir-9. We also identified 754 differentially expressed miRNAs in the mammary gland tissue at the 3 different stages and 6 groups of miRNA clusters that had unique expression patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that GO terms such as mammary gland development (GO:0030879) and mammary gland morphogenesis (GO:0060443) and important signaling pathways, including the insulin signaling pathway (chx04910), hippo signaling pathway (chx04390) and estrogen signaling pathway (chx04915), were enriched. We screened miRNAs and potential target genes that may be involved in the regulation of lactation, mammary gland growth and differentiation, cell apoptosis, and substance transport and synthesis and detected the expression patterns of important genes at the three stages. These miRNAs and critical target genes may be important factors for mammary gland development and lactation regulation and potentially valuable molecular markers, which may provide a theoretical reference for further investigation of mammary gland physiology.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Cabras/fisiologia , Lactação/genética , Glândulas Mamárias Animais/crescimento & desenvolvimento , MicroRNAs/metabolismo , Gravidez/genética , Animais , Apoptose/genética , Indústria de Laticínios , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Glândulas Mamárias Animais/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/genética
13.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: covidwho-382126

RESUMO

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Estrogênios/química , Estrogênios/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/virologia , Pandemias , Pneumonia Viral/virologia , Receptor CB2 de Canabinoide/antagonistas & inibidores
14.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1280-L1281, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: covidwho-326936

RESUMO

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Estrogênios/farmacologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Estrogênios/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo
15.
Nanotoxicology ; 14(6): 740-756, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32401081

RESUMO

Despite numerous studies on the environmental health and safety (EHS) of silver nanoparticles (AgNPs), most studies looked into their gross toxicities with rather limited understanding on their labyrinthine implicit effects on the target sites, such as the endocrine system. Burgeoning evidence documents the disrupting effects of AgNPs on endocrine functions; however, little research has been invested to recognize the potential impacts on the mammary gland, a susceptible estrogen-responsive organ. Under this setting, we here aimed to scrutinize AgNP-induced effects on the development of pubertal mammary glands at various concentrations that bear significant EHS relevance. We unearthed that AgNPs could accumulate in mouse mammary glands and result in a decrease in the percentage of ducts and terminal ducts in the adult mice after chronic exposure. Strikingly, smaller sized AgNPs showed greater capability to alter the pubertal mammary development than larger sized particles. Intriguingly, mechanistic investigation revealed that the reduction of epithelial proliferation in response to AgNPs was ascribed to reduced ERα expression, which, at least partially, accounted for diseased epithelial morphology in mammary glands. Meanwhile, the decline in fibrous collagen deposition around the epithelium was found to contribute to the compromised development of mammary glands under the exposure of AgNPs. Moreover, as an extension of the mechanism, AgNPs diminished serum levels of estradiol in exposed animals. Together, these results uncovered a novel toxicity feature of AgNPs: compromised development of mouse pubertal mammary glands through the endocrine-disrupting actions. This study would open a new avenue to unveil the EHS impacts of AgNPs.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/farmacocinética , Epitélio/efeitos dos fármacos , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Transdução de Sinais , Prata/farmacocinética , Propriedades de Superfície , Distribuição Tecidual
16.
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
17.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1280-L1281, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432918

RESUMO

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Estrogênios/farmacologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Estrogênios/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo
19.
Eur J Contracept Reprod Health Care ; 25(3): 233-234, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469251

RESUMO

Objective: Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women, there seem to be sex differences in mortality rate and vulnerability to the disease: more men than women are dying. Methods: We have explored the potential role of estrogens in this COVID-19 gendered impact. Results: Estrogens stimulate the humoral response to viral infections, while testosterone and progesterone give an immune suppression of both innate and cell-mediated immune responses. We hypothesise that estrogens, in particular estradiol but also synthetic estrogen such as ethinylestradiol, could protect women from the most serious complications of COVID-19. The use of medications that keep hormonal levels high and stable, such as combined hormonal contraceptive, could therefore play a protective role. These potential benefits overtake the thrombotic risk in healthy women. As stated by the World Health Organization, all modern methods of contraception were safe to use during the COVID-19 pandemic.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Estrogênios/metabolismo , Pneumonia Viral/metabolismo , Progesterona/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Imunidade Celular , Hormônio Luteinizante/metabolismo , Masculino , Pandemias , Fatores Sexuais
20.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471272

RESUMO

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Estrogênios/química , Estrogênios/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/virologia , Pandemias , Pneumonia Viral/virologia , Receptor CB2 de Canabinoide/antagonistas & inibidores
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