RESUMO
With rapid modernization, environmental pollutants have become a major concern for human health, contributing to diseases such as asthma, cardiovascular diseases, obesity, infertility, and cancers [...].
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Disruptores Endócrinos , Poluentes Ambientais , Humanos , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Poluentes Ambientais/efeitos adversos , Animais , Exposição Ambiental/efeitos adversosRESUMO
INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.
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Hidrocarbonetos Policíclicos Aromáticos , Humanos , Gravidez , Recém-Nascido , Feminino , Hidrocarbonetos Policíclicos Aromáticos/urina , Estudos Transversais , Metabolômica , Metaboloma , Aminoácidos/metabolismoRESUMO
About 40% of women with infertility and 70% of women with pelvic pain suffer from endometriosis. The pregnancy rate in women undergoing IVF with low endometrial integrin αvß3 (LEI) expression is significantly lower compared to the women with high endometrial integrin αvß3 (HEI). Mid-secretory eutopic endometrial biopsies were obtained from healthy controls (C; n=3), and women with HEI (n=4) and LEI (n=4) and endometriosis. Changes in gene expression were assessed using human gene arrays and DNA methylation data were derived using 385 K Two-Array Promoter Arrays. Transcriptional analysis revealed that LEI and C groups clustered separately with 396 differentially expressed genes (DEGs) (P<0.01: 275 up and 121 down) demonstrating that transcriptional and epigenetic changes are distinct in the LEI eutopic endometrium compared to the C and HEI group. In contrast, HEI vs C and HEI vs LEI comparisons only identified 83 and 45 DEGs, respectively. The methylation promoter array identified 1304 differentially methylated regions in the LEI vs C comparison. The overlap of gene and methylation array data identified 14 epigenetically dysregulated genes and quantitative RT-PCR analysis validated the transcriptomic findings. The analysis also revealed that aryl hydrocarbon receptor (AHR) was hypomethylated and significantly overexpressed in LEI samples compared to C. Further analysis validated that AHR transcript and protein expression are significantly (P<0.05) increased in LEI women compared to C. The increase in AHR, together with the altered methylation status of the 14 additional genes, may provide a diagnostic tool to identify the subset of women who have endometriosis-associated infertility.
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Metilação de DNA , Endometriose/genética , Endométrio/metabolismo , Infertilidade Feminina/etiologia , Integrina alfaVbeta3/biossíntese , Transcriptoma , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biópsia , Regulação para Baixo , Endometriose/complicações , Endometriose/metabolismo , Endométrio/patologia , Feminino , Humanos , Infertilidade Feminina/genética , Integrina alfaVbeta3/genética , Pessoa de Meia-Idade , Análise de Componente Principal , Receptores de Hidrocarboneto Arílico/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Adulto JovemRESUMO
MOTIVATION: Both ß-value and M-value have been used as metrics to measure methylation levels. The M-value is more statistically valid for the differential analysis of methylation levels. However, the ß-value is much more biologically interpretable and needs to be reported when M-value method is used for conducting differential methylation analysis. There is an urgent need to know how to interpret the degree of differential methylation from the M-value. In M-value linear regression model, differential methylation M-value ΔM can be easily obtained from the coefficient estimate, but it is not straightforward to get the differential methylation ß-value, Δß since it cannot be obtained from the coefficient alone. RESULTS: To fill the gap, we have built a bridge to connect the statistically sound M-value linear regression model and the biologically interpretable Δß. In this article, three methods were proposed to calculate differential methylation values, Δß from M-value linear regression model and compared with the Δß directly obtained from ß-value linear regression model. We showed that under the condition that M-value linear regression model is correct, the method M-model-coef is the best among the four methods. M-model-M-mean method works very well too. If the coefficients α0, α2, αp are not given (as 'MethLAB' package), the M-model-M-mean method should be used. The Δß directly obtained from ß-value linear regression model can give very biased results, especially when M-values are not in (-2, 2) or ß-values are not in (0.2, 0.8). AVAILABILITY AND IMPLEMENTATION: The dataset for example is available at the National Center for Biotechnology Information Gene Expression Omnibus repository, GSE104778. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metilação de DNA , Projetos de Pesquisa , Modelos LinearesRESUMO
Damage-induced long noncoding RNA (DINO) is a long noncoding RNA that directly interacts with p53 and thereby enhances p53 stability and activity in response to various cellular stresses. Here, we demonstrate that nuclear receptor subfamily 2 group E member 3 (NR2E3) plays a crucial role in maintaining active DINO epigenetic status for its proper induction and subsequent p53 activation. In acetaminophen (APAP)- or carbon tetrachloride-induced acute liver injuries, NR2E3 knockout (KO) mice exhibited far more severe liver injuries due to impaired DINO induction and p53 activation. Mechanistically, NR2E3 loss both in vivo and in vitro induced epigenetic DINO repression accompanied by reduced DINO chromatin accessibility. Furthermore, compared with the efficient reversal by a typical antidote N-acetylcysteine (NAC) treatment of APAP-induced liver injury in wild-type mice, the liver injury of NR2E3 KO mice was not effectively reversed, indicating that an intact NR2E3-DINO-p53-signaling axis is essential for NAC-mediated recovery against APAP-induced hepatotoxicity. These findings establish that NR2E3 is a critical component in p53 activation and a novel susceptibility factor to drug- or toxicant-induced acute liver injuries.-Khanal, T., Leung, Y.-K., Jiang, W., Timchenko, N., Ho, S.-M., Kim, K. NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.
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Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Falência Hepática Aguda/metabolismo , Receptores Nucleares Órfãos/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Acetilcisteína/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Epigênese Genética/efeitos dos fármacos , Células Hep G2 , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Camundongos , Camundongos Knockout , Receptores Nucleares Órfãos/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
MOTIVATION: 5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are important epigenetic regulators of gene expression. 5mC and 5hmC levels can be computationally inferred at single base resolution using sequencing or array data from paired DNA samples that have undergone bisulfite and oxidative bisulfite conversion. Current estimation methods have been shown to produce irregular estimates of 5hmC level or are extremely computation intensive. RESULTS: We developed an efficient method oxBS-MLE based on binomial modeling of paired bisulfite and oxidative bisulfite data from sequencing or array analysis. Evaluation in several datasets showed that it outperformed alternative methods in estimate accuracy and computation speed. AVAILABILITY AND IMPLEMENTATION: oxBS-MLE is implemented in Bioconductor package ENmix. CONTACT: niulg@ucmail.uc.eduSupplementary information: Supplementary data are available at Bioinformatics online.
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5-Metilcitosina/análogos & derivados , 5-Metilcitosina/química , Biologia Computacional/métodos , Metilação de DNA , DNA/química , Ilhas de CpG , Modelos Teóricos , Análise de Sequência de DNARESUMO
PURPOSE: Existing data regarding the expression of estrogen receptors (ERs) and prostate cancer outcomes have been limited. We evaluated the relationship of expression profiles of ERß subtypes and the ER GPR30 (G-protein-coupled receptor-30) with patient factors at diagnosis and outcomes following radical prostatectomy. MATERIALS AND METHODS: Tissue microarrays constructed using samples from 566 men with long-term clinical followup were analyzed by immunohistochemistry targeting ERß1, ERß2, ERß5 and GPR30. An experienced pathologist scored receptor distribution and staining intensity. Tumor staining characteristics were evaluated for associations with patient characteristics, recurrence-free survival and prostate cancer specific mortality following radical prostatectomy. RESULTS: Prostate cancer cells had unique receptor subtype staining patterns. ERß1 demonstrated predominantly nuclear localization while ERß2, ERß5 and GPR30 were predominantly cytoplasmic. After controlling for patient factors intense cytoplasmic ERß1 staining was independently associated with time to recurrence (HR 1.7, 95% CI 1.1-2.6, p = 0.01) and prostate cancer specific mortality (HR 6.6, 95% CI 1.8-24.9, p = 0.01). Intense nuclear ERß2 staining was similarly independently associated with prostate cancer specific mortality (HR 3.9, 95% CI 1.1-13.4, p = 0.03). Patients with cytoplasmic ERß1 and nuclear ERß2 co-staining had significantly worse 15-year prostate cancer specific mortality than patients with expression of only cytoplasmic ERß1, only nuclear ERß2 and neither ER (16.4%, 4.3%, 0.0% and 2.0 %, respectively, p = 0.001). CONCLUSIONS: Increased cytoplasmic ERß1 and nuclear ERß2 expression is associated with worse cancer specific outcomes following radical prostatectomy. These findings suggest that tumor ERß1 and ERß2 staining patterns provide prognostic information on patients treated with radical prostatectomy.
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Receptor beta de Estrogênio/metabolismo , Próstata/metabolismo , Prostatectomia/métodos , Neoplasias da Próstata/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Idoso , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Próstata/patologia , Próstata/cirurgia , Prostatectomia/efeitos adversos , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Análise de Sobrevida , Análise Serial de TecidosRESUMO
Gestational diabetes mellitus (GDM) has increased dramatically in the past 20 years together with the obesity epidemic. Mirroring the increase in incidence of GDM is increasing use of endocrine disrupting chemicals (EDCs). EDCs are structurally similar to endogenous hormones and interfere with synthesis, secretion, activity, or elimination of natural hormones, resulting in adverse health effects, including diabetes, obesity, developmental disorders, etc. Although the association between bisphenol A (BPA), a well-studied EDC, and type 2 diabetes has been repeatedly investigated in epidemiological and animal studies, there is a dearth of studies examining EDCs and GDM. In fact, the impact of environmental toxins on perinatal health outcomes has largely been overlooked.Recognizing this research gap, the American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and International Federation of Gynecology and Obstetrics recently joined leading scientists and clinicians in a call for action to prioritize research in the consequences of exposure to toxic environmental agents on women's health. Evidence is emerging to suggest signaling molecules and EDCs are involved in the control of microRNA (miRNA) expression in trophoblast cells. We reviewed existing scientific evidence of EDCs as a risk factor for GDM as well as the potential role of miRNA in this association.
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Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Disruptores Endócrinos/farmacologia , MicroRNAs/metabolismo , Linhagem Celular , Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/toxicidade , Exossomos , Feminino , Humanos , MicroRNAs/análise , Fenóis/farmacologia , Placenta/química , Gravidez , Fatores de RiscoRESUMO
Electronic waste (e-waste) generation is increasing worldwide, and its management becomes a significant challenge because of the many toxicants present in electronic devices. The U.S. is a major producer of e-waste, although its management practice and policy regulation are not sufficient to meet the challenge. We reviewed e-waste generation, current management practices and trends, policy challenges, potential health impact, and toxicant exposure prevention in the U.S. A large amount of toxic metals, flame retardants, and other persistent organic pollutants exist in e-waste or can be released from the disposal of e-waste (e.g., landfill, incineration, recycling). Landfill is still a major method used to dispose of obsolete electronic devices, and only about half of the states have initiated a landfill ban for e-waste. Recycling of e-waste is an increasing trend in the past few years. There is potential, however, for workers to be exposed to a mixture of toxicants in e-waste and these exposures should be curtailed. Perspectives and recommendations are provided regarding managing e-waste in the U.S. to protect public health, including enacting federal legislation, discontinuing landfill disposal, protecting workers in recycling facilities from toxicant exposure, reducing toxicant release into the environment, and raising awareness of this growing environmental health issue among the public.
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Resíduo Eletrônico , Saúde Pública , Gerenciamento de Resíduos/métodos , Humanos , Reciclagem , Estados Unidos , Instalações de Eliminação de ResíduosRESUMO
Disorders of the prostate and lower urinary tract are common in elderly men. We investigated the role of metallothionein-1 (MT1) in prostate carcinogenesis by generating a prostate-specific, MT1-expressing mouse. Unexpectedly, genomic analyses revealed that a 12.1-kb genomic region harboring several conserved noncoding elements was unintentionally deleted, upstream of the transgene integration site in the mouse, which we named it 12.1ΔMT1. Male 12.1ΔMT1 mice chronically treated with testosterone (T) plus 17ß-estradiol (E2) to induce prostate cancer exhibited no evidence of precancerous or cancerous lesions. Instead, most of them exhibited a bladder outlet obstruction (BOO) phenotype not observed in treated wild-type (WT) mice. Thus, we hypothesized that 12.1ΔMT1 is a novel model for studying the hormonal requirement for BOO induction. Adult male 12.1ΔMT1 and WT mice were treated with T, E2, bisphenol A (BPA), T+E2, or T+BPA for up to 6 months. Histologic and immunohistochemical analysis of the prostate, bladder, and urethra were performed. No significant prostate pathologies were observed in WT or 12.1ΔMT1 mice treated with any of the hormone regimens. As expected, prostatic regression occurred in all E2-treated animals (WT and 12.1ΔMT1). Of great interest, despite a small prostate, 100% of E2-treated 12.1ΔMT1 mice, but only 40% of E2-treated WT mice, developed severe BOO (P<0.01). In contrast, T+E2 treatment was less effective than E2 treatment in inducing severe BOO in 12.1ΔMT1 mice (68%, P<0.05) and was completely ineffective in WT animals. Similarly, T, BPA, and T+BPA treatments did not induce BOO in either WT or 12.1ΔMT1 mice. The BOO pathology includes a thinner detrusor wall, narrowing of bladder neck and urethral lumen, and basal cell hyperplasia in the bladder body and urethra. These findings indicate that 12.1ΔMT1 mice exhibit enhanced susceptibility to E2-induced BOO that is independent of prostate enlargement but that is attenuated by the conjoint treatment with T.
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Estradiol/farmacologia , Metalotioneína/genética , Obstrução do Colo da Bexiga Urinária/genética , Animais , Modelos Animais de Doenças , Feminino , Deleção de Genes , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Fenótipo , Próstata/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/análise , Receptores de N-Metil-D-Aspartato/metabolismo , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologiaRESUMO
Bisphenol A (BPA) is an endocrine disruptor associated with poor pregnancy outcomes in human and rodents. The effects of butterfat diets on embryo implantation and whether it modifies BPA's actions are currently unknown. We aimed to determine the effects of butterfat diet on embryo implantation success in female rats exposed to an environmentally relevant dose of BPA. Female Sprague-Dawley rats were exposed to dietary butterfat (10% or 39% kcal/kg body weight [BW]) in the presence or absence of BPA (250 µg/kg BW) or ethinylestradiol (0.1 µg/kg BW) shortly before and during pregnancy to assess embryo implantation potentials by preimplantation development and transport, in vitro blastulation, outgrowth, and implantation. On gestational day (GD) 4.5, rats treated with BPA alone had higher serum total BPA level (2.3-3.7 ng/ml). They had more late-stage preimplantation embryos, whereas those receiving high butterfat (HBF) diet had the most advanced-stage embryos; dams cotreated with HBF and BPA had the most number of advanced embryos. BPA markedly delayed embryo transport to the uterus, but neither amount of butterfat had modifying effects. An in vitro implantation assay showed HBF doubled the outgrowth area, with BPA having no effect. In vivo, BPA reduced the number of implanted embryos on GD8, and cotreatment with HBF eliminated this adverse effect. HBF diet overall resulted in more and larger GD8 embryos. This study reveals the implantation disruptive effects of maternal exposure to an environmentally relevant dose of BPA and identifies HBF diet as a modifier of BPA in promoting early embryonic health.
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Compostos Benzidrílicos/farmacologia , Dieta , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Ghee , Fenóis/farmacologia , Animais , Etinilestradiol/farmacologia , Feminino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: African Americans (AAs) have been shown to exhibit a higher incidence of colorectal cancer and experience lower survival compared with whites. There is disagreement regarding the age at which to initiate screening in AAs. OBJECTIVES: To calculate the age-specific incidence in AAs compared with whites while controlling for differences in socioeconomic status (SES) and to calculate the joinpoint at which the incidence begins to increase in each race. DESIGN: Retrospective database review. SETTING: Surveillance, Epidemiology, and End Results database. PATIENTS: All patients with adenocarcinoma of the colon or rectum from 2000 through 2011 in the SEER 18 database. INTERVENTIONS: We calculated the joinpoint of the upward trend of the age-adjusted incidence rate to determine the age at which the slope of the incidence curve began to increase in each race, while controlling for differences in SES by using a composite socioeconomic index. MAIN OUTCOME MEASUREMENTS: Age-adjusted incidence of colon and rectal cancer. RESULTS: The age-specific incidence of colorectal cancer (cases per 100,000 population) was 0.3 versus 0.4 in whites compared with AAs at 20 years of age. At 50 years of age, the incidence was 44.2 compared with 62.6 in whites compared with AAs. The model indicated a joinpoint at 47 years of age for whites (95% confidence interval, 45-49) and 43 for AAs (95% confidence interval, 42-45) (P < .001.) When SES was considered in stratification, joinpoints for whites were 48, 47, and 46 at high, middle, and low SES, respectively. Conversely, joinpoints of 43, 44, and 42 in the corresponding SES for AAs were noted (P ≤ .001). LIMITATIONS: There was no intervention, and we cannot conclude that changing screening policy would affect this disparity. CONCLUSION: There is a disparity in the age-specific incidence of colorectal cancer in AAs compared with whites beginning at 45 years of age. These differences persist across socioeconomic strata.
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Adenocarcinoma/etnologia , Negro ou Afro-Americano , Neoplasias Colorretais/etnologia , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Programa de SEER , Adenocarcinoma/diagnóstico , Distribuição por Idade , Fatores Etários , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Existing epidemiological studies of the association between oxidative stress and erectile dysfunction (ED) are sparse and inconclusive, which is likely due to cross-sectional design and small sample size. Therefore, we investigated the association between biomarkers of oxidative stress and ED in prospective setting among a relatively large sample size of men. METHODS: We conducted the prospective study among 917 men ages between 47 and 80 years at the time of blood draw, which is a part of nested prospective case-control study of prostate cancer in the Health Professionals Follow-up Study. Plasma fluorescent oxidation products (FlOPs), a global biomarker for oxidative stress, were measured at three excitation/emission wavelengths (360/420 nm named as FlOP_360; 320/420 nm named as FlOP_320 and 400/475 nm named as FlOP_400). RESULTS: Approximately 35% of men developed ED during follow-up. We did not find an independent association between FlOP_360, FlOP_320, FlOP_400 and risk of ED in the multivariable adjusted model (Tertile 3 vs. tertile 1: odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.61-1.34, P(trend) = 0.54 for FlOP_360; OR = 0.73, 95% CI = 0.49-1.07, P(trend) = 0.27 for FlOP_320; and OR = 0.98, 95% CI = 0.66-1.45, P(trend) = 0.72 for FlOP_400). Further analysis of the association between FlOPs and ED in the fasting samples or controls only (free of prostate cancer incidence) did not change the results appreciably. CONCLUSIONS: Plasma FlOPs were not associated with the risk of ED, suggesting oxidative stress may not be an independent risk factor for ED.
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Produtos da Oxidação Avançada de Proteínas/sangue , Disfunção Erétil/sangue , Disfunção Erétil/epidemiologia , Espécies Reativas de Oxigênio/sangue , Espectrometria de Fluorescência/métodos , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Medição de Risco/métodos , Sensibilidade e Especificidade , Estados Unidos/epidemiologiaRESUMO
Embryonic eyelid closure involves forward movement and ultimate fusion of the upper and lower eyelids, an essential step of mammalian ocular surface development. Although its underlying mechanism of action is not fully understood, a functional mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is required for eyelid closure. Here we investigate the molecular signatures of MAP3K1 in eyelid morphogenesis. At mouse gestational day E15.5, the developmental stage immediately prior to eyelid closure, MAP3K1 expression is predominant in the eyelid leading edge (LE) and the inner eyelid (IE) epithelium. We used laser capture microdissection (LCM) to obtain highly enriched LE and IE cells from wild type and MAP3K1-deficient fetuses and analyzed genome-wide expression profiles. The gene expression data led to the identification of three distinct developmental features of MAP3K1. First, MAP3K1 modulated Wnt and Sonic hedgehog signals, actin reorganization, and proliferation only in LE but not in IE epithelium, illustrating the temporal-spatial specificity of MAP3K1 in embryogenesis. Second, MAP3K1 potentiated AP-2α expression and SRF and AP-1 activity, but its target genes were enriched for binding motifs of AP-2α and SRF, and not AP-1, suggesting the existence of novel MAP3K1-AP-2α/SRF modules in gene regulation. Third, MAP3K1 displayed variable effects on expression of lineage specific genes in the LE and IE epithelium, revealing potential roles of MAP3K1 in differentiation and lineage specification. Using LCM and expression array, our studies have uncovered novel molecular signatures of MAP3K1 in embryonic eyelid closure.
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Pálpebras/embriologia , Pálpebras/metabolismo , Regulação da Expressão Gênica , MAP Quinase Quinase Quinase 1/biossíntese , MAP Quinase Quinase Quinase 1/genética , Animais , DNA Complementar/metabolismo , Perfilação da Expressão Gênica , Genótipo , Microdissecção e Captura a Laser/métodos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , RNA/metabolismo , Fator de Resposta Sérica/metabolismo , Transdução de Sinais , Fatores de Tempo , Distribuição Tecidual , Fator de Transcrição AP-2/metabolismoRESUMO
Estrogen receptor (ER) ß1 and ERα have overlapping and distinct functions despite their common use of estradiol as the physiological ligand. These attributes are explained in part by their differential utilization of coregulators and ligands. Although Tip60 has been shown to interact with both receptors, its regulatory role in ERß1 transactivation has not been defined. In this study, we found that Tip60 enhances transactivation of ERß1 at the AP-1 site but suppresses its transcriptional activity at the estrogen-response element (ERE) site in an estradiol-independent manner. However, different estrogenic compounds can modify the Tip60 action. The corepressor activity of Tip60 at the ERE site is abolished by diarylpropionitrile, genistein, equol, and bisphenol A, whereas its coactivation at the AP-1 site is augmented by fulvestrant (ICI 182,780). GRIP1 is an important tethering mediator for ERs at the AP-1 site. We found that coexpression of GRIP1 synergizes the action of Tip60. Although Tip60 is a known acetyltransferase, it is unable to acetylate ERß1, and its coregulatory functions are independent of its acetylation activity. In addition, we showed the co-occupancy of ERß1 and Tip60 at ERE and AP-1 sites of ERß1 target genes. Tip60 differentially regulates the endogenous expression of the target genes by modulating the binding of ERß1 to the cis-regulatory regions. Thus, we have identified Tip60 as the first dual-function coregulator of ERß1.
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Receptor beta de Estrogênio/metabolismo , Histona Acetiltransferases/metabolismo , Elementos de Resposta/fisiologia , Transcrição Gênica/fisiologia , Ativação Transcricional/fisiologia , Acetilação , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Receptor beta de Estrogênio/genética , Células HEK293 , Histona Acetiltransferases/genética , Humanos , Lisina Acetiltransferase 5 , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/ß-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/ß-catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/ß-catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, ß-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/ß-catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/ß-catenin signaling pathway that promotes HCC development.
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Carcinoma Hepatocelular , Epigênese Genética , Neoplasias Hepáticas , Camundongos Knockout , Via de Sinalização Wnt , beta Catenina , Animais , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Via de Sinalização Wnt/genética , Camundongos , Epigênese Genética/genética , beta Catenina/metabolismo , beta Catenina/genética , Humanos , Modelos Animais de Doenças , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Regulação Neoplásica da Expressão Gênica/genética , Linhagem Celular TumoralRESUMO
Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.
Environmental factors are important in inflammatory bowel diseases. It is a high priority to identify environmental factors impacting different disease stages and in different populations, develop biomarkers for such exposures, and generate evidence for modifying them to improve outcomes.
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Exposição Ambiental , Doenças Inflamatórias Intestinais , Humanos , Exposição Ambiental/efeitos adversos , Doenças Inflamatórias Intestinais/etiologia , Colite Ulcerativa/etiologia , Fatores de RiscoRESUMO
Background: Exposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations. Method: This study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values < 0.05 and presented results by limiting results with a genomic inflation factor of 1±0.5. Additionally, gene set enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomics pathways. Results: Among the 29 chemical biomarkers assessed for differential methylation, maternal concentrations of PAH metabolites (1-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxypyrene), monocarboxyisononyl phthalate, mono-3-carboxypropyl phthalate, and bisphenol A were associated with altered methylation in placenta (maternal or fetal side). Among exposure biomarkers associated with epigenetic changes, 1-hydroxynaphthalene, and mono-3-carboxypropyl phthalate were consistently associated with differential CpG methylation in the placenta. Gene enrichment analysis indicated that maternal 1-hydroxynaphthalene was associated with lipid metabolism and cellular processes of the placenta. Additionally, mono-3-carboxypropyl phthalate was associated with organismal systems and genetic information processing of the placenta. Conclusion: Among the 29 chemical biomarkers assessed during delivery, 1-hydroxynaphthalene and mono-3-carboxypropyl phthalate were associated with DNA methylation in the placenta. Supplementary Information: The online version contains supplementary material available at 10.1186/s43682-024-00027-7.
RESUMO
Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants in the past three decades. These compounds are lipophilic and easily cross the placenta from pregnant woman to fetus. It is not clear whether hydroxylated PBDEs (OH-PBDEs), with greater hydrophilicity, have different concentrations in maternal and cord serum samples. We analyzed PBDEs (BDE-28, -47, -99, -100, -153, -154, -209) and OH-PBDEs (6-OH-BDE-47, 5-OH-BDE-47, 4'-OH-BDE-49, 5'-OH-BDE-99) in 20 pairs of maternal and cord serum samples collected in Cincinnati, OH in 2011. The geometric mean concentration of ∑OH-BDEs (the sum of four OH-PBDEs) was 49.76 pg/mL in cord sera, higher than 32.84 pg/mL in maternal sera. Similarly, cord serum total BDEs had a higher geometric mean than maternal serum (45.51 vs 32.07 ng/g lipid). Equal or higher levels of total OH-BDEs and total BDEs in cord serum were observed in 85% and 80% of the mother-neonate pairs, respectively. The study suggests fetuses might receive higher OH-PBDE and PBDE exposure than their mothers.
Assuntos
Éteres Difenil Halogenados/sangue , Mães , Cordão Umbilical/metabolismo , Adulto , Peso ao Nascer , Intervalos de Confiança , Feminino , Humanos , Hidroxilação , Ohio , Gravidez , Análise de RegressãoRESUMO
Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would be a holy grail of cancer research and therapy. We propose that a stem cell versus genetic theory of cancer may not only enable us to track and trace the biological evolution of cancer but also empower us to attenuate its clinical course and optimize the clinical outcome of patients with cancer. Hence, a biomarker that identifies cancer stem cells (CSCs) and distinguishes them from non-CSCs may serve to elucidate inter-tumoral and intra-tumoral heterogeneity, elevate the values and utility of current prognostic and predictive tests, and enhance drug versus therapy development in cancer care. From this perspective, we focus on CSC biomarkers and discuss stemness or stem-like biomarkers in the context of a unified theory and a consideration of stem cell versus genetic origin. We review their role in primary and mixed tumors, in the elaboration of tumor subtypes, and in the imaging and monitoring of minimal residual diseases. We investigate how scientific theories influence the direction of scientific research and interpretation of experimental results, and how genomics and epigenomics affect the dynamics and trajectories of biomarkers in the conduct of cancer research and in the practice of cancer care.