Targeting 'histone mark': Advanced approaches in epigenetic regulation of telomere dynamics in cancer.

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.

Targeting the 'DNA methylation mark': Analysis of early epigenetic-alterations in children chronically exposed to arsenic.

Chronic exposure to arsenic causes adverse health effects in children. Aberrant epigenetic modifications including altered DNA methylation pattern are one of the major steps towards malignant transformation of cells. Our group has previously identified significant alteration in DNA methylation mark in arsenic exposed adults, affecting major biological pathways. Till date, no information is available exploring the altered DNA methylation mark in telomere regulation and altered mitochondrial functionality in association with DNA damage in arsenic-exposed children. Our study aims in identifying signature epigenetic pattern associated with telomere lengthening, mitochondrial functionality and DNA damage repair in children with special emphasis on DNA methylation. Biological samples (blood and urine) and drinking water were collected from the children aged between 5 and 16 years of arsenic exposed areas (N = 52) of Murshidabad district and unexposed areas (N = 50) of East Midnapur districts, West Bengal, India. Methylation-specific PCR was performed to analyse subtelomeric methylation status and promoter methylation status of target genes. Results revealed altered DNA methylation profile in the exposed children compared to unexposed. Promoter hypermethylation was observed in MLH1 and MSH2 (p < 0.05 and p < 0.001) indicating inefficiency in DNA damage repair. Hypomethylation in mitochondrial D-loop (p < 0.05) and TFAM promoter region (p < 0.05) along with increased mitochondrial DNA copy number among exposed children was also observed. Significant increase in telomere length and region specific subtelomeric hypermethylation (XpYp, p < 0.05) was found. Analysis of S-Adenosyl Methionine (SAM) and 8-oxoDG level revealed significant depletion of SAM (p < 0.001) and elevated oxidative DNA damage (p < 0.001) respectively in arsenic toxicity. Our study identified key methylation patterns in arsenic-exposed children which may act as an early predictive biomarker in the near future. Further in-depth studies involving large sample size and transcriptomic analysis are required for understanding the mechanistic details.

Genetic and epigenetic instability induced by betel quid associated chemicals.

Over the years, betel quid chewing and tobacco use have attracted considerable interest as they are implicated as the most likely causative risk factors of oral and esophageal cancers. Although areca nut use and betel quid chewing may lead to apoptosis, chronic exposure to areca nut and slaked lime may promote pre-malignant and malignant transformation of oral cells. The putative mutagenic and carcinogenic mechanisms may involve endogenous nitrosation of areca and tobacco alkaloids as well as the presence of direct alkylating agents in betel quid and smokeless tobacco. Metabolic activation of carcinogenic N-nitrosamines by phase-I enzymes is required not only to elicit the genotoxicity via the reactive intermediates but also to potentiate the mutagenicity with the sporadic alkylations of nucleotide bases, resulting in the formation of diverse DNA adducts. Persistent DNA adducts provides the impetus for genetic and epigenetic lesions. The genetic and epigenetic factors cumulatively influence the development and progression of disorders such as cancer. Accumulation of numerous genetic and epigenetic aberrations due to long-term betel quid (with or without tobacco) chewing and tobacco use culminates into the development of head and neck cancers. We review recent evidence that supports putative mechanisms for mutagenicity and carcinogenicity of betel quid chewing along with tobacco (smoking and smokeless) use. The detailed molecular mechanisms of the extent of accumulation and patterns of genetic alterations, indicative of the prior exposure to carcinogens and alkylating agents because of BQ chewing and tobacco use, have not yet been elucidated.

Investigating the synergistic role of heavy metals in Arsenic-induced skin lesions in West Bengal, India.

BACKGROUND: Arsenic toxicity is one of the major health issues throughout the world. Approximately 108 countries that account for more than 230 million people worldwide are at high risk of arsenic poisoning mainly through drinking water and diet. Chronic exposure to arsenic causes several pathophysiological end-points including skin lesions, peripheral neuropathy, cancer, etc. In India, the population living in the lower Gangetic basin possesses a great risk of arsenicosis and other diseases. Scientists are trying to understand the gene-environmental interactions behind arsenic toxicity revealing the potential role of genetic variants of individuals. Few pieces of the literature showed that the population is not exposed to a mixture of metals. Hence, in this study, an attempt has been made to explore whether some other metals play a synergistic role in As-induced toxicity. METHODS: For this, an assessment of the level of heavy metals using ED-XRF in soil, vegetables from As-exposed areas along with quantification of the heavy metal concentration in human blood and hair of the As-exposed population were conducted. RESULTS: Results show the concentration of urinary arsenic is very high signifying the magnitude of the exposure. In addition to this, the levels of iron (Fe), copper (Cu), chromium (Cr) were found to be very high in soil and Fe, manganese (Mn), lead (Pb) in vegetables were exceeding the WHO/FAO recommended permissible limit. However, Fe and zinc (Zn) were predominantly high in whole blood and hair of the arsenic-exposed population when compared with the control population. CONCLUSION: It can be confirmed that the population from Murshidabad is exposed to As and other heavy metals through drinking water as well as food. Particularly for this population, Fe, Zn and rubidium (Rb) may play a synergistic role in arsenic-induced toxicity. However, further studies on the large population-based investigation are required to establish the chemistry of the metal toxicity.

Identification of Biomarkers for Arsenicosis Employing Multiple Kernel Learning Embedded Multiobjective Swarm Intelligence.

Arsenic is a carcinogen, and long-term exposure to it may result in the development of multi-organ disease. Understanding the underlying intricate molecular network of toxicity and carcinogenicity is crucial for identifying a small set of differentially expressed biomarker genes to predict the risk of the exposed population. In this paper, a multiple kernel learning (MKL) embedded multi-objective swarm intelligence technique has been proposed to identify the candidate biomarker genes from the transcriptomic profile of arsenicosis samples. To achieve the optimal classification accuracy along with the minimum number of genes, a multi-objective random spatial local best particle swarm optimization (MO-RSplbestPSO) has been utilized. The proposed MO-RSplbestPSO also guides the multiple kernel learning mechanism which provides data specific classification. The proposed computational framework has been applied to the developed whole genome DNA microarray prepared using blood samples collected from a specific arsenic exposed area of the Indian state of West Bengal. A set of twelve biomarker genes, with four novel genes, are successfully identified for the classification of exposure to arsenic and its subcategories, which can be used as future prognostic biomarkers for screening of arsenic exposed populations. Also, the biological significance of each gene is detailed to delineate the complex molecular networking and mode of toxicity.

Mutational Landscape Screening Through Comprehensive In Silico Analysis for Polycystic Ovarian Syndrome-Related Genes.

Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy of indistinguishable etiopathogenesis that is liable to entail genetic and environmental machinery synergistically interacting with its phenotypic expression. It has been hypothesized that the environment secondarily interacts with genes to define the quantifiable phenotype in a primary, genetically determined, hyper-androgenic ovarian defect. The severity and prevalence of the disease are escalating due to uncontrolled diet and lifestyle, the influence of multiple environmental factors as well as genetic disorders. Many candidate genes have been identified to be one of the causes of PCOS. Different studies have been carried out to find the genetic correlation of PCOS. The mutational landscape analysis scans the entire genes for SNPs which usually occurs more frequently in patients and not in healthy individuals. In this study, an extensive computational analysis of all reported nsSNPs of the 27 selected PCOS-related genes was performed to infer the most pathogenic forms associated with PCOS. As a result, 28 genetic variants from 11 genes were predicted to be most harmful. Results of the present study can be useful for building an integrative genotype-phenotype database for further studies.

Dichotomy in Growth and Invasion from Low- to High-Grade Glioma Cellular Variants.

Glial dysfunction outraging CNS plasticity and integrity results in one of the most dangerous cancers, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not properly related so far. The present study is aimed to find a relationship between this featured quadrangle from lower to higher grades (HG) of post-operative glioma tissues and their invading subsets. Elevated Ki67-associated proliferation in lower grades (LG) was supported with VEGF dependent angiogenic maintenance which found a decrease unlikely in HG. In contrast, MMP 2 and 9-associated invasions augmented high in HG with the dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1-associated methylation. Marked differences found in ECM invading cellular subsets of HG showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of the same grade. Thus in LG, the neoplastic lesion is more inclined to its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low- to high-grade transition and aggressive progression.

Depletion of S-adenosylmethionine pool and promoter hypermethylation of Arsenite methyltransferase in arsenic-induced skin lesion individuals: A case-control study from West Bengal, India.

Methylation of arsenic compounds in the human body occurs following a series of biochemical reactions in the presence of methyl donor S-adenosylmethionine (SAM) and catalyzed by arsenite methyltransferase (AS3MT). However, the extent and pattern of methylation differs among the arsenic exposed individuals leading to differential susceptibility. The mechanism for such inter-individual difference is enigmatic. In the present case-control study we recruited exposed individuals with and without arsenic induced skin lesion (WSL and WOSL), and an unexposed cohort, each having 120 individuals. Using ELISA, we observed a reduction in SAM levels (p < 0.05) in WSL compared to WOSL. Linear regression analysis revealed a negative correlation between urinary arsenic concentration and SAM concentration between the study groups. qRT-PCR revealed a significant down-regulation (p < 0.01) of key regulatory genes like MTHFR, MTR, MAT2A and MAT2B of SAM biogenesis pathway in WSL cohort. Methylation-specific PCR revealed significant promoter hypermethylation of AS3MT (WSL vs. WOSL: p < 0.01) which resulted in its subsequent transcriptional repression (WSL vs. WOSL: p < 0.001). Linear regression analysis also showed a negative correlation between SAM concentration and percentage of promoter methylation. Taken together, these results indicate that reduction in SAM biogenesis along with a higher utilization of SAM results in a decreased availability of methyl donor. These along with epigenetic down-regulation of AS3MT may be responsible for higher susceptibility in arsenic exposed individuals.

Mutational spectra of SARS-CoV-2 orf1ab polyprotein and signature mutations in the United States of America.

The pandemic COVID-19 outbreak has been caused due to SARS-CoV-2 pathogen, resulting in millions of infections and deaths worldwide, the United States being on top at the present moment. The long, complex orf1ab polyproteins of SARS-CoV-2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of the orf1ab polyprotein from the NCBI virus database from affected patients across various states of the United States from December 2019 to 25 April 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12), and P5828L and Y5865C (both at nsp 13) were identified in important nonstructural proteins, which function either as replicase or helicase. A comparative analysis shows 265 T→I, 5828 P→L, and 5865Y→C are unique to the United States and not reported from Europe or Asia; while one, 4715 P→L is predominant in both Europe and the United States. Mutational changes in amino acids are predicted to alter the structure and function of the corresponding proteins, thereby, it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.

Theaflavin-Containing Black Tea Extract: A Potential DNA Methyltransferase Inhibitor in Human Colon Cancer Cells and Ehrlich Ascites Carcinoma-Induced Solid Tumors in Mice.

Tea is the most popularly consumed beverage in the world. Theaflavin and thearubigins are the key bioactive compounds of black tea that have anticarcinogenic properties as reported in several studies. However, the epigenetic potential of these compounds has not yet been explored. DNA methyltransferase (DNMT) enzymes induce methylation of DNA at cytosine residues and play a significant role in epigenetic regulation and cancer therapy. The present study has explored the role of black tea as a DNMT inhibitor in the prevention of cancer. Herein, the effect of theaflavin has been studied in colon cancer cell line (HCT-116) and EAC-induced solid tumors in mice. It was found that theaflavin prevented cell proliferation and inhibited tumor progression as well. In silico study showed that theaflavin interacted with DNMT1 and DNMT3a enzymes and blocked their activity. Theaflavin also decreased DNMT activity In Vitro and In Vivo as evident from the DNMT activity assay. Results of immunohistochemistry revealed that theaflavin reduced DNMT expression in the tumors of mice. Taken together, our findings showed that theaflavin has a potential role as a DNMT inhibitor in HCT-116 cell line and EAC induced solid tumors in mice.

Recent Advances in Arsenic Research: Significance of Differential Susceptibility and Sustainable Strategies for Mitigation.

Arsenic contamination in drinking water and associated adverse outcomes are one of the major health issues in more than 50 countries worldwide. The scenario is getting even more detrimental with increasing number of affected people and newer sites reported from all over the world. Apart from drinking water, the presence of arsenic has been found in various other dietary sources. Chronic arsenic toxicity affects multiple physiological systems and may cause malignancies leading to death. Exposed individuals, residing in the same area, developed differential dermatological lesion phenotypes and varied susceptibility toward various other arsenic-induced disease risk, even after consuming equivalent amount of arsenic from the similar source, over the same duration of time. Researches so far indicate that differential susceptibility plays an important role in arsenic-induced disease manifestation. In this comprehensive review, we have identified major population-based studies of the last 20 years, indicating possible causes of differential susceptibility emphasizing arsenic methylation capacity, variation in host genome (single nucleotide polymorphism), and individual epigenetic pattern (DNA methylation, histone modification, and miRNA expression). Holistic multidisciplinary strategies need to be implemented with few sustainable yet cost-effective solutions like alternative water source, treatment of arsenic-contaminated water, new adaptations in irrigation system, simple modifications in cooking strategy, and dietary supplementations to combat this menace. Our review focuses on the present perspectives of arsenic research with special emphasis on the probable causes of differential susceptibility toward chronic arsenic toxicity and sustainable remediation strategies.

Epigenetic alteration of mitochondrial biogenesis regulatory genes in arsenic exposed individuals (with and without skin lesions) and in skin cancer tissues: A case control study.

Chronic arsenic toxicity has become a global concern due to its adverse pathophysiological outcome and carcinogenic potential. It is already established that arsenic induced reactive oxygen species alters mitochondrial functionality. Major regulatory genes for mitochondrial biogenesis, i.e., PGC1α, Tfam, NRF1and NRF2 are located in the nucleus. As a result, mitochondria-nucleus crosstalk is crucial for proper mitochondrial function. This previous hypothesis led us to investigateinvolvement of epigenetic alteration behindenhanced mitochondrial biogenesis in chronic arsenic exposure. An extensive case-control study was conducted with 390 study participants (unexposed, exposed without skin lesion, exposed with skin lesion and exposed skin tumour) from highly arsenic exposed areas ofWest Bengal, India. Methylation specific PCRrevealed significant promoter hypomethylation oftwo key biogenesis regulatory genes, PGC1αandTfam in arsenic exposed individuals and also in skin tumour tissues. Linear regression analysis indicated significant negative correlation between urinary arsenic concentration and promoter methylation status. Increased expression of biogenesis regulatory genes wasobtained by quantitative real-time PCR analysis. Moreover, altered mitochondrial fusion-fission regulatory gene expression was also observed in skin tumour tissues. miR663, having tumour suppressor gene like function was known to be epigenetically regulated through mitochondrial retrograde signal. Promoter hypermethylation with significantly decreased expression of miR663 was found in skin cancer tissues compared to non-cancerous control tissue. In conclusion, results indicated crucial role of epigenetic alteration in arsenic induced mitochondrial biogenesis and arsenical skin carcinogenesis for the first time. However, further mechanistic studies are necessary for detailed understanding of mitochondria-nucleus crosstalk in arsenic perturbation.

Understanding the mechanistic insight of arsenic exposure and decoding the histone cipher.

BACKGROUND: The study of heritable epigenetic changes in arsenic exposure has intensified over the last decade. Groundwater arsenic contamination causes a great threat to humans and, to date, no accurate measure has been formulated for remediation. The fascinating possibilities of epi-therapeutics identify the need for an in-depth mechanistic understanding of the epigenetic landscape. OBJECTIVE: In this comprehensive review, we have set to analyze major studies pertaining to histone post-translational modifications in arsenic-mediated disease development and carcinogenesis during last ten years (2008-2018). RESULTS: The role of the specific histone marks in arsenic toxicity has been detailed. A comprehensive list that includes major arsenic-induced histone modifications identified for the last 10 years has been documented and details of different states of arsenic, organisms, exposure type, study platform, and findings were provided. An arsenic signature panel was suggested to help in early prognosis. An attempt has been made to identify the grey areas of research. PROSPECTS: Future prospective multi-target analyses of the inter-molecular crosstalk among different histone marks are needed to be explored further in order to understand the mechanism of arsenic toxicity and carcinogenicity and to confirm the suitability of these epi-marks as prognostic markers.

Epigenetic regulations in alternative telomere lengthening: Understanding the mechanistic insight in arsenic-induced skin cancer patients.

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.

Epigenetic alteration of mismatch repair genes in the population chronically exposed to arsenic in West Bengal, India.

INTRODUCTION: Arsenic exposure and its adverse health outcome, including the association with cancer risk are well established from several studies across the globe. The present study aims to analyze the epigenetic regulation of key mismatch repair (MMR) genes in the arsenic-exposed population. METHOD: A case-control study was conducted involving two hundred twenty four (N=224) arsenic exposed [with skin lesion (WSL=110) and without skin lesion (WOSL=114)] and one hundred and two (N=102) unexposed individuals. The methylation status of key MMR genes i.e. MLH1, MSH2, and PMS2 were analyzed using methylation-specific PCR (MSP). The gene expression was studied by qRTPCR. The expression of H3K36me3, which was earlier reported to be an important regulator of MMR pathway, was assessed using ELISA. RESULTS: Arsenic-exposed individuals showed significant promoter hypermethylation (p < 0.0001) of MLH1 and MSH2 compared to those unexposed with consequent down-regulation in their gene expression [MLH1 (p=0.001) and MSH2 (p<0.05)]. However, no significant association was found in expression and methylation of PMS2 with arsenic exposure. We found significant down-regulation of H3K36me3 in the arsenic-exposed group, most significantly in the WSL group (p<0.0001). The expression of SETD2, the methyltransferase of an H3K36me3 moiety was found to be unaltered in arsenic exposure, suggesting the involvement of other regulatory factors yet to be identified. DISCUSSION: In summary, the epigenetic repression of DNA damage repair genes due to promoter hypermethylation of MLH1 and MSH2 and inefficient recruitment of MMR complex at the site of DNA damage owing to the reduced level of H3K36me3 impairs the mismatch repair pathway that might render the arsenic-exposed individuals more susceptible towards DNA damage and associated cancer risk.

Association of H3K79 monomethylation (an epigenetic signature) with arsenic-induced skin lesions.

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.

Arsenic toxicity and epimutagenecity: the new LINEage.

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.

Association of single nucleotide polymorphism with arsenic-induced skin lesions and genetic damage in exposed population of West Bengal, India.

Long term consumption of arsenic contaminated water causes a number of dermatological and non-dermatological health problems and cancer. In a Genome Wide Association Study (GWAS) on Bangladesh population, a significant association of asingle nucleotide polymorphism (SNP) in the C10orf32 region (rs 9527; G>A) with urinary metabolites and arsenic induced skin lesions was reported. This study aims to evaluate the association of the C10orf32 G to A polymorphism (rs9527), concerned with As3MT read-through transcription, with the development of arsenic induced skin lesions in the arsenic exposed individuals of West Bengal, India. A total of 157 individuals with characteristic skin lesions (cases) and 158 individuals without any skin lesion (controls) were recruited for this study. The G>A polymorphism (rs9527) having at least one minor allele 'A' was found to be significantly higher in cases compared to controls, implying increased risk toward the development of skin lesions. The risk genotype was also found to be significantly associated with cytogenetic damage as measured by chromosomal aberrations and micronuclei formation in lymphocytes. Hence, it can be concluded that G>A change in the C10orf32 region plays an important role in arsenic induced toxicity and susceptibility.

Risk of occupational exposure to asbestos, silicon and arsenic on pulmonary disorders: Understanding the genetic-epigenetic interplay and future prospects.

BACKGROUND: Epidemiological studies suggest strong association of lung disorders with occupational exposure to asbestos, silicon and arsenic. The chronic occupational exposure primarily through inhalation results in adverse outcome on the respiratory tract which may also be fatal. Although several mechanisms have attributed towards these diseases; the molecular pathogenesis is still unknown. OBJECTIVE: In this review, we investigated the plausible molecular mechanism based on current research that may identify the genetic and epigenetic susceptibility of respiratory disorders upon such occupational exposures in humans. METHODS: We considered genetic variants and epigenetic alterations associated with pulmonary exposure hazards leading to asbestosis, silicosis and arsenicosis. Our review is stringently based on the literatures available through peer-reviewed articles mostly published in the last 10 years. Relevant search were conducted using keywords like "occupational lung disorders" along with "asbestos", "silicon" and "arsenic". RESULTS: Till September 2015, pubmed search yielded approximately 780 articles relating to asbestos exposure; 240 articles for silicon exposure and 60 articles for arsenic exposure. Extensive screening for genetic and epigenetic factors identified certain genes and related pathways that are important to determine the susceptibility of an individual towards such occupational exposure. CONCLUSION: The link between genotype and phenotype and its association with disease susceptibility is very complex in nature due to several factors like person's environment, lifestyle and nutritional status. The epigenome is dynamic as well as reversible and can be reshaped further by certain dietary components throughout its life. In the present review, we have addressed the role of molecular pathogenesis of occupational lung diseases based on the genetic variability and epigenetic alterations and also attempted to highlight the promising aspect of dietary interventions to counter toxic outcomes upon occupational exposure to asbestos, silicon or arsenic.

Arsenic exposure through drinking water leads to senescence and alteration of telomere length in humans: A case-control study in West Bengal, India.

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.