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1.
Nature ; 451(7175): 202-6, 2008 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-18185590

RESUMO

Tumour suppressor genes (TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer. DNA methylation is commonly associated with TSG silencing, yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown. An intriguing possible mechanism for gene regulation involves widespread non-coding RNAs such as microRNA, Piwi-interacting RNA and antisense RNAs. Widespread sense-antisense transcripts have been systematically identified in mammalian cells, and global transcriptome analysis shows that up to 70% of transcripts have antisense partners and that perturbation of antisense RNA can alter the expression of the sense gene. For example, it has been shown that an antisense transcript not naturally occurring but induced by genetic mutation leads to gene silencing and DNA methylation, causing thalassaemia in a patient. Here we show that many TSGs have nearby antisense RNAs, and we focus on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukaemia. We found an inverse relation between p15 antisense (p15AS) and p15 sense expression in leukaemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer-independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus, natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Epigênese Genética , Genes Supressores de Tumor , RNA Antissenso/genética , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Metilação de DNA , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Heterocromatina/genética , Heterocromatina/metabolismo , Leucemia/genética , Camundongos , Modelos Genéticos , Regiões Promotoras Genéticas/genética , RNA Antissenso/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismo
2.
Food Chem Toxicol ; 176: 113799, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37088127

RESUMO

Information in the published literature indicates that consumption of CBD can result in developmental and reproductive toxicity and hepatotoxicity outcomes in animal models. The trend of CBD-induced male reproductive toxicity has been observed in phylogenetically disparate organisms, from invertebrates to non-human primates. CBD has also been shown to inhibit various cytochrome P450 enzymes and certain efflux transporters, resulting in the potential for drug-drug interactions and cellular accumulation of xenobiotics that are normally transported out of the cell. The mechanisms of CBD-mediated toxicity are not fully understood, but they may involve disruption of critical metabolic pathways and liver enzyme functions, receptor-specific binding activity, disruption of testosterone steroidogenesis, inhibition of reuptake and degradation of endocannabinoids, and the triggering of oxidative stress. The toxicological profile of CBD raises safety concerns, especially for long term consumption by the general population.


Assuntos
Canabidiol , Animais , Humanos , Masculino , Canabidiol/toxicidade , Canabidiol/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas de Transporte , Interações Medicamentosas , Testosterona
3.
J Appl Toxicol ; 32(9): 643-53, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22334439

RESUMO

The term epigenetics was coined in the context of developmental studies, but the meaning of the term has evolved over time. Epigenetic modulators of gene expression are now known to include DNA methylation, chromatin modifications and noncoding RNAs. The observation that epigenetic changes can be transmitted transgenerationally makes the science of epigenetics very relevant to the field of environmental and molecular toxicology. Heavy metals constitute an important class of environmental contaminants that have been known to influence gene expression directly by binding various metal response elements in the target gene promoters. Recent research suggests that metals can also influence gene expression through epigenetic mechanisms; this adds a new twist to the complexity of metal-mediated gene expression. Here, we review recent studies that investigate the epigenetic, gene expression, and biological effects of various inorganic and organic forms of heavy metals, such as cadmium, arsenic, nickel, chromium, methylmercury, lead, copper and organotin compounds.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Metais Pesados/toxicidade , Compostos Organometálicos/toxicidade , Animais , Metilação de DNA , Histonas/química , Histonas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional , RNA não Traduzido
4.
Mol Cancer Res ; 6(2): 243-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18314485

RESUMO

We have previously shown that hydrogen peroxide-resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H(2)O(2), etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H(2)O(2), etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos-overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos-overexpressing cells were exposed to 5-aza-2'-deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H(2)O(2), etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1(-/-)) or DNMT3B (DNMT3B(-/-)) were shown to be more sensitive to the cytotoxicity of H(2)O(2), etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H(2)O(2)) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/enzimologia , Neoplasias/patologia , Animais , Antineoplásicos/farmacologia , Azacitidina/farmacologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/deficiência , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , DNA Metiltransferase 3B
5.
Clin Pharmacol Ther ; 104(3): 426-429, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30066384

RESUMO

The United States Pharmacopeia (USP) is an independent, nonprofit, science-based organization whose mission is to improve global health through public quality standards for dietary supplements, medicines, and food ingredients.1 Before developing standards for dietary supplement ingredients, the USP performs an "Admission Evaluation" (Figure 1), which includes an assessment to ascertain that an ingredient does not present a serious health risk.2 This article discusses the challenges encountered during the evaluation of botanicals and proposes possible solutions.


Assuntos
Qualidade de Produtos para o Consumidor/normas , Suplementos Nutricionais/normas , Segurança do Paciente/normas , Farmacopeias como Assunto/normas , Fitoterapia/normas , Preparações de Plantas/normas , Controle de Qualidade , Melhoria de Qualidade/normas , Animais , Suplementos Nutricionais/efeitos adversos , Humanos , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos , Medição de Risco , Estados Unidos
6.
Food Chem Toxicol ; 109(Pt 1): 170-193, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28867342

RESUMO

A new dataset of cosmetics-related chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 552 chemicals with 219, 40, and 293 chemicals in Cramer Classes I, II, and III, respectively. Data were integrated and curated to create a database of No-/Lowest-Observed-Adverse-Effect Level (NOAEL/LOAEL) values, from which the final COSMOS TTC dataset was developed. Criteria for study inclusion and NOAEL decisions were defined, and rigorous quality control was performed for study details and assignment of Cramer classes. From the final COSMOS TTC dataset, human exposure thresholds of 42 and 7.9 µg/kg-bw/day were derived for Cramer Classes I and III, respectively. The size of Cramer Class II was insufficient for derivation of a TTC value. The COSMOS TTC dataset was then federated with the dataset of Munro and colleagues, previously published in 1996, after updating the latter using the quality control processes for this project. This federated dataset expands the chemical space and provides more robust thresholds. The 966 substances in the federated database comprise 245, 49 and 672 chemicals in Cramer Classes I, II and III, respectively. The corresponding TTC values of 46, 6.2 and 2.3 µg/kg-bw/day are broadly similar to those of the original Munro dataset.


Assuntos
Cosméticos/toxicidade , Cosméticos/análise , Bases de Dados Factuais , Substâncias Perigosas/análise , Substâncias Perigosas/toxicidade , Humanos , Nível de Efeito Adverso não Observado
7.
Food Chem Toxicol ; 70: 68-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24824476

RESUMO

Differences in the physiology and biological susceptibilities of adults and infants have led to growing interest in safety evaluation methods for exposures from infant formula packaging. In addition to potential physiological differences, infants aged 0-6 months may consume a sole source of food, infant formula or breast milk, and consume higher amounts of food relative to body weight compared to adults. While the duration of the exposure is short compared to the expected lifespan of the individual, it occurs during a period of important developmental processes. The purpose of this document is to (1) review key biological and exposure elements that may impact the evaluation of safety for food contact products intended for use by infants, (2) summarize the current reproductive and developmental toxicity testing protocols available, and (3) identify potential data gaps concerning this period of development.


Assuntos
Desenvolvimento Infantil , Embalagem de Alimentos , Alimentos Infantis/análise , Testes de Toxicidade/métodos , Dieta , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/crescimento & desenvolvimento , Determinação de Ponto Final , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/crescimento & desenvolvimento , Lactente , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Cuidado Pós-Natal , Reprodutibilidade dos Testes , Reprodução/efeitos dos fármacos , Medição de Risco , Toxicocinética
8.
Food Chem Toxicol ; 59: 187-90, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23778052

RESUMO

The mouse lymphoma L5178Y Tk(+/-) assay is broadly used in toxicology to assess genotoxicity because of its known sensitivity to genotoxicants that act through a variety of mechanisms, which may include epigenetic DNA methylation. This brief article highlights the studies that have contributed to this conjecture and suggests an addition to the experimental design that could identify if the test substance is a potential epimutagen acting via hypermethylation.


Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Repressão Epigenética/efeitos dos fármacos , Leucemia L5178/metabolismo , Testes de Mutagenicidade , Mutagênicos/toxicidade , Proteínas de Neoplasias/metabolismo , Timidina Quinase/metabolismo , Aminopterina/metabolismo , Aminopterina/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estudos de Avaliação como Assunto , Hipoxantina/metabolismo , Leucemia L5178/tratamento farmacológico , Leucemia L5178/enzimologia , Camundongos , Mutação/efeitos dos fármacos , Proteínas de Neoplasias/genética , Timidina/metabolismo , Timidina Quinase/genética , Trifluridina/metabolismo , Trifluridina/farmacologia
9.
Expert Opin Drug Metab Toxicol ; 6(7): 793-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20491519

RESUMO

Over 10 years ago, the Office of Food Additive Safety (OFAS) in the FDA's Center for Food Safety and Applied Nutrition implemented the formal use of structure-activity relationship analysis and quantitative structure-activity relationship (QSAR) analysis in the premarket review of food-contact substances. More recently, OFAS has implemented the use of multiple QSAR software packages and has begun investigating the use of metabolism data and metabolism predictive models in our QSAR evaluations of food-contact substances. In this article, we provide an overview of the programs used in OFAS as well as a perspective on how to apply multiple QSAR tools in the review process of a new food-contact substance.


Assuntos
Biologia Computacional/legislação & jurisprudência , Bases de Dados Factuais/legislação & jurisprudência , Aditivos Alimentares/efeitos adversos , Toxicologia/legislação & jurisprudência , United States Food and Drug Administration/legislação & jurisprudência , Animais , Biologia Computacional/métodos , Humanos , Segurança , Toxicologia/métodos , Estados Unidos
10.
Cancer Cell ; 17(1): 41-52, 2010 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-20129246

RESUMO

The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.


Assuntos
Envelhecimento/fisiologia , Transformação Celular Neoplásica/genética , Genes Supressores de Tumor , Mitocôndrias/metabolismo , Sirtuína 3/genética , Estresse Fisiológico/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Estresse Oxidativo/fisiologia , Sirtuína 3/metabolismo , Superóxidos/metabolismo
11.
Eukaryot Cell ; 5(4): 762-70, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16607023

RESUMO

The ribosome-associated molecular chaperone complexes RAC (Ssz1p/Zuo1p) and Ssb1p/Ssb2p expose a link between protein folding and translation. Disruption of the conserved nascent peptide-associated complex results in cell growth and translation fidelity defects. To better understand the consequences of deletion of either RAC or Ssb1p/2p, experiments relating to cell growth and programmed ribosomal frameshifting (PRF) were assayed. Genetic analyses revealed that deletion of Ssb1p/Ssb2p or of Ssz1p/Zuo1p resulted in specific inhibition of -1 PRF and defects in Killer virus maintenance, while no effects were observed on +1 PRF. These factors may provide a new set of targets to exploit against viruses that use -1 PRF. Quantitative measurements of growth profiles of isogenic wild-type and mutant cells showed that translational inhibitors exacerbate underlying growth defects in these mutants. Previous studies have identified -1 PRF signals in yeast chromosomal genes and have demonstrated an inverse relationship between -1 PRF efficiency and mRNA stability. Analysis of published DNA microarray experiments reveals conditions under which Ssb1, Ssb2, Ssz1, and Zuo1 transcript levels are regulated independently of those of genes encoding ribosomal proteins. Thus, the findings presented here suggest that these trans-acting factors could be used by cells to posttranscriptionally regulate gene expression through -1 PRF.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura/genética , Mudança da Fase de Leitura do Gene Ribossômico/fisiologia , Proteínas de Choque Térmico HSP70/genética , Chaperonas Moleculares/metabolismo , Processamento de Proteína Pós-Traducional , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Modelos Moleculares , Chaperonas Moleculares/genética , Proteínas Repressoras/fisiologia , Ribossomos/química , Proteínas de Saccharomyces cerevisiae/metabolismo
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