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1.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L356-L367, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33325804

RESUMO

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed redox balance and increased production of reactive oxygen species (ROS), which is believed to contribute to epithelial injury and fibrotic lung scarring. The main pulmonary sources of ROS include mitochondria and NADPH oxidases (NOXs), of which the NOX4 isoform has been implicated in IPF. Non-receptor SRC tyrosine kinases (SFK) are important for cellular homeostasis and are often dysregulated in lung diseases. SFK activation by the profibrotic transforming growth factor-ß (TGF-ß) is thought to contribute to pulmonary fibrosis, but the relevant SFK isoform and its relationship to NOX4 and/or mitochondrial ROS in the context of profibrotic TGF-ß signaling is not known. Here, we demonstrate that TGF-ß1 can rapidly activate the SRC kinase FYN in human bronchial epithelial cells, which subsequently induces mitochondrial ROS (mtROS) production, genetic damage shown by the DNA damage marker γH2AX, and increased expression of profibrotic genes. Moreover, TGF-ß1-induced activation of FYN involves initial activation of NOX4 and direct cysteine oxidation of FYN, and both FYN and mtROS contribute to TGF-ß-induced induction of NOX4. NOX4 expression in lung tissues of IPF patients is positively correlated with disease severity, although FYN expression is down-regulated in IPF and does not correlate with disease severity. Collectively, our findings highlight a critical role for FYN in TGF-ß1-induced mtROS production, DNA damage response, and induction of profibrotic genes in bronchial epithelial cells, and suggest that altered expression and activation of NOX4 and FYN may contribute to the pathogenesis of pulmonary fibrosis.


Assuntos
Brônquios/metabolismo , Células Epiteliais/metabolismo , Mitocôndrias/metabolismo , NADPH Oxidase 4/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Brônquios/patologia , Células Epiteliais/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Mitocôndrias/patologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
2.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299170

RESUMO

Previous research has shown that a perinatal obesogenic, high-fat diet (HFD) is able to exacerbate ozone-induced adverse effects on lung function, injury, and inflammation in offspring, and it has been suggested that mitochondrial dysfunction is implicated herein. The aim of this study was to investigate whether a perinatal obesogenic HFD affects ozone-induced changes in offspring pulmonary oxidant status and the molecular control of mitochondrial function. For this purpose, female Long-Evans rats were fed a control diet or HFD before and during gestation, and during lactation, after which the offspring were acutely exposed to filtered air or ozone at a young-adult age (forty days). Directly following this exposure, the offspring lungs were examined for markers related to oxidative stress; oxidative phosphorylation; and mitochondrial fusion, fission, biogenesis, and mitophagy. Acute ozone exposure significantly increased pulmonary oxidant status and upregulated the molecular machinery that controls receptor-mediated mitophagy. In female offspring, a perinatal HFD exacerbated these responses, whereas in male offspring, responses were similar for both diet groups. The expression of the genes and proteins involved in oxidative phosphorylation and mitochondrial biogenesis, fusion, and fission was not affected by ozone exposure or perinatal HFD. These findings suggest that a perinatal HFD influences ozone-induced responses on pulmonary oxidant status and the molecular control of mitophagy in female rat offspring.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Pulmão/patologia , Mitocôndrias/patologia , Mitofagia , Oxidantes/metabolismo , Ozônio/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Feminino , Perfilação da Expressão Gênica , Pulmão/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Long-Evans
3.
Int J Cancer ; 147(8): 2091-2100, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32285440

RESUMO

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.


Assuntos
Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/etiologia , Estudos de Coortes , Feminino , Seguimentos , Frutas , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fumar/efeitos adversos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
4.
J Lipid Res ; 60(7): 1250-1259, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064776

RESUMO

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring's hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (Lpin1), a gene involved in lipid metabolism. Furthermore, DNA methylation of Lpin1 TF binding sites correlated with mRNA expression of Lpin1 These findings suggest that the effect of a prenatal HF diet on the adult offspring's metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , DNA/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
5.
Epidemiology ; 30(3): 458-465, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30601243

RESUMO

BACKGROUND: Few studies have modeled smoking histories by combining smoking intensity and duration to show what profile of smoking behavior is associated with highest risk of bladder cancer. This study aims to provide insight into the association between smoking exposure history and bladder cancer risk by modeling both smoking intensity and duration in a pooled analysis. METHODS: We used data from 15 case-control studies included in the bladder cancer epidemiology and nutritional determinants study, including a total of 6,874 cases and 17,727 controls. To jointly interpret the effects of intensity and duration of smoking, we modeled excess odds ratios per pack-year by intensity continuously to estimate the risk difference between smokers with long duration/low intensity and short duration/high intensity. RESULTS: The pattern observed from the pooled excess odds ratios model indicated that for a fixed number of pack-years, smoking for a longer duration at lower intensity was more deleterious for bladder cancer risk than smoking more cigarettes/day for a shorter duration. We observed similar patterns within individual study samples. CONCLUSIONS: This pooled analysis shows that long duration/low intensity smoking is associated with a greater increase in bladder cancer risk than short duration/high intensity smoking within equal pack-year categories, thus confirming studies in other smoking-related cancers and demonstrating that reducing exposure history to a single metric such as pack-years was too restrictive.


Assuntos
Modelos Biológicos , Fumar/epidemiologia , Fumar/psicologia , Neoplasias da Bexiga Urinária/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fatores de Risco , Fatores de Tempo
6.
Cancer Causes Control ; 29(7): 675-683, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29846846

RESUMO

BACKGROUND: Smoking is a major risk factor for bladder cancer, but the relationship between smoking cessation after initial treatment and bladder cancer recurrence has been investigated less frequently and not prospectively yet. METHODS: 722 non-muscle-invasive bladder cancer (NMIBC) patients (pTa, pT1, and CIS) from the prospective Bladder Cancer Prognosis Programme (BCPP) cohort, selected in the UK between 2005 and 2011, provided complete data on smoking behavior before and up to 5 years after diagnosis. The impact of smoking behavior on NMIBC recurrence was explored by multivariable Cox regression models investigating time-to-first NMIBC recurrence. RESULTS: Over a median follow-up period of 4.21 years, 403 pathologically confirmed NMIBC recurrences occurred in 210 patients. Only 25 current smokers at diagnosis quit smoking (14%) during follow-up and smoking cessation after diagnosis did not decrease risk of recurrence compared to continuing smokers (p = 0.352). CONCLUSIONS: Although quitting smoking after diagnosis might reduce the risk of recurrence based on retrospective evidence, this is not confirmed in this prospective study because the number of NMIBC patients quitting smoking before their first recurrence was too low. Nevertheless, this indicates an important role for urologists and other health care professionals in promoting smoking cessation in NMIBC.


Assuntos
Abandono do Hábito de Fumar/métodos , Fumar/efeitos adversos , Neoplasias da Bexiga Urinária/etiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
7.
Chem Res Toxicol ; 31(6): 462-471, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29727173

RESUMO

The WHO study group on tobacco product regulation (TobReg) advised regulating and lowering toxicant levels in cigarette smoke. Aldehydes are one of the chemical classes on the TobReg smoke toxicants priority list. To provide insight in factors determining aldehyde yields, the levels of 12 aldehydes in mainstream cigarette smoke of 11 Dutch brands were quantified. Variations in smoking behavior and cigarette design affecting human exposure to aldehydes were studied by using four different machine testing protocols. Machine smoking was based on the International Standardization Organization (ISO) and Health Canada Intense (HCI) regime, both with and without taping the filter vents. The 11 cigarette brands differed in (i) design and blend characteristics; (ii) tar, nicotine, and carbon monoxide (TNCO) levels; (iii) popularity; and (iv) manufacturer. Cigarette smoke was trapped on a Cambridge filter pad and carboxen cartridge. After being dissolved in methanol/CS2 and derivatization with DNPH, the aldehyde yields were determined using HPLC-DAD. Using an intense smoking regime (increased puff volume, shorter puff interval) significantly increased aldehyde yields, following the pattern: ISO < ISO-taped < HCI-untaped < HCI. For all of the regimes, acetaldehyde and acrolein yields were strongly correlated ( r = 0.804). The difference in TNCO and aldehyde levels between regular and highly ventilated low-TNCO cigarettes (as measured using ISO) diminished when smoking intensely; this effect is stronger when combined with taping filter vents. The highly ventilated low-TNCO brands showed six times more aldehyde production per mg nicotine for the intense smoking regimes. In conclusion, acetaldehyde and acrolein can be used as representatives for the class of volatile aldehydes for the different brands and smoking regimes. The aldehyde-to-nicotine ratio increased when highly ventilated cigarettes were smoked intensely, similar to real smokers. Thus, a smoker of highly ventilated low-TNCO cigarettes has an increased potential for higher aldehyde exposures compared to a smoker of regular cigarettes.


Assuntos
Aldeídos/análise , Nicotiana , Fumaça/análise , Monóxido de Carbono/análise , Nicotina/análise , Fumar , Alcatrões/análise , Produtos do Tabaco , Ventilação
8.
Biomarkers ; 23(8): 735-741, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29871536

RESUMO

PURPOSE: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue. METHODS: Bulky DNA adduct levels were measured using 32P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman's correlation coefficient. RESULTS: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR = 1.41 per SD increase, 95%CI: 0.92-2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR = 0.60 per SD increase, 95%CI: 0.34-1.07). Blood and colon DNA adduct levels were inversely correlated (ρ = -0.20). CONCLUSIONS: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.


Assuntos
Neoplasias Colorretais/etiologia , Adutos de DNA/análise , Mucosa Intestinal/química , Adenoma/etiologia , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prevalência , Proteína de Xeroderma Pigmentoso Grupo A/genética
9.
Int J Cancer ; 140(2): 272-284, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27649841

RESUMO

The energy restriction (ER)-colorectal cancer (CRC) association is inconsistent in literature. To strengthen the biological plausibility of the ER-CRC association, we investigated whether genetic variation in the insulin-like growth factor (IGF) pathway, a putative underlying mechanism, modulated this association in the Netherlands Cohort Study. Participants completed a questionnaire (n = 120,852) and provided toenail clippings for DNA (∼75%) at baseline. Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. Genotyping was performed for 3,768 subcohort members and 2,580 CRC cases (case-cohort with 16.3 years follow-up). Cox hazard ratios for CRC were estimated across combined categories of ER and a genetic sum score of unfavorable alleles based on 18 single nucleotide polymorphisms in IGF-related genes and ER and an IGF1 19-CA repeat polymorphism. The reference included ER exposed individuals, so that increased hazard ratios were expected in higher combined categories for calculating relative excess risks due to interaction (additive interactions). Wald tests for multiplicative interactions were also performed. Multiplicative and additive interactions were nonsignificant. Combined ER-genetic sum score categories showed increasing CRC risks in men, but confidence intervals were wide. Women carrying two variant IGF1 19-CA repeat alleles versus those carrying two wild type IGF1 19-CA repeat alleles were at an ∼50% decreased CRC risk, irrespective of ER exposure. In conclusion, data indicate that the IGF pathway might be involved in the ER-CRC association in men, but not women, although interactions were nonsignificant, hampering definite conclusions.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fatores de Risco , Transdução de Sinais/genética
10.
J Urol ; 195(4 Pt 1): 872-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26523878

RESUMO

PURPOSE: Although cigarette smoking is a well established risk factor for urothelial cancer, its role in urothelial cancer prognosis is still undetermined. In this meta-analysis we quantify the role of lifetime smoking history in bladder cancer recurrence, progression and survival by pooling available data on nonmuscle invasive bladder cancer, muscle invasive bladder cancer and upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 24 studies, comprising data from 13,114 patients with bladder cancer and 2,259 patients with upper tract urothelial carcinoma, were included in this meta-analysis. Publication bias was addressed through Egger's test, and the heterogeneity among studies was assessed by the I(2) test statistic and subgroup analyses. RESULTS: Current smokers at diagnosis are at increased risk for local recurrence in nonmuscle invasive bladder cancer (HR 1.27, 95% CI 1.09-1.46) and smokers with muscle invasive bladder cancer have an increased risk of dying of bladder cancer (HR 1.23, 95% CI 1.02-1.44). In the upper tract urothelial carcinoma population smokers have an increased risk of recurrence in the operative bed (HR 1.57, 95% CI 1.19-1.95) and of death from upper tract urothelial carcinoma (HR 1.53, 95% CI 1.13-1.92). We did not identify significant heterogeneity among included studies. CONCLUSIONS: The body of evidence is limited due to the absence of prospective studies. However, the results from this meta-analysis unambiguously support the hypothesis that lifetime cigarette smokers are at increased risk for a more malignant type of urothelial carcinoma associated with a worse prognosis.


Assuntos
Carcinoma de Células de Transição/etiologia , Neoplasias Renais/etiologia , Fumar/efeitos adversos , Neoplasias Ureterais/etiologia , Neoplasias da Bexiga Urinária/etiologia , Progressão da Doença , Humanos , Fatores de Tempo
11.
Arch Toxicol ; 90(4): 839-51, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25995008

RESUMO

The tumour suppressor p53 is one of the most important cancer genes. Previous findings have shown that p53 expression can influence DNA adduct formation of the environmental carcinogen benzo[a]pyrene (BaP) in human cells, indicating a role for p53 in the cytochrome P450 (CYP) 1A1-mediated biotransformation of BaP in vitro. We investigated the potential role of p53 in xenobiotic metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with BaP. BaP-DNA adduct levels, as measured by (32)P-postlabelling analysis, were significantly higher in liver and kidney of Trp53(-/-) mice than of Trp53(+/+) mice. Complementarily, significantly higher amounts of BaP metabolites were also formed ex vivo in hepatic microsomes from BaP-pretreated Trp53(-/-) mice. Bypass of the need for metabolic activation by treating mice with BaP-7,8-dihydrodiol-9,10-epoxide resulted in similar adduct levels in liver and kidney in all mouse lines, confirming that the influence of p53 is on the biotransformation of the parent compound. Higher BaP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with higher CYP1A protein levels and increased CYP1A enzyme activity in these animals. Our study demonstrates a role for p53 in the metabolism of BaP in vivo, confirming previous in vitro results on a novel role for p53 in CYP1A1-mediated BaP metabolism. However, our results also suggest that the mechanisms involved in the altered expression and activity of the CYP1A1 enzyme by p53 in vitro and in vivo are different.


Assuntos
Benzo(a)pireno/farmacocinética , Carcinógenos Ambientais/farmacocinética , Dano ao DNA/genética , Proteína Supressora de Tumor p53/genética , Ativação Metabólica , Animais , Benzo(a)pireno/metabolismo , Carcinógenos Ambientais/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Adutos de DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , Inativação Metabólica , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteína Supressora de Tumor p53/metabolismo
12.
Am J Respir Crit Care Med ; 191(2): 201-7, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25474185

RESUMO

RATIONALE: A reliable asthma diagnosis is difficult in wheezing preschool children. OBJECTIVES: To assess whether exhaled biomarkers, expression of inflammation genes, and early lung function measurements can improve a reliable asthma prediction in preschool wheezing children. METHODS: Two hundred two preschool recurrent wheezers (aged 2-4 yr) were prospectively followed up until 6 years of age. At 6 years of age, a diagnosis (asthma or transient wheeze) was based on symptoms, lung function, and asthma medication use. The added predictive value (area under the receiver operating characteristic curve [AUC]) of biomarkers to clinical information (assessed with the Asthma Predictive Index [API]) assessed at preschool age in diagnosing asthma at 6 years of age was determined with a validation set. Biomarkers in exhaled breath condensate, exhaled volatile organic compounds (VOCs), gene expression, and airway resistance were measured. MEASUREMENTS AND MAIN RESULTS: At 6 years of age, 198 children were diagnosed (76 with asthma, 122 with transient wheeze). Information on exhaled VOCs significantly improved asthma prediction (AUC, 89% [increase of 28%]; positive predictive value [PPV]/negative predictive value [NPV], 82/83%), which persisted in the validation set. Information on gene expression of toll-like receptor 4, catalase, and tumor necrosis factor-α significantly improved asthma prediction (AUC, 75% [increase of 17%]; PPV/NPV, 76/73%). This could not be confirmed after validation. Biomarkers in exhaled breath condensate and airway resistance (pre- and post- bronchodilator) did not improve an asthma prediction. The combined model with VOCs, gene expression, and API had an AUC of 95% (PPV/NPV, 90/89%). CONCLUSIONS: Adding information on exhaled VOCs and possibly expression of inflammation genes to the API significantly improves an accurate asthma diagnosis in preschool children. Clinical trial registered with www.clinicaltrial.gov (NCT 00422747).


Assuntos
Asma/diagnóstico , Testes Respiratórios , Perfilação da Expressão Gênica/métodos , Inflamação/diagnóstico , Sons Respiratórios/diagnóstico , Resistência das Vias Respiratórias/genética , Resistência das Vias Respiratórias/fisiologia , Asma/genética , Asma/fisiopatologia , Biomarcadores/metabolismo , Catalase/sangue , Catalase/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Inflamação/etiologia , Inflamação/genética , Modelos Logísticos , Masculino , Países Baixos , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Sons Respiratórios/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Compostos Orgânicos Voláteis/análise
13.
Carcinogenesis ; 36 Suppl 1: S61-88, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26106144

RESUMO

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos Ambientais/efeitos adversos , Exposição Ambiental/efeitos adversos , Instabilidade Genômica/efeitos dos fármacos , Substâncias Perigosas/efeitos adversos , Neoplasias/induzido quimicamente , Neoplasias/etiologia , Animais , Humanos
14.
Carcinogenesis ; 36 Suppl 1: S254-96, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26106142

RESUMO

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos Ambientais/efeitos adversos , Exposição Ambiental/efeitos adversos , Substâncias Perigosas/efeitos adversos , Neoplasias/induzido quimicamente , Neoplasias/etiologia , Animais , Humanos
15.
Cell Mol Life Sci ; 71(2): 271-85, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23892892

RESUMO

The research field of fetal programming has developed tremendously over the years and increasing knowledge suggests that both maternal and paternal unbalanced diet can have long-lasting effects on the health of offspring. Studies implicate that macronutrients play an important role in fetal programming, although the importance of micronutrients is also becoming increasingly apparent. Folic acid and vitamins B2, B6 and B12 are essential for one-carbon metabolism and are involved in DNA methylation. They can therefore influence the programming of the offspring's epigenome. Also, other micronutrients such as vitamins A and C, iron, chromium, zinc and flavonoids play a role in fetal programming. Since it is estimated that approximately 78 % of pregnant women in the US take vitamin supplements during pregnancy, more attention should be given to the long-term effects of these supplements on offspring. In this review we address several different studies which illustrate that an unbalanced diet prior and during pregnancy, regarding the intake of micronutrients of both mother and father, can have long-lasting effects on the health of adult offspring.


Assuntos
Epigenômica , Micronutrientes/metabolismo , DNA/metabolismo , Metilação de DNA , Disruptores Endócrinos/toxicidade , Feminino , Flavonoides/farmacologia , Humanos , Relações Materno-Fetais , Estresse Oxidativo/efeitos dos fármacos , Gravidez
16.
FASEB J ; 27(7): 2873-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23538710

RESUMO

Paternal exposure to high levels of radioactivity causes heritable germline minisatellite mutations. However, the effect of more general paternal exposures, such as cigarette smoking, on germline mutations remains unexplored. We analyzed two of the most commonly used minisatellite loci (CEB1 and B6.7) to identify germline mutations in blood samples of complete mother-father-child triads from the Norwegian Mother and Child Cohort Study (MoBa). The presence of mutations was subsequently related to general lifestyle factors, including paternal smoking before the partner became pregnant. Paternally derived mutations at the B6.7 locus (mutation frequency 0.07) were not affected by lifestyle. In contrast, high gross yearly income as a general measure of a healthy lifestyle coincided with low-mutation frequencies at the CEB1 locus (P=0.047). Income was inversely related to smoking behavior, and paternally derived CEB1 mutations were dose dependently increased when the father smoked in the 6 mo before pregnancy, 0.21 vs. 0.05 in smoking and nonsmoking fathers, respectively (P=0.061). These results suggest that paternal lifestyle can affect the chance of heritable mutations in unstable repetitive DNA sequences. To our knowledge, this is the first study reporting an effect of lifestyle on germline minisatellite mutation frequencies in a human population with moderate paternal exposures.


Assuntos
Mutação em Linhagem Germinativa , Peptídeos e Proteínas de Sinalização Intracelular/genética , Repetições Minissatélites/genética , Fumar , Adulto , Alelos , Criança , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Renda , Estilo de Vida , Masculino , Taxa de Mutação , Núcleo Familiar , Comportamento Paterno , Gravidez , Estudos Prospectivos , Inquéritos e Questionários
17.
FASEB J ; 27(8): 3323-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23603834

RESUMO

The mechanisms through which environmental and dietary factors modulate DNA repair are still unclear but may include dysregulation of gene expression due to altered epigenetic markings. In a mouse model, we investigated the effect of maternal folate depletion during pregnancy and lactation, and high-fat feeding from weaning, on base excision repair (BER) and DNA methylation and expression of selected BER-related genes in the brain of adult offspring. While folate depletion did not affect BER activity of the mothers, BER increased in the offspring at weaning (P=0.052). In the long term, as observed in 6-mo-old offspring, the double insult, i.e., maternal low-folate supply and high-fat feeding from weaning, decreased BER activity significantly in the cortex, cerebellum, hippocampus, and subcortical regions (P≤0.017). This fall in BER activity was associated with small changes in methylation or expression of BER-related genes. Maternal folate depletion led to slightly increased oxidative DNA damage levels in subcortical regions of adult offspring, which may increase sensitivity to oxidative stress and predispose to neurological disorders. In summary, our data suggest that low-folate supply during early life may leave an epigenetic mark that can predispose the offspring to further dietary insults, causing adverse effects during adult life.


Assuntos
Encéfalo/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Ácido Fólico/farmacologia , Fenômenos Fisiológicos da Nutrição Materna , 5-Metilcitosina/metabolismo , Animais , Sequência de Bases , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Dano ao DNA , DNA Glicosilases/genética , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Feminino , Ácido Fólico/administração & dosagem , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/farmacologia , Desmame , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
18.
Mutagenesis ; 29(6): 481-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25199627

RESUMO

Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIFα can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elucidate the mechanism behind the ability of hypoxia to increase mutagenicity of carcinogens, we examined the activation and detoxification of BaP under hypoxic conditions. To this end, the human lung carcinoma cell line A549 was treated with BaP under 20%, 5% or 0.2% oxygen for 18h and alterations in BaP metabolism were assayed. First, BaP-induced expression of key metabolic enzymes was analysed; expression levels of the activating CYP1A1 and CYP1B1 were increased, while the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. To evaluate whether these changes had an effect on metabolism, levels of BaP and several of its metabolites were determined. Cells under hypoxia have a reduced capacity to metabolise BaP leaving more of the parent molecule intact. Additionally, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations. Finally, under hypoxia, DNA adducts accumulated over a period of 168 h, whereas adducts were efficiently removed in 20% oxygen conditions. The delayed detoxification kinetics resulted in a 1.5-fold increase in DNA adducts. These data indicate that the metabolism under hypoxic conditions has shifted towards increased activation of BaP instead of detoxification and support the idea that modulation of carcinogen metabolism is an important additional mechanism for the observed HIF1 mediated genetic instability.


Assuntos
Benzo(a)pireno/toxicidade , Poluentes Ambientais/toxicidade , Mutagênicos/toxicidade , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Meios de Cultura/química , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Adutos de DNA/metabolismo , Di-Hidroxi-Di-Hidrobenzopirenos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Inativação Metabólica/efeitos dos fármacos , Cinética , Oxigênio/farmacologia , Fatores de Tempo
19.
Int J Cancer ; 132(12): 2738-47, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23175176

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity.


Assuntos
Adutos de DNA , Reparo do DNA , Fenótipo , Hidrocarbonetos Policíclicos Aromáticos , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade
20.
Am J Epidemiol ; 177(12): 1388-98, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23722011

RESUMO

Flavonoids are natural antioxidants found in various foods, and a major source is black tea. Some experimental evidence indicates that flavonoids could prevent prostate cancer. We investigated the associations between flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which includes 58,279 men who provided detailed baseline information on several cancer risk factors. From 1986 to 2003, 3,362 prostate cancers were identified, including 1,164 advanced (stage III/IV) cancers. Cox proportional hazards regression using the case-cohort approach was used to estimate hazard ratios and 95% confidence intervals. Intake of total catechin, epicatechin, kaempferol, and myricetin and consumption of black tea were associated with a decreased risk of stage III/IV or stage IV prostate cancer. Hazard ratios of stage III/IV and stage IV prostate cancer for the highest versus the lowest category of black tea consumption (≥5 versus ≤1 cups/day) were 0.75 (95% confidence interval: 0.59, 0.97) and 0.67 (95% confidence interval: 0.50, 0.91), respectively. No associations were observed for overall and nonadvanced prostate cancer. In conclusion, dietary flavonoid intake and black tea consumption were associated with a decreased risk of advanced stage prostate cancer.


Assuntos
Antioxidantes/administração & dosagem , Flavonoides/administração & dosagem , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/prevenção & controle , Idoso , Índice de Massa Corporal , Catequina/administração & dosagem , Estudos de Coortes , Dieta , Exercício Físico , Humanos , Incidência , Quempferóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/efeitos dos fármacos , Fatores de Risco , Fatores Socioeconômicos , Chá
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