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1.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199457

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds comprised of carbon and hydrogen molecules in a cyclic arrangement. PAHs are associated with risks to human health, especially carcinogenesis. One form of exposure to these compounds is through ingestion of contaminated food, which can occur during preparation and processing involving high temperatures (e.g., grilling, smoking, toasting, roasting, and frying) as well as through PAHs present in the soil, air, and water (i.e., environmental pollution). Differently from changes caused by microbiological characteristics and lipid oxidation, consumers cannot sensorially perceive PAH contamination in food products, thereby hindering their ability to reject these foods. Herein, the occurrence and biological effects of PAHs were comprehensively explored, as well as analytical methods to monitor their levels, legislations, and strategies to reduce their generation in food products. This review updates the current knowledge and addresses recent regulation changes concerning the widespread PAHs contamination in several types of food, often surpassing the concentration limits deemed acceptable by current legislations. Therefore, effective measures involving different food processing strategies are needed to prevent and reduce PAHs contamination, thereby decreasing human exposure and detrimental health effects. Furthermore, gaps in literature have been addressed to provide a basis for future studies.


Assuntos
Carcinogênese/efeitos dos fármacos , Poluição Ambiental/efeitos adversos , Alimentos/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Benzopirenos/efeitos adversos , Carcinogênese/genética , Carvão Vegetal/efeitos adversos , Culinária , Adutos de DNA/efeitos adversos , Análise de Alimentos , Manipulação de Alimentos , Humanos
2.
Chem Res Toxicol ; 34(1): 12-23, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33417435

RESUMO

O6-carboxymethylguanine (O6-CMG) is a mutagenic DNA adduct that forms at increased levels when people eat meat. It has been studied as a potential initiating event in colorectal carcinogenesis. It can arise from alkylation of guanine in DNA by electrophilic degradation products of N-nitroso compounds. There is significant data regarding biochemical and cellular process, including DNA repair and translesion DNA synthesis that control O6-CMG accumulation, persistence, and mutagenicity. Mutation spectra arising from the adduct closely resemble common mutations in colorectal cancer; however, gaps remain in understanding the biochemical processes that regulate how and where the damage persists in the genome. Addressing such questions relies on advances in chemistry such as synthesis approaches and bioanalytical methods. Results of research in this area help advance our understanding of the toxicological relevance of O6-CMG-modified DNA. Further attention should focus on understanding how a combination of genetic and environmental factors control its biological persistence and how this information can be used as a basis of biomoniotoring and prevention efforts to help mitigate colon cancer risk.


Assuntos
Neoplasias Colorretais/metabolismo , Adutos de DNA/metabolismo , DNA de Neoplasias/metabolismo , Guanina/análogos & derivados , Neoplasias Colorretais/patologia , Adutos de DNA/efeitos adversos , Guanina/efeitos adversos , Guanina/metabolismo , Humanos , Carne Vermelha/efeitos adversos
3.
Chem Res Toxicol ; 34(3): 675-677, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33508200

RESUMO

DNA damage and mutations are a major primary cause of cancer. Chemical bombardment of DNA is a major contributor to DNA damage. The Division of Chemical Toxicology recently hosted a panel of researchers who provided updates on the field of chemical toxicology at the nexus of DNA damage and repair.


Assuntos
Adutos de DNA/efeitos adversos , DNA de Neoplasias/efeitos dos fármacos , Neoplasias/induzido quimicamente , Dano ao DNA , Reparo do DNA , DNA de Neoplasias/genética , Humanos , Neoplasias/genética
4.
Mutagenesis ; 34(5-6): 413-420, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31612222

RESUMO

The environmental carcinogen benzo[a]pyrene (BaP) is presumed to exert its genotoxic effects after metabolic activation by cytochrome P450 (CYP) enzymes. However, studies using the Hepatic Reductase Null (HRN) mouse model, in which cytochrome P450 oxidoreductase (POR), the electron donor to CYP enzymes, is deleted specifically in hepatocytes, have shown that loss of hepatic POR-mediated CYP function leads to greater BaP-DNA adduct formation in livers of these mice than in wild-type (WT) mice. Here, we used CRISPR/Cas9 technology to knockout (KO) POR expression in mouse hepatoma Hepa1c1c7 cells to create an in vitro model that can mimic the HRN mouse model. Western blotting confirmed the deletion of POR in POR KO Hepa1c1c7 cells whereas expression of other components of the mixed-function oxidase system including cytochrome b5 (Cyb5) and NADH:cytochrome b5 reductase (which can also serve as electron donors to CYP enzymes), and CYP1A1 was similar in BaP-exposed WT and POR KO Hepa1c1c7 cells. BaP exposure caused cytotoxicity in WT Hepa1c1c7 cells but not in POR KO Hepa1c1c7 cells. In contrast, CYP-catalysed BaP-DNA adduct levels were ~10-fold higher in POR KO Hepa1c1c7 cells than in WT Hepa1c1c7 cells, in concordance with the presence of higher levels of BaP metabolite (e.g. BaP-7,8-dihydrodiol) in the medium of cultured BaP-exposed POR KO Hepa1c1c7 cells. As was seen in the HRN mouse model, these results suggest that Cyb5 contributes to the bioactivation of BaP in POR KO Hepa1c1c7 cells. These results indicate that CYP enzymes may play a more important role in the detoxication of BaP, as opposed to its bioactivation.


Assuntos
Benzo(a)pireno/efeitos adversos , Sistema Enzimático do Citocromo P-450/genética , Adutos de DNA/efeitos dos fármacos , Dano ao DNA/genética , Oxirredutases/genética , Ativação Metabólica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Adutos de DNA/efeitos adversos , Adutos de DNA/genética , Dano ao DNA/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos
5.
Anticancer Res ; 37(11): 6245-6249, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29061807

RESUMO

BACKGROUND/AIM: Lactoperoxidase (LPO) is an antimicrobial protein present in milk, saliva, gastric secretions, tears and upper respiratory tract secretions. LPO constitutes an important enzyme of the human immune defense system. However, LPO has also been suggested to be involved in breast cancer etiology through production of reactive free radicals and activation of carcinogenic aromatic compounds. Aromatic compounds are generally highly lipophilic and thus accumulate in highly fatty breast tissues. The aromatic compounds 4-aminobiphenyl (ABP) and 4,4'-diaminobiphenyl (BZ) are known to have carcinogenic properties. LPO catalyzes their oxidation and converts them into reactive products which bind to DNA and form adducts. These DNA adducts subsequently lead to breast cancer. MATERIALS AND METHODS: The crystal structure of LPO was obtained from Protein Data Bank. Structures of ABP and BZ were retrieved from PubChem database. Induced Fit Docking was performed using glide module from Schrodinger. RESULTS: The present study reports the structural binding of ABP and BZ with LPO using in silico approaches. The amino acid residues of LPO involved in the binding with the two aromatic ligands were characterized and binding energy values were calculated. CONCLUSION: Both ABP and BZ were placed in the substrate binding site present in the distal heme cavity of LPO with good affinity. The binding mode mimicked that of the natural substrate since these compounds did not disturb the water molecule that plays an important role in the oxidation reaction. Thus, the water molecule is potentially available for facilitating the subsequent activation of the aromatic amines to reactive species which may form DNA adducts leading to breast cancer.


Assuntos
Compostos de Aminobifenil/metabolismo , Neoplasias da Mama/induzido quimicamente , Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Radicais Livres/química , Lactoperoxidase/metabolismo , Compostos de Aminobifenil/efeitos adversos , Compostos de Aminobifenil/química , Sítios de Ligação , Neoplasias da Mama/enzimologia , Carcinógenos/química , Adutos de DNA/efeitos adversos , Adutos de DNA/química , Feminino , Humanos , Lactoperoxidase/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Conformação Proteica
6.
Environ Health Perspect ; 124(1): 30-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26008800

RESUMO

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure. OBJECTIVES: Our study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence. METHODS: Residential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996-1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960-1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH-DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression. RESULTS: The odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960-1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic-breast cancer association was higher for those with estrogen/progesterone-negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants]. CONCLUSIONS: In our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise. CITATION: Mordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P Jr., Santella RM, Gammon MD. 2016. Vehicular traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: the Long Island Breast Cancer Study Project (LIBCSP). Environ Health Perspect 124:30-38; http://dx.doi.org/10.1289/ehp.1307736.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Neoplasias da Mama/epidemiologia , Adutos de DNA/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Emissões de Veículos/toxicidade , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Incidência
7.
Oncotarget ; 6(32): 33226-36, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26431382

RESUMO

Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers.


Assuntos
Acroleína/metabolismo , Carcinogênese/genética , Adutos de DNA/metabolismo , Reparo do DNA/efeitos dos fármacos , Neoplasias Pulmonares/genética , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Neoplasias da Bexiga Urinária/genética , Acroleína/efeitos adversos , Animais , Carcinogênese/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Adutos de DNA/efeitos adversos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Neoplasias da Bexiga Urinária/patologia
8.
Cancer Causes Control ; 26(12): 1791-802, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26407953

RESUMO

PURPOSE: Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH-DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH-DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype. METHODS: In a population-based case-control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765-851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH-DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity. RESULTS: Women with detectable PAH-DNA adducts and methylated RARß (ROR 2.69, 95% CI 1.02-7.12; p for interaction = 0.03) or APC (ROR 1.76, 95% CI 0.87-3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls. CONCLUSIONS: Gene-specific methylation of RARß, and perhaps APC, may interact with PAH-DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest.


Assuntos
Neoplasias da Mama/epidemiologia , Adutos de DNA/efeitos adversos , Metilação de DNA , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Adulto , Idoso , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Razão de Chances , Regiões Promotoras Genéticas , Fatores de Risco
9.
Mutagenesis ; 30(4): 565-76, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25805023

RESUMO

Deregulation of Wnt/ß-catenin signalling plays an important role in the pathogenesis of colorectal cancer. Interestingly, this pathway has been recently implicated in transcriptional control of cytochrome P450 (CYP) family 1 enzymes, which are responsible for bioactivation of a number of dietary carcinogens. In the present study, we investigated the impact of inhibition of Wnt/ß-catenin pathway on metabolism and genotoxicity of benzo[a]pyrene (BaP), a highly mutagenic polycyclic aromatic hydrocarbon and an efficient ligand of the aryl hydrocarbon receptor, which is known as a primary regulator of CYP1 expression, in cellular models derived from colorectal tumours. We observed that a synthetic inhibitor of ß-catenin, JW74, significantly increased formation of BaP-induced DNA adducts in both colorectal adenoma and carcinoma-derived cell lines. Using the short interfering RNA (siRNA) targeting ß-catenin, we then found that ß-catenin knockdown in HCT116 colon carcinoma cells significantly enhanced formation of covalent DNA adducts by BaP and histone H2AX phosphorylation, as detected by (32)P-postlabelling technique and immunocytochemistry, respectively, and it also induced expression of DNA damage response genes, such as CDKN1A or DDB2. The increased formation of DNA adducts formed by BaP upon ß-catenin knockdown corresponded with enhanced production of major BaP metabolites, as well as with an increased expression/activity of CYP1 enzymes. Finally, using siRNA-mediated knockdown of CYP1A1, we confirmed that this enzyme plays a major role in formation of BaP-induced DNA adducts in HCT116 cells. Taken together, the present results indicated that the siRNA-mediated inhibition of ß-catenin signalling, which is aberrantly activated in a majority of colorectal cancers, modulated genotoxicity of dietary carcinogen BaP in colon cell model in vitro, via a mechanism involving up-regulation of CYP1 expression and activity.


Assuntos
Benzo(a)pireno/efeitos adversos , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Citocromo P-450 CYP1A1/metabolismo , Adutos de DNA/efeitos adversos , Dano ao DNA , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Apoptose , Western Blotting , Carcinógenos Ambientais/efeitos adversos , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/genética , Humanos , Técnicas Imunoenzimáticas , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , beta Catenina/genética , beta Catenina/metabolismo
10.
Carcinogenesis ; 35(5): 1172-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24501327

RESUMO

The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM-DNA adducts were measurable by TAM-DNA chemiluminescence immunoassay. Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, whereas unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.


Assuntos
Adutos de DNA/metabolismo , DNA/metabolismo , Tamoxifeno/metabolismo , Útero/metabolismo , Animais , DNA/química , Adutos de DNA/efeitos adversos , Adutos de DNA/química , Endométrio/metabolismo , Erythrocebus patas , Feminino , Humanos , Miométrio/metabolismo , Tamoxifeno/química
11.
Carcinogenesis ; 35(7): 1461-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24398669

RESUMO

Aflatoxin B1 (AFB1) is a known carcinogen associated with early-onset hepatocellular carcinoma (HCC) and is thought to contribute to over half a million new HCCs per year. Although some of the fundamental risk factors are established, the molecular basis of AFB1-induced mutagenesis in primate cells has not been rigorously investigated. To gain insights into genome instability that is produced as a result of replicating DNAs containing AFB1 adducts, site-specific mutagenesis assays were used to establish the mutagenic potential of the persistent ring-opened AFB1 adduct, AFB1-formamidopyrimidine (AFB1-FAPY). This lesion was highly mutagenic, yielding replication error frequencies of 97%, with the predominant base substitution being a G to T transversion. This transversion is consistent with previous mutational data derived from aflatoxin-associated HCCs. In vitro translesion synthesis assays demonstrated that polymerase (pol) ζ was the most likely candidate polymerase that is responsible for the G to T mutations induced by this adduct.


Assuntos
Aflatoxina B1/efeitos adversos , Carcinoma Hepatocelular/genética , Adutos de DNA/efeitos adversos , Replicação do DNA/genética , Neoplasias Hepáticas/genética , Mutação/genética , Pirimidinas/efeitos adversos , Animais , Células COS , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Chlorocebus aethiops , DNA de Cadeia Simples/genética , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Mutagênese Sítio-Dirigida , Reação em Cadeia da Polimerase
12.
Environ Health Perspect ; 122(2): 193-200, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24252472

RESUMO

BACKGROUND: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development. OBJECTIVES: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. METHODS: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. RESULTS: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN. CONCLUSION: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.


Assuntos
Biomarcadores/análise , Carcinógenos/análise , Sangue Fetal/citologia , Hormônios/análise , Leucemia/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Linfócitos T/química , Carcinógenos/toxicidade , Criança , Estudos de Coortes , Adutos de DNA/efeitos adversos , Adutos de DNA/análise , Europa (Continente)/epidemiologia , Feminino , Sangue Fetal/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hormônios/efeitos adversos , Humanos , Leucemia/induzido quimicamente , Malondialdeído/efeitos adversos , Malondialdeído/análise , Testes para Micronúcleos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Linfócitos T/efeitos dos fármacos
13.
Photochem Photobiol Sci ; 12(1): 85-94, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23139090

RESUMO

Allergic contact dermatitis (ACD) to Parthenium hysterophorus is the most common cause of plant dermatitis in India. Parthenium dermatitis is caused by dry powder of leaves and flowers and hair-like structures (trichomes). Sesquiterpene lactones (SQLs) are the most important allergens responsible for ACD to parthenium. The different patterns include classical airborne contact dermatitis, chronic actinic dermatitis (CAD), exfoliative and widespread dermatitis. There is a definite trend towards a change from an airborne pattern to a CAD pattern in the natural history of parthenium dermatitis. In CAD, there is a reported increased sensitivity to UVB, UVA and even visible light. However, SQLs including parthenin, the major allergen in the Parthenium hysterophorus, has neither documented photoallergic nor phototoxic properties. Recently, the high photoreactivity of α-methylene-γ-butyrolactone ring toward thymidine and resulting photoadducts has been proposed as an explanation of the progressive evolution of allergic contact dermatitis toward chronic actinic dermatitis. However, more data is required to reach a conclusion on the mechanism of photosensitivity in parthenium dermatitis. Sunlight, especially UV radiation, may have a role in increasing the germination capacity and the amount of allergens in the Compositae family, especially in parthenium plants under appropriate conditions like summer and spring, which may contribute to high prevalence of parthenium dermatitis especially in northern India.


Assuntos
Asteraceae/química , Dermatite Alérgica de Contato/etiologia , Alérgenos/efeitos adversos , Alérgenos/química , Alérgenos/imunologia , Asteraceae/metabolismo , Adutos de DNA/efeitos adversos , Adutos de DNA/química , Dermatite Alérgica de Contato/imunologia , Humanos , Lactonas/química , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Timidina/química , Raios Ultravioleta
14.
Toxicol Lett ; 213(1): 83-90, 2012 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-21501670

RESUMO

To understand environmental causes of disease, unbiased methods are needed to characterize the human exposome, which represents all toxicants to which people are exposed from both exogenous and endogenous sources. Because they directly modify DNA and important proteins, reactive electrophiles are probably the most important constituents of the exposome. Exposures to reactive electrophiles can be characterized by measuring adducts from reactions between circulating electrophiles and blood nucleophiles. We define an 'adductome' as the totality of such adducts with a given nucleophilic target. Because of their greater abundance and residence times in human blood, adducts of hemoglobin (Hb) and human serum albumin (HSA) are preferable to those of DNA and glutathione for characterizing adductomes. In fact, the nucleophilic hotspot represented by the only free sulfhydryl group in HSA (HSA-Cys(34)) offers particular advantages for adductomic experiments. Although targeted adducts of HSA-Cys(34) have been monitored for decades, an unbiased method has only recently been reported for visualizing the HSA-Cys(34) 'subadductome'. The method relies upon a novel mass spectrometry application, termed fixed-step selected reaction monitoring (FS-SRM), to profile Cys(34) adducts in tryptic digests of HSA. Here, we selectively review the literature regarding the potential of adductomics to partially elucidate the human exposome, with particular attention to the HSA-Cys(34) subadductome.


Assuntos
Exposição Ambiental/efeitos adversos , Noxas/efeitos adversos , Adutos de DNA/efeitos adversos , Exposição Ambiental/análise , Monitoramento Ambiental , Humanos , Noxas/análise , Noxas/metabolismo , Proteínas/efeitos dos fármacos , Proteínas/metabolismo , Compostos de Sulfidrila/efeitos adversos , Compostos de Sulfidrila/metabolismo , Toxicologia/métodos , Xenobióticos/efeitos adversos , Xenobióticos/metabolismo
15.
Liver Int ; 31(9): 1366-72, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21745313

RESUMO

BACKGROUND & AIMS: Hepatitis B or C virus infection is considered to be the main cause of hepatocellular carcinoma (HCC) in Japan. Aflatoxin B1 (AFB1) is a carcinogen associated with HCC in regions with high exposure. Mutations in codon 249, exon 7 are a hallmark of AFB1 exposure. Therefore, to clarify the role of AFB1 in hepatocarcinogenesis, we examined AFB1-DNA in liver tissue and sequenced TP53 in Japanese patients with HCC. METHODS: Hepatocyte AFB1-DNA adducts were determined immunohistochemically and direct sequencing of TP53 was done to determine mutations in 188 of 279 patients who underwent hepatic resection for HCC. We assessed hepatitis C virus antibodies (HCV Ab) and HBSAg expression; patients without either were defined as having non-B non-C hepatocellular carcinoma (NBNC HCC). RESULTS: AFB1-DNA adducts were detected in hepatocyte nuclei in 18/279 patients (6%), including 13/83 patients (16%) with NBNC HCC and 5/51 patients (10%) expressing hepatitis B surface antigen. None of the patients with HCV Ab (n=136) were positive for AFB1-DNA. The incidence of the G-T transversion and mutations in exon 7 of TP53 in patients with AFB1-DNA adducts were significantly higher in patients with than in patients without AFB1-DNA adducts. All three patients with the codon 249 AGG-AGT mutation had AFB1-DNA adducts. CONCLUSION: Although exposure to AFB1 is thought to be low in Japan, it is still associated with hepatocarcinogenesis, particularly in NBNC HCC and hepatitis B individuals.


Assuntos
Aflatoxina B1/análise , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/genética , Adutos de DNA/análise , Neoplasias Hepáticas/química , Neoplasias Hepáticas/genética , Mutação , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Aflatoxina B1/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Distribuição de Qui-Quadrado , Adutos de DNA/efeitos adversos , Análise Mutacional de DNA , Feminino , Antígenos de Superfície da Hepatite B/sangue , Anticorpos Anti-Hepatite C/sangue , Humanos , Imuno-Histoquímica , Japão/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Adulto Jovem
16.
Free Radic Biol Med ; 48(2): 318-24, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19909805

RESUMO

Catechol quinones of estrogens react with DNA by 1,4-Michael addition to form depurinating N3Ade and N7Gua adducts. Loss of these adducts from DNA creates apurinic sites that can generate mutations leading to cancer initiation. We compared the reactions of the catechol quinones of the leukemogenic benzene (CAT-Q) and N-acetyldopamine (NADA-Q) with 2'-deoxyguanosine (dG) or DNA. NADA was used to prevent intramolecular cyclization of dopamine quinone. Reaction of CAT-Q or NADA-Q with dG at pH 4 afforded CAT-4-N7dG or NADA-6-N7dG, which lost deoxyribose with a half-life of 3 h to form CAT-4-N7Gua or 4 h to form NADA-6-N7Gua. When CAT-Q or NADA-Q was reacted with DNA, N3Ade adducts were formed and lost from DNA instantaneously, whereas N7Gua adducts were lost over several hours. The maximum yield of adducts in the reaction of CAT-Q or NADA-Q with DNA at pH 4 to 7 was at pH 4. When tyrosinase-activated CAT or NADA was reacted with DNA at pH 5 to 8, adduct levels were much higher (10- to 15-fold), and the highest yield was at pH 5. Reaction of catechol quinones of natural and synthetic estrogens, benzene, naphthalene, and dopamine with DNA to form depurinating adducts is a common feature that may lead to initiation of cancer or neurodegenerative disease.


Assuntos
Benzeno/metabolismo , Adutos de DNA/efeitos adversos , Dopamina/metabolismo , Neoplasias/etiologia , Doenças Neurodegenerativas/etiologia , Aminobutiratos/farmacologia , Animais , Benzeno/química , Catecóis/química , Bovinos , Transformação Celular Neoplásica , Cromatografia Líquida de Alta Pressão , Adutos de DNA/química , Dopamina/análogos & derivados , Dopamina/química , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Mutagênese/efeitos dos fármacos , Mutagênese/genética , Mutagênicos/efeitos adversos , Mutagênicos/química , Naftalenos/química , Naftalenos/metabolismo , Quinonas/química
17.
Future Oncol ; 6(1): 75-91, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20021210

RESUMO

Experiments on estrogen metabolism, formation of DNA adducts, mutagenicity, cell transformation and carcinogenicity have led to and supported the hypothesis that the reaction of specific estrogen metabolites, mostly the electrophilic catechol estrogen-3,4-quinones, with DNA can generate the critical mutations to initiate breast and other human cancers. Analysis of depurinating estrogen-DNA adducts in urine demonstrates that women at high risk of, or with breast cancer, have high levels of the adducts, indicating a critical role for adduct formation in breast cancer initiation. Men with prostate cancer or non-Hodgkin lymphoma also have high levels of estrogen-DNA adducts. This knowledge of the first step in cancer initiation suggests the use of specific antioxidants that can block formation of the adducts by chemical and biochemical mechanisms. Two antioxidants, N-acetylcysteine and resveratrol, are prime candidates to prevent breast and other human cancers because in various M in vitro and in vivo experiments, they reduce the formation of estrogen-DNA adducts.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Adutos de DNA/metabolismo , Estrogênios/metabolismo , Acetilcisteína/farmacologia , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Adutos de DNA/efeitos adversos , Feminino , Humanos , Masculino , Neoplasias/etiologia , Neoplasias/prevenção & controle , Resveratrol , Estilbenos/farmacologia
18.
Chem Res Toxicol ; 21(1): 93-101, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18052105

RESUMO

There is a clear association between the excessive exposure to estrogens and the development of cancer in hormone-sensitive tissues (breast, endometrium). It has become clear that there are likely multiple overlapping mechanisms of estrogen carcinogenesis. One major pathway is the extensively studied hormonal pathway, by which estrogen stimulates cell proliferation through nuclear estrogen receptor (ER)-mediated signaling, thus resulting in an increased risk of genomic mutations during DNA replication. A similar "nongenomic pathway", potentially involving newly discovered membrane-associated ERs, also appears to regulate extranuclear estrogen signaling pathways. This perspective is focused on a third pathway involving the metabolism of estrogens to catechols mediated by cytochrome P450 and further oxidation of these catechols to estrogen o-quinones. Oxidative enzymes, metal ions, and in some cases molecular oxygen can catalyze o-quinone formation, so that these electrophilic/redox-active quinones can cause damage within cells by alkylation and/or oxidation of cellular proteins and DNA in many tissues. It appears that the endogenous estrogen quinones primarily form unstable N3-adenine or N7-guanine DNA adducts, ultimately resulting in mutagenic apurinic sites. In contrast, equine estrogen quinones, formed from estrogens present in popular hormone replacement therapy prescriptions, generate a variety of DNA lesions, including bulky stable adducts, apurinic sites, DNA strand cleavage, and oxidation of DNA bases. DNA damage induced by these equine quinones is significantly increased in cells containing ERs, leading us to hypothesize a mechanism involving ER binding/alkylation by the catchol/quinone, resulting in a "Trojan horse". The "Trojan horse" carries the highly redox-active catechol to estrogen -sensitive genes, where high amounts of reactive oxygen species are generated, causing selective DNA damage. Our data further suggest that other key protein targets for estrogen o-quinones could be redox-sensitive enzymes (i.e, GST P1-1, QR). These proteins are involved in stress response cascades that are known to contribute to the regulation of cell proliferation and apoptosis. Finally, it has been shown that catechol estrogens can transform breast epithelial cells into a tumorigenic phenotype and that these transformed cells had differential gene expression of several genes involved in oxidative stress. Given the direct link between excessive exposure to estrogens, metabolism of estrogens, and increased risk of breast cancer, it is crucial that factors that affect the formation, reactivity, and cellular targets of estrogen quinoids be thoroughly explored.


Assuntos
Estrogênios/toxicidade , Neoplasias/induzido quimicamente , Quinonas/toxicidade , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Adutos de DNA/efeitos adversos , Dano ao DNA , Enzimas/efeitos dos fármacos , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/farmacocinética , Estrogênios de Catecol/farmacocinética , Estrogênios de Catecol/toxicidade , Feminino , Humanos , Oxirredução , Quinonas/farmacocinética , Receptores de Estrogênio/efeitos dos fármacos , Medição de Risco
19.
Environ Health Perspect ; 115(10): 1497-502, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17938742

RESUMO

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are air pollutants released by the World Trade Center (WTC) fires and urban combustion sources. BaP-DNA adducts provide a measure of PAH-specific genetic damage, which has been associated with increased risk of adverse birth outcomes and cancer. We previously reported that levels of BaP-DNA adducts in maternal and umbilical cord blood obtained at delivery were elevated among subjects who had resided within 1 mile of the WTC site during the month after 9/11; and that elevated blood adducts in combination with in utero exposure to environmental tobacco smoke (ETS) were significantly associated with decreased fetal growth. OBJECTIVE: Our aim was to assess possible effects of prenatal exposure to WTC pollutants on child development. METHODS: After 11 September 2001, we enrolled a cohort of nonsmoking pregnant women who delivered at three lower Manhattan hospitals. We have followed a subset of children through their third birthdays and measured cognitive and motor development using the Bayley-II Scales of Child Development (BSID-II). RESULTS: In multivariate analyses, we found a significant interaction between cord blood adducts and in utero exposure to ETS on mental development index score at 3 years of age (p = 0.02, n = 98) whereas neither adducts nor ETS alone was a significant predictor of (BSID-II) cognitive development. CONCLUSION: Although limited by small numbers, these results suggest that exposure to elevated levels of PAHs in conjunction with prenatal ETS exposure may have contributed to a modest reduction in cognitive development among cohort children.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Adutos de DNA/efeitos adversos , Exposição Ambiental/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Ataques Terroristas de 11 de Setembro , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Poluentes Atmosféricos/efeitos adversos , Biomarcadores , Pré-Escolar , Estudos de Coortes , Adutos de DNA/química , Deficiências do Desenvolvimento/induzido quimicamente , Feminino , Humanos , Lactente , Cidade de Nova Iorque , Gravidez , Características de Residência , População Urbana
20.
Int J Hyg Environ Health ; 210(3-4): 201-28, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17376741

RESUMO

Human biomonitoring (HBM) of dose and biochemical effect nowadays has tremendous utility providing an efficient and cost effective means of measuring human exposure to chemical substances. HBM considers all routes of uptake and all sources which are relevant making it an ideal instrument for risk assessment and risk management. HBM can identify new chemical exposures, trends and changes in exposure, establish distribution of exposure among the general population, identify vulnerable groups and populations with higher exposures and identify environmental risks at specific contaminated sites with relatively low expenditure. The sensitivity of HBM methods moreover enables the elucidation of human metabolism and toxic mechanisms of the pollutants. So, HBM is a tool for scientists as well as for policy makers. Blood and urine are by far the most approved matrices. HBM can be done for most chemical substances which are in the focus of the worldwide discussion of environmental medicine. This especially applies for metals, PAH, phthalates, dioxins, pesticides, as well as for aromatic amines, perfluorinated chemicals, environmental tobacco smoke and volatile organic compounds. Protein adducts, especially Hb-adducts, as surrogates of DNA adducts measuring exposure as well as biochemical effect very specifically and sensitively are a still better means to estimate cancer risk than measuring genotoxic substances and their metabolites in human body fluids. Using very sophisticated but nevertheless routinely applicable analytical procedures Hb-adducts of alkylating agents, aromatic amines and nitro aromatic compounds are determined routinely today. To extend the spectrum of biochemical effect monitoring further methods should be elaborated which put up with cleavage and separation of the adducted protein molecules as a measure of sample preparation. This way all sites of adduction as well as further proteins, like serum albumin could be used for HBM. DNA-adducts indicate the mutagenicity of a chemical substance as well as an elevated cancer risk. DNA-adducts therefore would be ideal parameters for HBM. Though there are very sensitive techniques for DNA adduct monitoring like P32-postlabelling and immunological methods they lack specificity. For elucidating the mechanism of carcinogenesis and for a broad applicability and comparability in epidemiological studies analytical methods must be elaborated which are strictly specific for the chemical structure of the DNA-adduct. Current analytical possibilities however meet their borders. In HBM studies with exposure to genotoxic chemicals especially the measurement of DNA strand breaks in lymphocytes and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in white blood cells has become very popular. However, there is still a lack of well-established dose-response relations between occupational or environmental exposures and the induction of 8-OHdG or formation of strand breaks which limits the applicability of these markers. Most of the biomarkers used in population studies are covered by standard operating procedures (SOPs) as well as by internal and external quality assessment schemes. Therefore, HBM results from the leading laboratories worldwide are analytically reliable and comparable. Newly upcoming substances of environmental relevance like perfluorinated compounds can rapidly be assessed in body fluids because there are very powerful laboratories which are able to elaborate the analytical prerequisites in due time. On the other hand, it is getting more and more difficult for the laboratories to keep up with a progress in instrumental analyses. In spite of this it will pay to reach the ultimate summit of HBM because it is the only way to identify and quantify human exposure and risk, elucidate the mechanism of toxic effects and to ultimately decide if measures have to be taken to reduce exposure. Risk assessment and risk management without HBM lead to wrong risk estimates and cause inadequate measures. In some countries like in USA and in Germany, thousands of inhabitants are regularly investigated with respect to their internal exposure to a broad range of environmentally occurring substances. For the evaluation of HBM results the German HBM Commission elaborates reference- and HBM-values.


Assuntos
Adutos de DNA/sangue , Desoxiguanosina/análogos & derivados , Monitoramento Ambiental/métodos , 8-Hidroxi-2'-Desoxiguanosina , Biomarcadores/urina , Ensaio Cometa , Adutos de DNA/efeitos adversos , Adutos de DNA/análise , Desoxiguanosina/urina , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Poluentes Ambientais/efeitos adversos , Poluentes Ambientais/análise , Humanos , Metais/efeitos adversos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Compostos Orgânicos/efeitos adversos , Valores de Referência
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