Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
1.
Biochim Biophys Acta Gene Regul Mech ; 1867(1): 195007, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38237857

RESUMO

Telomere integrity is required for the maintenance of genome stability and prevention of oncogenic transformation of cells. Recent evidence suggests the presence of epigenetic modifications as an important regulator of mammalian telomeres. Telomeric and subtelomeric regions are rich in epigenetic marks that regulate telomere length majorly through DNA methylation and post-translational histone modifications. Specific histone modifying enzymes play an integral role in establishing telomeric histone codes necessary for the maintenance of structural integrity. Alterations of crucial histone moieties and histone modifiers cause deregulations in the telomeric chromatin leading to carcinogenic manifestations. This review delves into the significance of histone modifications and their influence on telomere dynamics concerning cancer. Additionally, it highlights the existing research gaps that hold the potential to drive the development of therapeutic interventions targeting the telomere epigenome.


Assuntos
Epigênese Genética , Histonas , Animais , Histonas/metabolismo , Código das Histonas/genética , Telômero/genética , Telômero/metabolismo , Carcinogênese/genética , Mamíferos/genética
2.
J Biol Chem ; 298(1): 101521, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34952004

RESUMO

CD200R1 is an inhibitory surface receptor expressed in microglia and blood macrophages. Microglial CD200R1 is known to control neuroinflammation by keeping the microglia in resting state, and therefore, tight regulation of its expression is important. CCAAT/enhancer-binding protein ß (CEBPß) is the known regulator of CD200R1 transcription. In the present study, our specific intention was to find a possible posttranscriptional regulatory mechanism of CD200R1 expression. Here we investigated a novel regulatory mechanism of CD200R1 expression following exposure to an environmental stressor, arsenic, combining in silico analysis, in vitro, and in vivo experiments, as well as validation in human samples. The in silico analysis and in vitro studies with primary neonatal microglia and BV2 microglia revealed that arsenic demethylates the promoter of a microRNA, miR-129-5p, thereby increasing its expression, which subsequently represses CD200R1 by binding to its 3'-untranslated region and shuttling the CD200R1 mRNA to the cytoplasmic-processing body in mouse microglia. The role of miR-129-5p was further validated in BALB/c mouse by stereotaxically injecting anti-miR-129. We found that anti-miR-129 reversed the expression of CD200R1, as well as levels of inflammatory molecules IL-6 and TNF-α. Experiments with a CD200R1 siRNA-induced loss-of-function mouse model confirmed an miR-129-5p→CD200R1→IL-6/TNF-α signaling axis. These main findings were replicated in a human cell line and validated in human samples. Taken together, our study revealed miR-129-5p as a novel posttranscriptional regulator of CD200R1 expression with potential implications in neuroinflammation and related complications.


Assuntos
Arsênio , MicroRNAs , Doenças Neuroinflamatórias , Receptores de Orexina , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Interleucina-6/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias/metabolismo , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Genes Environ ; 42: 25, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884603

RESUMO

Hydroxychloroquine (HCQ) and Chloroquine (CQ) are two anti-malarial drugs that are now being extensively used by front-line healthcare workers and other common people as a prophylactic drug against the Corona Virus Disease - 19 (COVID-19) in India and as well as in many parts of the world. While only a few in vitro studies have pointed to some efficacy of these drugs as a prophylactic against COVID-19, to date, there are no clinical studies that have established any clinical efficacy of these drugs as a prophylactic. These drugs are commonly used for the treatment of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) because of its immunomodulatory effects. Previously, we have evaluated the genetic toxicology of different drugs and chemicals including antimalarial drug CQ both in vitro and in vivo. Thus, we recognize the need to critically review the mutagenic, genotoxic, and immunomodulatory effects of these drugs, to find out whether it is safe to use as a prophylactic drug against COVID-19. Existing literature suggests that CQ can induce mutagenic and genotoxic effects in multiple test systems and both the drugs have immunomodulatory effects. There was no data available to evaluate the mutagenicity and genotoxicity for HCQ. However, during metabolism about 60% of both the drugs remain unchanged and about 40% of the drugs are metabolized into two metabolites, desethylchloroquine and bisdesethylchloroquine by the action of the cytochrome P450 (CYP) enzymes in the liver. Both HCQ and CQ are immunomodulatory drugs and have the potential to suppress normal immune system activation. In this review, we have elucidated the mechanism of immunomodulation by both HCQ and CQ and highlighted the mutagenic and genotoxic effects from the available literature. This article is written with the sole objective that the reader will be able to recognize the adverse effects of these drugs when consumed by healthy individuals as a prophylactic. Current literature indicates that healthy individuals should refrain from the use of these drugs until further investigation.

4.
Sci Total Environ ; 704: 135388, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31837846

RESUMO

Telomere integrity is considered to be one of the primary mechanisms during malignant transformation. Arsenic, a group 1 carcinogenic metalloid, has been reported to cause telomere lengthening in a telomerase-independent manner. Recent studies suggest a significant role for epigenetic modifications in regulating telomeric length and integrity. Here, we have explored the role of epigenetic deregulation in alternative lengthening of telomeres (ALT) in arsenic-exposed skin cancer tissues and corresponding non-tumor tissues. The relative telomere length (RTL) was analyzed by qRT-PCR using 2-ΔΔCt method. The subtelomeric methylation pattern of the four chromosomes (7q, 18p, 21q and XpYp) were analysed by Methylation Specific PCR (MSP) in 40 pairs of arsenic exposed skin cancer tissues and its corresponding control. The role of constitutive heterochromatin histone marks in the regulation of telomere length (TL) was analyzed by targeted ELISA. A 2-fold increase of relative telomere length in 85% of the arsenic-induced skin cancer tissues was observed. Among the four chromosomes, subtelomere of XpYp was found to be hypermethylated (p < 0.001) whereas 18p was hypomethylated (p < 0.01). Additionally, the level of H4K20me3, a heterochromatic mark was found to be significantly down-regulated (p < 0.0003), and inversely correlated with telomere length indicating loss of heterochromatinization of telomeric DNA. These observations highlight the novel role of epigenetic regulation in the maintenance of constitutive heterochromatin structure at telomere. Alteration in subtelomeric DNA methylation patterns and depletion of H4K20me3 might lead to loss of heterochromatinization resulting in arsenic-induced telomeric elongation. We provide novel data indicating possible alternative determinants of telomere elongation through epigenetic modifications during arsenic-induced skin carcinogenesis which could be used as early 'epimarkers' in the near future. The findings provide new insights about the mechanism of arsenic-induced carcinogenesis.


Assuntos
Arsênio/toxicidade , Epigênese Genética , Neoplasias Cutâneas/induzido quimicamente , Homeostase do Telômero , Carcinogênese , Transformação Celular Neoplásica , Metilação de DNA , Humanos , Telomerase , Telômero
5.
Environ Sci Pollut Res Int ; 26(27): 28052-28061, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359311

RESUMO

Arsenic exposure by groundwater contamination is a menace which threatens more than 26 million individuals of West Bengal. Interestingly, with similar levels of arsenic exposure, only 15-20% of the population show arsenic-induced skin lesions, the hallmarks of chronic arsenic toxicity, but the rest do not. In this study, our aim was to identify whether microRNAs (miRNA) have any role to play in causing such arsenic susceptibility. Global plasma miRNA profiling was done in 12 arsenic-exposed individuals with skin lesions and 12 exposed individuals without skin lesions. Two hundred two miRNAs were found to be differentially regulated between the two study groups. Results were validated by quantitative real-time PCR in 30 exposed subjects from each of the groups, which showed that among others miR-21, miR-23a, miR-27a, miR-122, miR-124, miR-126, miR-619, and miR-3613 were significantly upregulated and miR-1282 and miR-4530 were downregulated in the skin lesion group compared with the no skin lesion group. Bioinformatic analyses predicted that these altered miRNAs have targets in 7 different biochemical pathways, including glycerophospholipid metabolism, colorectal cancer, glycosphingolipid biosynthesis, T cell receptor signaling, and neurotrophin signaling pathways; glycerophospholipid metabolism pathway being the most enriched pathway. Association study show that these microRNAs contribute significantly to the increased prevalence of other non-dermatological health effects like conjunctival irritations of the eyes and respiratory distress in the study subjects. To our knowledge, this is the first study of its kind involving miRNA expressions contributing to arsenic susceptibility in the exposed population of West Bengal.


Assuntos
Intoxicação por Arsênico/genética , Exposição Ambiental , Arsênio/análise , Intoxicação por Arsênico/epidemiologia , Humanos , Índia/epidemiologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Dermatopatias/epidemiologia , Regulação para Cima
6.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt A): 82-88, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389167

RESUMO

Increasing evidence of arsenic contamination in ground water and its associated adverse health outcomes affects millions of people worldwide. However, arsenic toxicity studies in children have gained impetus very recently due to the non-prominence of the hallmarks of arsenic toxicity i.e skin lesions. We recognized the need to evaluate the status of genetic damage brought about by early life exposure to arsenic in children as measured by micronucleus (MN) assay for three cell types namely buccal mucosa, urothelial cells and lymphocytes. A thorough health checkup and complete haematogram of the study participants was performed to measure overall health effects and changes in the blood profile in children exposed to arsenic through drinking water in West Bengal, India. Since telomere length alteration has been identified as a good indicator of arsenic toxicity in adults, we measured the telomere length of the arsenic exposed and unexposed children. We found that all the three cell types had significantly higher (P < 0.0001) MN frequency in the arsenic exposed children when compared to the unexposed. Blood profiling showed significantly altered neutrophil, eosinophil, lymphocyte and haemoglobin levels in the arsenic exposed children than their unexposed counterparts. Telomere length in the arsenic exposed children was slightly higher than the unexposed. This is a firsthand report of the genetic damage observed in children exposed to arsenic through drinking water in West Bengal, India.


Assuntos
Arsênio/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Linfócitos/patologia , Mucosa Bucal/patologia , Homeostase do Telômero/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Índia , Linfócitos/efeitos dos fármacos , Masculino , Testes para Micronúcleos , Mucosa Bucal/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos
7.
Toxicol Res ; 34(4): 311-324, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30370006

RESUMO

Arsenic is one of the most toxic environmental toxicants. More than 150 million people worldwide are exposed to arsenic through ground water contamination. It is an exclusive human carcinogen. Although the hallmarks of arsenic toxicity are skin lesions and skin cancers, arsenic can also induce cancers in the lung, liver, kidney, urinary bladder, and other internal organs. Arsenic is a non-mutagenic compound but can induce significant cytogenetic damage as measured by chromosomal aberrations, sister chromatid exchanges, and micronuclei formation in human systems. These genotoxic end points are extensively used to predict genotoxic potentials of different environmental chemicals, drugs, pesticides, and insecticides. These cytogenetic end points are also used for evaluating cancer risk. Here, by critically reviewing and analyzing the existing literature, we conclude that inorganic arsenic is a genotoxic carcinogen.

8.
PLoS One ; 13(8): e0202579, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30114287

RESUMO

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.


Assuntos
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Adulto , Arsênio/efeitos adversos , Carcinoma Basocelular/induzido quimicamente , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Água Potável/efeitos adversos , Regulação Neoplásica da Expressão Gênica , Humanos , Índia/epidemiologia , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia
9.
Mutat Res ; 807: 1-9, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29161537

RESUMO

Arsenic, a non mutagenic carcinogen, poses a profound health risk upon prolonged exposure. The objective of the study was to analyze the post-translational modifications of the major histone H3 and the associated molecular crosstalk to identify the epigenetic signature of arsenic susceptibility. Herein, we identified significant upregulation of H3K79me1, in individuals with arsenic-induced skin lesion (WSL), and H3K79me1 was found to be regulated by the upstream methyltransferase DOT1L. Moreover, the downstream target molecule 53BP1, a tumor suppressor protein that has a docking preference for H3K79me1 at a site of a double-strand break (DSB), was downregulated, indicating greater DNA damage in the WSL group. Western blot data confirmed higher levels of γH2AX, a known marker of DSBs, in group WSL. In vitro dose-response analysis also confirmed the association of the H3K79me1 signature with arsenic toxicity. Taken together, our findings revealed that H3K79me1 and DOT1L could be a novel epigenetic signature of the arsenic-exposed WSL group.


Assuntos
Arsênio/toxicidade , Histonas/metabolismo , Metiltransferases/metabolismo , Dermatopatias/induzido quimicamente , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Adulto , Linhagem Celular , Dano ao DNA/genética , Epigênese Genética/genética , Feminino , Células HEK293 , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Metilação , Processamento de Proteína Pós-Traducional
10.
Environ Pollut ; 233: 596-603, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29107899

RESUMO

Arsenic induced senescence (AIS) has been identified in the population of West Bengal, India very recently. Also there is a high incidence of arsenic induced peripheral neuropathy (PN) throughout India. However, the epigenetic regulation of AIS and its contribution in arsenic induced PN remains unexplored. We recruited seventy two arsenic exposed and forty unexposed individuals from West Bengal to evaluate the role of senescence associated miRNAs (SA-miRs) in AIS and their involvement if any, in PN. The downstream molecules of the miRNA associated with the disease outcome, was also checked by immuoblotting. In vitro studies were conducted with HEK 293 cells and sodium arsenite exposure. Our results show that all the SA-miRs were upregulated in comparison to unexposed controls. miR-29a was the most significantly altered, highest expression being in the arsenic exposed group with PN, suggesting its association with the occurrence of PN. We looked for the expression of peripheral myelin protein 22 (PMP22), a specific target of miR-29a associated with myelination and found that both in vitro and in vivo results showed over-expression of the protein. Since this was quite contrary to miRNA regulation, we checked for intermediate players ß-catenin and GSK-3ß upon arsenic exposure which affects PMP22 expression. We found that ß-catenin was upregulated in vitro and was also highest in the arsenic exposed group with PN while GSK-3ß followed the reverse pattern. Our findings suggest that arsenic exposure alters the expression of SA-miRs and the mir-29a/beta catenin/PMP22 axis might be responsible for arsenic induced PN.


Assuntos
Arsênio/toxicidade , Poluentes Ambientais/toxicidade , Doenças do Sistema Nervoso Periférico/genética , Arsênio/análise , Intoxicação por Arsênico/epidemiologia , Epigênese Genética , Quinase 3 da Glicogênio Sintase , Células HEK293 , Humanos , Índia/epidemiologia , MicroRNAs/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Regulação para Cima , beta Catenina
11.
Proteomics Clin Appl ; 11(11-12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28731282

RESUMO

Modulation of signaling pathways upon chronic arsenic exposure remains poorly studied. Here, we carried out SILAC-based quantitative phosphoproteomics analysis to dissect the signaling induced upon chronic arsenic exposure in human skin keratinocyte cell line, HaCaT. We identified 4171 unique phosphosites derived from 2000 proteins. We observed differential phosphorylation of 406 phosphosites (twofold) corresponding to 305 proteins. Several pathways involved in cytoskeleton maintenance and organization were found to be significantly enriched (p<0.05). Our data revealed altered phosphorylation of proteins associated with adherens junction remodeling and actin polymerization. Kinases such as protein kinase C iota type (PRKCI), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), tyrosine-protein kinase BAZ1B (BAZ1B) and STE20 like kinase (SLK) were found to be hyperphosphorylated. Our study provides novel insights into signaling perturbations associated with chronic arsenic exposure in human skin keratinocytes. All MS/MS data have been deposited to the ProteomeXchange with identifier PXD004868.


Assuntos
Arsênio/toxicidade , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Humanos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Titânio/química
12.
Biometals ; 30(4): 505-515, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28516305

RESUMO

Global methylation pattern regulates the normal functioning of a cell. Research have shown arsenic alter these methylation landscapes within the genome leading to aberrant gene expression and inducts various pathophysiological outcomes. Long interspersed nuclear elements (LINE-1) normally remains inert due to heavy methylation of it's promoters, time and various environmental insults, they lose these methylation signatures and begin retro-transposition that has been associated with genomic instability and cancerous outcomes. Of the various high throughput technologies available to detect global methylation profile, development of LINE-1 methylation index shall provide a cost effect-screening tool to detect epimutagenic events in the wake of toxic exposure in a large number of individuals. In the present review, we tried to discuss the state of research and whether LINE-1 methylation can be considered as a potent epigenetic signature for arsenic toxicity.


Assuntos
Intoxicação por Arsênico/genética , Arsênio/toxicidade , Exposição Ambiental/efeitos adversos , Epigênese Genética , Elementos Nucleotídeos Longos e Dispersos , Neoplasias/genética , Intoxicação por Arsênico/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Ilhas de CpG , Metilação de DNA , Ácido Fólico/metabolismo , Genoma Humano , Humanos , Neoplasias/induzido quimicamente , Neoplasias/metabolismo , Neoplasias/patologia , Regiões Promotoras Genéticas , S-Adenosilmetionina/metabolismo
13.
Toxicology ; 378: 10-16, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28069514

RESUMO

More than 26 million people in West Bengal, India, are exposed to arsenic through drinking water, leading to several deleterious endpoints including precancerous and cancerous skin lesions and other non-dermatological health effects. Here, our aim was to identify whether miR21 is associated with such dermatological and non-dermatological health outcomes in chronically exposed humans. A total of 123 subjects from West Bengal were recruited for this study (45 exposed individuals with skin lesions, 38 exposed individuals without skin lesions and 40 unexposed individuals). The miR21 expression patterns in the lymphocytes were studied by quantitative realtime PCR and the effects on downstream targets were validated by Western blotting. Associations between the miR21 expression patterns and non-dermatological health effects were determined from epidemiological survey data. In vitro studies were done with low dose (0.05ppm) of chronic arsenic exposure to HaCaT cells for 15 passages. Interestingly, within the exposed group, the skin lesion individuals showed almost 4.5 fold up-regulation of miR21 compared to the no skin lesion group. The expression of the downstream targets of miR21 (PTEN and PDCD4) varied inversely, while the expression of pAKT and PI3K varied proportionately with its expression levels. Results of in vitro studies showed similar trends. Again miR21 was 2.03 fold up-regulated in the exposed individuals with respiratory diseases compared to the individuals without the same. This study for the first time shows that miR21 plays an important role in contributing to arsenic induced dermatological and non-dermatological health outcomes in an exposed population.


Assuntos
Arsênio/toxicidade , MicroRNAs , Transtornos Respiratórios , Dermatopatias , Poluentes Químicos da Água/toxicidade , Adulto , Arsênio/análise , Arsênio/urina , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Água Potável/análise , Exposição Ambiental , Feminino , Predisposição Genética para Doença , Humanos , Índia/epidemiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transtornos Respiratórios/induzido quimicamente , Transtornos Respiratórios/epidemiologia , Transtornos Respiratórios/genética , Transtornos Respiratórios/urina , Dermatopatias/induzido quimicamente , Dermatopatias/epidemiologia , Dermatopatias/genética , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/urina
14.
Proteomics ; 17(6)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28000977

RESUMO

Chronic exposure to arsenic is associated with dermatological and nondermatological disorders. Consumption of arsenic-contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs, and gastrointestinal tract. Although arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-induced carcinogenesis is not completely understood. We developed a cell line based model to understand the molecular mechanisms involved in arsenic-mediated toxicity and carcinogenicity. Human skin keratinocyte cell line, HaCaT, was chronically exposed to 100 nM sodium arsenite over a period of 6 months. We observed an increase in basal ROS levels in arsenic-exposed cells. SILAC-based quantitative proteomics approach resulted in identification of 2111 proteins of which 42 proteins were found to be overexpressed and 54 downregulated (twofold) upon chronic arsenic exposure. Our analysis revealed arsenic-induced overexpression of aldo-keto reductase family 1 member C2 (AKR1C2), aldo-keto reductase family 1 member C3 (AKR1C3), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) among others. We observed downregulation of several members of the plakin family including periplakin (PPL), envoplakin (EVPL), and involucrin (IVL) that are essential for terminal differentiation of keratinocytes. MRM and Western blot analysis confirmed differential expression of several candidate proteins. Our study provides insights into molecular alterations upon chronic arsenic exposure on skin.


Assuntos
Aminoácidos/metabolismo , Arsênio/toxicidade , Marcação por Isótopo/métodos , Queratinócitos/metabolismo , Proteômica/métodos , Pele/citologia , Sequência de Aminoácidos , Western Blotting , Linhagem Celular , Biologia Computacional , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Queratinócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteoma/química , Proteoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos
15.
Biometals ; 29(4): 731-41, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27465741

RESUMO

Early life exposure to arsenic has profound effect towards development of arsenic induced toxic outcomes. Some districts in the state of West Bengal, India are highly affected by arsenic, mainly through ground water. In children, not much of the toxic outcomes like dermatological lesions are observed but it is thought that the exposure leads to transient alteration in their biological processes that leads to various deleterious health effects later on. We evaluated the global methylation status by analyzing the LINE-1 methylation profile in children from arsenic exposed region between the age group 5-15 years along with the cytogenetic stress induced by arsenic as measured by lymphocyte micronucleus (MN) frequency. A total of 52 arsenic exposed and 32 unexposed children were analyzed. Whole blood DNA was used to measure the LINE-1 methylation by qRT-MSP. We found a significant association of MN-frequency in exposed individuals with highly depleted LINE-1 methylation compared to the exposed individuals with near baseline (which was comparable to unexposed control) methylation index as well as with those with the hypermethylated LINE-1 promoters. From our results, we interpret that LINE-1 methylation index may serve as a potent global epigenetic mark to detect the degree of arsenic genotoxicity at a very early age. We propose that this may be utilized to determine the extent of toxic influence exerted by arsenic, from a very early age.


Assuntos
Arsênio/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Adolescente , Criança , Pré-Escolar , Dano ao DNA/genética , Feminino , Humanos , Contagem de Linfócitos , Masculino , Regiões Promotoras Genéticas/genética
16.
Environ Int ; 81: 8-17, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25898228

RESUMO

Arsenic toxicity is a global issue, addressed by the World Health Organization as one of the major natural calamities faced by humans. More than 137 million individuals in 70 nations are affected by arsenic mainly through drinking water and also through diet. Chronic arsenic exposure leads to various types of patho-physiological end points in humans including cancers. Arsenic, a xenobiotic substance, is biotransformed in the body to its methylated species by using the physiological S-adenosyl methionine (SAM). SAM dictates methylation status of the genome and arsenic metabolism leads to depletion of SAM leading to an epigenetic disequilibrium. Since epigenetics is one of the major phenomenon at the interface between the environment and human health impact, its disequilibrium by arsenic inflicts upon the chromatin compaction, gene expression, genomic stability and a host of biomolecular interactions, the interactome within the cell. Since arsenic is not mutagenic but is carcinogenic in nature, arsenic induced epimutagenesis has come to the forefront since it determines the transcriptional and genomic integrity of the cell. Arsenic toxicity brings forth several pathophysiological manifestations like dermatological non-cancerous, pre-cancerous and cancerous lesions, peripheral neuropathy, DNA damage, respiratory disorders and cancers of several internal organs. Recently, several diseases of similar manifestations have been explained with the relevant epigenetic perspectives regarding the possible molecular mechanism for their onset. Hence, in the current review, we comprehensively try to intercalate the information on arsenic-induced epigenetic alterations of DNA, histones and microRNA so as to understand whether the arsenic-induced toxic manifestations are brought about by the epigenetic changes. We highlight the need to understand the aspect of epimutagenesis and subsequent alterations in the cellular interactome due to arsenic-induced molecular changes, which may be utilized to develop putative therapeutic strategies targeting both oxidative potential and epimutagenesis in humans.


Assuntos
Arsênio/toxicidade , Carcinógenos/toxicidade , Poluentes Ambientais/toxicidade , Epigênese Genética , Animais , Intoxicação por Arsênico/tratamento farmacológico , Humanos
17.
Genes Environ ; 37: 23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27350818

RESUMO

Arsenic toxicity in humans manifests several outcomes in humans, which include arsenic-induced genomic instability, DNA damage, impaired DNA repair, carcinogenesis, dermatological lesions and other health related problems. Of the 137 million individuals affected, nearly 26 million individuals are in the state of West Bengal, India. Studies have identified dermatological lesions like keratosis, basal cell carcinoma, Bowen's diseases, squamous cell carcinoma, etc., as key indicators of aggressive arsenic toxicity in humans. Although a large number of individuals are exposed to arsenic but only about 15 to 20 % individuals showed arsenic induced skin lesions. This clearly indicates that genetic susceptibility plays an important role in arsenic susceptibility. Analyses of genetic susceptibility have been carried out to study the prevalence of single nucleotide polymorphisms (SNPs) in number of genes as they might be involved arsenic metabolism and detoxification. It has been observed that a number SNPs in these genes were significantly associated with arsenic induced skin lesions and other health effects. In the present review we try to coalesce the different observations and associations of SNPs with arsenic-induced toxicity, with special emphasis on the study population from West Bengal. We have adopted certain candidate gene approaches to evaluate the association of arsenic-induced toxic outcomes like skin lesions, conjunctival irritations, DNA damage, epimutagenesis, cancer, etc. This review shall be helpful in understanding the importance of genetic make-up of an individual towards evaluating the xenotoxic outcomes, like those in case of arsenic exposure.

18.
Environ Int ; 75: 180-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25481297

RESUMO

Arsenic (As), cited as the most hazardous substance by the U.S. Agency for Toxic Substance and Disease Registry (ATSDR, 2005), is an ubiquitous metalloid which when ingested for prolonged periods cause extensive health effects leading to ultimate untimely death. Plants and microbes can help mitigate soil and groundwater As problem since they have evolved elaborate detoxification machineries against this toxic metalloid as a result of their coexistence with this since the origin of life on earth. Utilization of the phytoremediation and bioremediation potential of the plants and microbes, respectively, is now regarded as two innovative tools that encompass biology, geology, biotechnology and allied sciences with cutting edge applications for sustainable mitigation of As epidemic. Discovery of As hyperaccumulating plants that uptake and concentrate large amounts of this toxic metalloid in their shoots or roots offered new hope to As phytoremediation, solar power based nature's own green remediation. This review focuses on how phytoremediation and bioremediation can be merged together to form an integrated phytobial remediation which could synergistically achieve the goal of large scale removal of As from soil, sediment and groundwater and overcome the drawbacks of the either processes alone. The review also points to the feasibility of the introduction of transgenic plants and microbes that bring new hope for more efficient treatment of As. The review identifies one critical research gap on the importance of remediation of As contaminated groundwater not only for drinking purpose but also for irrigation purpose and stresses that more research should be conducted on the use of constructed wetland, one of the most suitable areas of application of phytobial remediation. Finally the review has narrowed down on different phytoinvestigation and phytodisposal methods, which constitute the most essential and the most difficult part of pilot scale and field scale applications of phytoremediation programs.


Assuntos
Arsênio/metabolismo , Poluentes do Solo/metabolismo , Poluentes Químicos da Água/metabolismo , Bactérias/metabolismo , Biodegradação Ambiental , Plantas/metabolismo , Microbiologia do Solo , Áreas Alagadas
19.
Mol Carcinog ; 54(9): 800-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24665044

RESUMO

Arsenic (As) induces pre-malignant and malignant dermatological lesions, non-dermatological health effects and cancers in humans. Senescence involves telomere length changes and acquisition of senescence-associated secretory phenotype (SASP), which promotes carcinogenesis. Though in vitro studies have shown that As induces senescence, population based studies are lacking. We investigated the arsenic-induced senescence, telomere length alteration and its contribution towards development of As-induced skin cancer. The study participants included 60 each of As-exposed individuals with skin lesion (WSL), without skin lesions (WOSL) and 60 unexposed controls. Exposure assessment of drinking water and urine was done. SA ß-gal activity, ELISA, and quantification of senescence proteins, alternative lengthening of telomere (ALT) associated proteins and telomerase activity were performed. Relative telomere length (RTL) was determined by qPCR. A significantly higher number of senescent cells, over-expression of p53 and p21 were observed in the As-exposed individuals when compared to unexposed. SASP markers, MMP-1/MMP-3 were significantly higher in the WSL but not IL-6/IL-8. A significant increase of RTL was observed in the WSL group, which was telomerase-independent but exhibited an over-expression of ALT associated proteins TRF-1 and TRF-2 with higher increase in TRF-2. An increased risk for developing As-induced skin lesions was found for individuals having RTL greater than 0.827 (odds ratio, 13.75; 95% CI: 5.66-33.41; P < 0.0001). Arsenic induces senescence in vivo, but the SASP markers are not strictly over-expressed in the As-induced skin lesion group, whereas telomerase-independent elongation of telomere length might be useful for predicting the risk of development of As-induced skin lesions.


Assuntos
Envelhecimento/efeitos dos fármacos , Arsênio/toxicidade , Água Potável/efeitos adversos , Telômero/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Adulto , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Água Potável/análise , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/epidemiologia , Dermatopatias/metabolismo , Dermatopatias/patologia , Telomerase/metabolismo , Telômero/patologia , Proteína Supressora de Tumor p53/metabolismo
20.
BMC Complement Altern Med ; 14: 327, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25183356

RESUMO

BACKGROUND: Darjeeling tea, a most popular variety of black tea, though consumed by the people in different parts of world but its beneficial health effects have not been investigated in details. In this study, the antimutagenic and anticancer effect of Darjeeling tea extract (DTE) has been evaluated. METHODS: Antimutagenic activity of the DTE was carried out in two different strains of Salmonella typhimurium by AMES test against a known mutagen benzo[a]pyrene (B[a]P) with S9 activation. Moreover, anticlastogenic property of DTE was also measured by micronuclei formation (MN) against B[a]P with S9 activation in human lymphocytes. The anticancer activity of the same was studied on U937 cell line. Here, Human PBMCs were used as the normal cell control to identify selective anticancer activity of the extract against U937 cells. RESULTS: The results showed significant antimutagenic activity on bacterial strains. A significant decrease in MN was also observed in the DTE treated human lymphocyte cultures pretreated with B[a]P when compared with B[a]P treated cultures alone. The study clearly exhibited anticancer activity of the extract on U937 cell line. Further studies also revealed that apoptosis induction is an important mechanism behind the anticancer effect of DTE. CONCLUSION: Overall, this study indicates that DTE has significant antimutagenic and anticancer activities on bacterial and mammalian cells respectively.


Assuntos
Antimutagênicos/farmacologia , Antineoplásicos/farmacologia , Camellia sinensis/química , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Humanos , Testes de Mutagenicidade , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Chá , Células U937
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...