Publications by authors named "Pritha Bhattacharjee"

31 Publications

Altered Food Habits? Understanding the Feeding Preference of Free-Ranging Gray Langurs Within an Urban Settlement.

Front Psychol 2021 26;12:649027. Epub 2021 Apr 26.

Department of Environmental Science, University of Calcutta, Kolkata, India.

Urbanization affects concurrent human-animal interactions as a result of altered resource availability and land use pattern, which leads to considerable ecological consequences. While some animals have lost their habitat due to urban encroachment, few of them managed to survive within the urban ecosystem by altering their natural behavioral patterns. The feeding repertoire of folivorous colobines, such as gray langur, largely consists of plant parts. However, these free-ranging langurs tend to be attuned to the processed high-calorie food sources to attain maximum benefits within the concrete jungle having insignificant greenery. Therefore, besides understanding their population dynamics, the effective management of these urbanized, free-ranging, non-human primate populations also depends on their altered feeding habits. Here, we have used a field-based experimental setup that allows gray langurs to choose between processed and unprocessed food options, being independent of any inter-specific conflicts over resources due to food scarcity. The multinomial logit model reveals the choice-based decision-making of these free-ranging gray langurs in an urban settlement of West Bengal, India, where they have not only learned to recognize the human-provisioned processed food items as an alternative food source but also shown a keen interest in it. However, such a mismatch between the generalized feeding behavior of folivorous colobines and their specialized gut physiology reminds us of Liem's paradox and demands considerable scientific attention. While urbanization imposes tremendous survival challenges to these animals, it also opens up for various alternative options for surviving in close proximity to humans which is reflected in this study, and could guide us for the establishment of a sustainable urban ecosystem in the future.
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http://dx.doi.org/10.3389/fpsyg.2021.649027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107681PMC
April 2021

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

Cell Mol Neurobiol 2021 May 12. Epub 2021 May 12.

Immunobiology Laboratory, Department of Zoology, Panihati Mahavidyalaya, Kolkata, West Bengal, India.

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.
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http://dx.doi.org/10.1007/s10571-021-01096-1DOI Listing
May 2021

Promising role of curcumin against viral diseases emphasizing COVID-19 management: A review on the mechanistic insights with reference to host-pathogen interaction and immunomodulation.

J Funct Foods 2021 Jul 20;82:104503. Epub 2021 Apr 20.

Environmental Epigenomics Lab, Department of Environmental Science, Ballygunge Science College, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.

Curcumin has already acknowledged immense interest from both medical and scientific research because of its multifaceted activity. To date, the promising effects of curcumin were perceived against numerous inflammatory diseases. Besides, curcumin's role as a medicine has been studied in many virus infections like influenza, HIV, etc. There is a need to analyze the cellular mechanisms of curcumin including host-pathogen interaction and immunomodulatory effects, to explore the role of curcumin against COVID-19. With this background, our study suggests that curcumin can prevent COVID-19 infections by inhibiting the pathogen entry, viral genome replication and steps in the endosomal pathway along with inhibition of T-cell signalling by impairing the autophagy-mediated antigen-presenting pathway. This review explicit the possible mechanisms behind curcumin-induced cellular immunity and a therapeutive dosage of curcumin suggesting a preventive strategy against COVID-19.
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http://dx.doi.org/10.1016/j.jff.2021.104503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057770PMC
July 2021

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.

Environ Res 2021 07 22;198:111184. Epub 2021 Apr 22.

Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2021.111184DOI Listing
July 2021

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

Front Public Health 2020 8;8:464. Epub 2020 Oct 8.

Department of Environmental Science, University of Calcutta, Kolkata, India.

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.
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http://dx.doi.org/10.3389/fpubh.2020.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578365PMC
May 2021

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

Nutr Cancer 2020 Oct 8:1-13. Epub 2020 Oct 8.

Department of Environmental Science, University of Calcutta, Kolkata, India.

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. 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.
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http://dx.doi.org/10.1080/01635581.2020.1828943DOI Listing
October 2020

Chronic exposure to environmentally relevant concentration of fluoride alters Ogg1 and Rad51 expressions in mice: Involvement of epigenetic regulation.

Ecotoxicol Environ Saf 2020 Oct 11;202:110962. Epub 2020 Jul 11.

Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India. Electronic address:

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110962DOI Listing
October 2020

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

J Med Virol 2021 03 25;93(3):1428-1435. Epub 2020 Aug 25.

Environmental Epigenomics Lab, Department of Environmental Science, University of Calcutta, Kolkata, India.

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.
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http://dx.doi.org/10.1002/jmv.26417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436414PMC
March 2021

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.

Chemosphere 2020 Nov 5;258:127305. Epub 2020 Jun 5.

Department of Environmental Science, University of Calcutta, Kolkata, 700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127305DOI Listing
November 2020

The impact of human waste hair reprocessing occupation on environmental degradation-A case study from rural West Bengal, India.

Environ Geochem Health 2020 Oct 19;42(10):3157-3170. Epub 2020 Mar 19.

Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India.

Human hair is considered as a potential biowaste worldwide, and improper disposal of hair can create multiple environmental problems. Due to unique characteristic features, human waste hair can be efficiently utilized for versatile applications, from agricultural industries to fashion industries. There is a huge business of human hair in many multinational countries and also in some rural areas of India. The continuous demand of such keratinous waste for human need in turn is producing residual waste at an alarming rate that causes environmental degradation. Therefore, our study aims to investigate the possible impacts of waste hair reprocessing activity on environmental health in rural India, citing examples from Radhapur village. Physico-chemical parameters of pond water and soil from the dumpsite were assessed. Along with this, elemental profile of waste hair, pond water and soil was estimated. To assess the deterioration of water quality, zooplankton diversity was also measured. Water quality index showed that the studied ponds are unsuitable for drinking purpose and aquaculture. The Shannon index further indicated comparatively lower diversity of zooplankton community in the studied ponds. Due to the presence of total organic carbon and available N-P-K, the soil can sustain the growth and survival of plants; however, the risk of toxic metal accumulation may be persisted. Hence, to enhance the utilization of waste hair in a large scale, a policy framework is extremely required that will incorporate environmental and social well-being and provide necessary support towards sustainable development. Future study needs to be carried out to eliminate the toxic elements from the water and soil using some phytoremediation strategies.
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http://dx.doi.org/10.1007/s10653-020-00551-0DOI Listing
October 2020

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

Sci Total Environ 2020 Feb 23;704:135388. Epub 2019 Nov 23.

Department of Environmental Science, University of Calcutta, Kolkata 700019, India. Electronic address:

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 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.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135388DOI Listing
February 2020

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

Toxicology 2020 01 2;430:152340. Epub 2019 Dec 2.

Department of Environmental Science, University of Calcutta, Kolkata 700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.tox.2019.152340DOI Listing
January 2020

Evaluatıon of health effects, genetıc damage and telomere length ın children exposed to arsenic in West Bengal, İndia.

Mutat Res Genet Toxicol Environ Mutagen 2018 Dec 7;836(Pt A):82-88. Epub 2018 Jun 7.

Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700 032, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.mrgentox.2018.06.012DOI Listing
December 2018

Hypomethylation of mitochondrial D-loop and ND6 with increased mitochondrial DNA copy number in the arsenic-exposed population.

Toxicology 2018 09 22;408:54-61. Epub 2018 Jun 22.

Department of Environmental Science, University of Calcutta, Kolkata 700019, India. Electronic address:

Groundwater arsenic contamination has become a serious global concern due to its adverse effects on human health. Arsenic-induced reactive oxygen species trigger oxidative stress inside mitochondria, which initiate a cascade of events including altered mitochondrial (mt) membrane potential, uncoupling of electron transport chain, and mtDNA damage. A case-control study was conducted to examine the association between arsenic exposure and differences in mtDNA methylation and to assess the downstream consequences. We recruited 221 arsenic-exposed individuals, including 106 individuals with skin lesions (WSL) and 115 subjects without any skin lesions (WOSL) from the Murshidabad district, West Bengal, India. The unexposed group included 101 individuals from the arsenic unexposed area in East Midnapore. We analyzed the status of mtDNA methylation in D-loop region and ND6 gene by methylation-specific PCR. Gene expression was studied by quantitative real-time PCR. Significant hypomethylation in both D-loop and ND6 was observed with a consequent increase in their target gene expression and higher mtDNA copy number in arsenic-exposed populations compared to controls. Further mechanistic insights regarding mitochondrial epigenetic alteration in arsenic exposure will be of critical importance for the prevention of adverse health effects.
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http://dx.doi.org/10.1016/j.tox.2018.06.012DOI Listing
September 2018

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

Environ Res 2018 05 27;163:289-296. Epub 2018 Feb 27.

Department of Environmental Science, University of Calcutta, Kolkata 700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2018.01.002DOI Listing
May 2018

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

Mutat Res 2018 01 14;807:1-9. Epub 2017 Nov 14.

Department of Environmental Science, University of Calcutta, Kolkata 700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.mrfmmm.2017.11.001DOI Listing
January 2018

DCM associated LMNA mutations cause distortions in lamina structure and assembly.

Biochim Biophys Acta Gen Subj 2017 Nov 24;1861(11 Pt A):2598-2608. Epub 2017 Aug 24.

Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India. Electronic address:

Background: A and B-type lamins are integral scaffolding components of the nuclear lamina which impart rigidity and shape to all metazoan nuclei. Over 450 mutations in A-type lamins are associated with 16 human diseases including dilated cardiomyopathy (DCM). Here, we show that DCM mutants perturb the self-association of lamin A (LA) and it's binding with lamin B1 (LB1).

Methods: We used confocal and superresolution microscopy (NSIM) to study the effect of LA mutants on the nuclear lamina. We further used circular dichroism, fluorescence spectroscopy and isothermal titration calorimetry (ITC) to probe the structural modulations, self-association and heteropolymeric association of mutant LA.

Results: Transfection of mutants in cultured cell lines result in the formation of nuclear aggregates of varied size and distribution. Endogenous LB1 is sequestered into these aggregates. This is consistent with the ten-fold increase in association constant of the mutant proteins compared to the wild type. These mutants exhibit differential heterotypic interaction with LB1, along with significant secondary and tertiary structural alterations of the interacting proteins. Thermodynamic studies demonstrate that the mutants bind to LB1 with different stoichiometry, affinity and energetics.

Conclusions: In this report we show that increased self-association propensity of mutant LA modulates the LA-LB1 interaction and precludes the formation of an otherwise uniform laminar network.

General Significance: Our results might highlight the role of homotypic and heterotypic interactions of LA in the pathogenesis of DCM and hence laminopathies in the broader sense.
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http://dx.doi.org/10.1016/j.bbagen.2017.08.016DOI Listing
November 2017

Arsenic toxicity and epimutagenecity: the new LINEage.

Biometals 2017 08 17;30(4):505-515. Epub 2017 May 17.

Department of Environmental Science, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, India.

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.
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http://dx.doi.org/10.1007/s10534-017-0021-2DOI Listing
August 2017

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

Mutat Res 2016 Oct 9;809:50-56. Epub 2016 Sep 9.

Department of Environmental Science, University of Calcutta, Kolkata-700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.mrgentox.2016.09.006DOI Listing
October 2016

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

Environ Res 2016 May 9;147:425-34. Epub 2016 Mar 9.

Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2016.02.038DOI Listing
May 2016

Molecular Events in Lamin B1 Homopolymerization: A Biophysical Characterization.

J Phys Chem B 2015 Nov 27;119(44):14014-21. Epub 2015 Oct 27.

Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics , 1/AF Bidhannagar, Kolkata-700064, India.

Lamin B1 is one of the major constituents of the nuclear lamina, a filamentous network underlying the nucleoplasmic side of the inner nuclear membrane. Homopolymerization of lamin B1, coupled to the homotypic and heterotypic association of other lamin types, is central to building the higher order network pattern inside the nucleus. This in turn maintains the mechanical and functional integrity of the lamina. We have characterized the molecular basis of the self-association of lamin B1 using spectroscopic and calorimetric methods. We report that concentration dependent lamin B1 oligomerization involves significant alterations in secondary and tertiary structures of the protein resulting in fairly observable compaction in size. Comparison of the energetics of the homotypic association of lamin B1 with that of lamin A reported earlier led to the finding that lamin A oligomers had higher thermodynamic stability. This leads us to conjecture that lamin B1 has less stress bearing ability compared to lamin A.
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http://dx.doi.org/10.1021/acs.jpcb.5b07320DOI Listing
November 2015

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

Mol Carcinog 2015 Sep 24;54(9):800-9. Epub 2014 Mar 24.

Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 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 β-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.
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http://dx.doi.org/10.1002/mc.22150DOI Listing
September 2015

Viscoelastic behavior of human lamin A proteins in the context of dilated cardiomyopathy.

PLoS One 2013 30;8(12):e83410. Epub 2013 Dec 30.

Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, West Bengal, India.

Lamins are intermediate filament proteins of type V constituting a nuclear lamina or filamentous meshwork which lines the nucleoplasmic side of the inner nuclear membrane. This protein mesh provides a supporting scaffold for the nuclear envelope and tethers interphase chromosome to the nuclear periphery. Mutations of mainly A-type lamins are found to be causative for at least 11 human diseases collectively termed as laminopathies majority of which are characterised by aberrant nuclei with altered structural rigidity, deformability and poor mechanotransduction behaviour. But the investigation of viscoelastic behavior of lamin A continues to elude the field. In order to address this problem, we hereby present the very first report on viscoelastic properties of wild type human lamin A and some of its mutants linked with Dilated cardiomyopathy (DCM) using quantitative rheological measurements. We observed a dramatic strain-softening effect on lamin A network as an outcome of the strain amplitude sweep measurements which could arise from the large compliance of the quasi-cross-links in the network or that of the lamin A rods. In addition, the drastic stiffening of the differential elastic moduli on superposition of rotational and oscillatory shear stress reflect the increase in the stiffness of the laterally associated lamin A rods. These findings present a preliminary insight into distinct biomechanical properties of wild type lamin A protein and its mutants which in turn revealed interesting differences.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875444PMC
September 2014

Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member, GSTM2.

Sci Rep 2013 ;3:2704

1] Molecular and Human Genetics Division, Kolkata - 700 032, India [2].

The gene for glutathione-S-transferase (GST) M1 (GSTM1), a member of the GST-superfamily, is widely studied in cancer risk with regard to the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity. Many of these studies have reported inconsistent findings regarding its association with cancer risk. Therefore, we employed in silico, in vitro, and in vivo approaches to investigate whether the absence of a functional GSTM1 enzyme in a null variant can be compensated for by other family members. Through the in silico approach, we identified maximum structural homology between GSTM1 and GSTM2. Total plasma GST enzymatic activity was similar in recruited individuals, irrespective of their GSTM1 genotype (positive/null). Furthermore, expression profiling using real-time PCR, western blotting, and GSTM2 overexpression following transient knockdown of GSTM1 in HeLa cells confirmed that the absence of GSTM1 activity can be compensated for by the overexpression of GSTM2.
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http://dx.doi.org/10.1038/srep02704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776957PMC
June 2014

Human urothelial micronucleus assay to assess genotoxic recovery by reduction of arsenic in drinking water: a cohort study in West Bengal, India.

Biometals 2013 Oct 2;26(5):855-62. Epub 2013 Aug 2.

Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata, 700032, WB, India.

Chronic exposure to arsenic through drinking water affects nearly 26 million individuals in West Bengal, India. Cytogenetic biomarkers like urothelial micronucleus (MN) are extensively used to monitor arsenic exposed population. In 2004-2005, 145 arsenic exposed individuals and 60 unexposed controls were surveyed of which 128 exposed individuals and 54 unexposed controls could be followed up in 2010-2011. In 2004-2005, the extent of arsenic content in the drinking water was 348.23 ± 102.67 μg/L, which was significantly lowered to 5.60 ± 10.83 μg/L in 2010-2011. Comparing the data obtained between 2004-2005 and 2010-2011, there was a significant decline in the MN frequency, when assayed in 2010-2011 compared to 2004-2005. Hence, we infer that urothelial MN can be utilized as a good biomarker in detecting remedial effects from toxicity of the low dose of arsenic through drinking water.
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http://dx.doi.org/10.1007/s10534-013-9652-0DOI Listing
October 2013

High arsenic in rice is associated with elevated genotoxic effects in humans.

Sci Rep 2013 ;3:2195

Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata - 700 032, India.

Arsenic in drinking water may cause major deleterious health impacts including death. Although arsenic in rice has recently been demonstrated to be a potential exposure route for humans, there has been to date no direct evidence for the impact of such exposure on human health. Here we show for the first time, through a cohort study in West Bengal, India, involving over 400 human subjects not otherwise significantly exposed to arsenic through drinking water, elevated genotoxic effects, as measured by micronuclei (MN) in urothelial cells, associated with the staple consumption of cooked rice with >200 μg/kg arsenic. Further work is required to determine the applicability to populations with different dietary and genetic characteristics, but with over 3 billion people in the world consuming rice as a staple food and several percent of this rice containing such elevated arsenic concentrations, this study raises considerable concerns over the threat to human health.
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http://dx.doi.org/10.1038/srep02195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505394PMC
February 2014

Structural alterations of Lamin A protein in dilated cardiomyopathy.

Biochemistry 2013 Jun 5;52(24):4229-41. Epub 2013 Jun 5.

Biophysics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India.

Lamin A protein, encoded by the LMNA gene, belongs to the type V intermediate filament protein family and is a major nuclear protein component of higher metazoan organisms, including humans. Lamin A along with B-type lamins impart structural rigidity to the nucleus by forming a lamina that is closely apposed to the inner nuclear membrane and is also present as a filamentous network in the interior of the nucleus. A vast number of mutations that lead to a diverse array of at least 11 diseases in humans, collectively termed laminopathies, are being gradually uncovered in the LMNA gene. Dilated cardiomyopathy (DCM) is one such laminopathy in which ventricular dilation leads to an increase in systolic and diastolic volumes, resulting in cardiac arrhythmia and ultimately myocardial infarction. The point mutations in lamin A protein span the entire length of the protein, with a slight preponderance in the central α-helical coiled-coil forming domain. In this work, we have focused on three such important mutations that had been previously observed in DCM-afflicted patients producing severe symptoms. This is the first report to show that these mutations entail significant alterations in the secondary and tertiary structure of the protein, hence perturbing the intrinsic self-association behavior of lamin A protein. Comparison of the enthalpy changes accompanying the deoligomerization process for the wild type and the mutants suggests a difference in the energetics of their self-association. This is further corroborated by the formation of the aggregates of different size and distribution formed inside the nuclei of transfected cells.
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http://dx.doi.org/10.1021/bi400337tDOI Listing
June 2013

Association of NALP2 polymorphism with arsenic induced skin lesions and other health effects.

Mutat Res 2013 Jul 2;755(1):1-5. Epub 2013 May 2.

Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.

Prolonged consumption of arsenic-laden water above the threshold limit of 10μg/L causes a plethora of dermatological and non-dermatological multi-organ health problems, including cancer and death. Among several mechanisms of arsenic-induced toxicity and carcinogenicity studied so far, role of arsenic in impairment of immune system is less understood. Epidemiological data, animal model as well as cell line based studies have indicated that arsenic targets immune system and is associated with characteristic immunosupression, which may further adversely affect respiratory function. However, to the best of our knowledge, there is no study with respect to arsenic susceptibility investigating the role of genetic variation having immunological function. Hence, we have recruited a total of 432 arsenic-exposed individuals, of which 219 individuals with characteristic arsenic-induced skin lesions (cases) and 213 individuals without arsenic-induced skin lesion(controls), from arsenic-exposed districts of West Bengal, India. To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) in NALP2 gene, an important component of inflammasome complex, we screened the entire coding region (exon) in all the study participants. Among 9 SNPs found in NALP2 gene, the A1052E polymorphism (at least with one minor allele), was significantly overrepresented in controls and hence implies decreased risk toward the development of skin lesions [OR=0.67, 95% CI: 0.46-0.97]. Since, development of non-dermatological health effects are also important factor to properly look into, we have attempted to correlate the genetic variation of NALP2 with the extent of cytogenetic damage as measured by chromosomal aberration assay and adverse health effects including peripheral neuropathy, eye problem and respiratory diseases in the study population. We observed individuals with the protective genotype had less chromosomal aberration (p<0.05), and were also less susceptible toward arsenic-related respiratory diseases [OR=0.47; 95%CI: 0.23-0.89]. These findings suggest that NALP2 A1052E SNP plays an important role toward development of arsenic-induced skin lesions, chromosomal damage and respiratory diseases.
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http://dx.doi.org/10.1016/j.mrgentox.2013.04.010DOI Listing
July 2013

Systems biology approaches to evaluate arsenic toxicity and carcinogenicity: an overview.

Int J Hyg Environ Health 2013 Aug 20;216(5):574-86. Epub 2013 Jan 20.

Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Kolkata, India.

Long term exposure to arsenic, either through groundwater, food stuff or occupational sources, results in a plethora of dermatological and non-dermatological health effects including multi-organ cancer and early mortality. Several epidemiological studies, across the globe have reported arsenic-induced health effects and cancerous outcomes; but the prevalence of such diseases varies depending on environmental factors (geographical location, exposure level), and genetic makeup (and variants thereof); which is further modulated by several other factors like ethnicity, age-sex, smoking status, diet, etc. It is also interesting to note that, chronic arsenic exposure to a similar extent, even among the same family members, result in wide inter-individual variations. To understand the adverse effect of this toxic metabolite on biological system (cellular targets), and to unravel the underlying molecular basis (at the level of transcript, proteome, or metabolite), a holistic, systems biology approach was taken. Due to the paradoxical nature and unavailability of any suitable animal model system; the literature review is primarily based on cell line and population based studies. Thus, here we present a comprehensive review on the systems biology approaches to explore the underlying mechanism of arsenic-induced carcinogenicity, along with our own observations and an overview of mitigation strategies and their effectiveness till date.
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http://dx.doi.org/10.1016/j.ijheh.2012.12.008DOI Listing
August 2013

Role of genomic instability in arsenic-induced carcinogenicity. A review.

Environ Int 2013 Mar 8;53:29-40. Epub 2013 Jan 8.

Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata-700 032, India.

Exposure to chronic arsenic toxicity is associated with cancer. Although unstable genome is a characteristic feature of cancer cells, the mechanisms leading to genomic instability in arsenic-induced carcinogenesis are poorly understood. While there are excellent reviews relating to genomic instability in general, there is no comprehensive review presenting the mechanisms involved in arsenic-induced genomic instability. This review was undertaken to present the current state of research in this area and to highlight the major mechanisms that may involved in arsenic-induced genomic instability leading to cancer. Genomic instability is broadly classified into chromosomal instability (CIN), primarily associated with mitotic errors; and microsatellite instability (MIN), associated with DNA level instability. Arsenic-induced genomic instability is essentially multi-factorial in nature and involves molecular cross-talk across several cellular pathways, and is modulated by a number of endogenous and exogenous factors. Arsenic and its metabolites generate oxidative stress, which in turn induces genomic instability through DNA damage, irreversible DNA repair, telomere dysfunction, mitotic arrest and apoptosis. In addition to genetic alteration; epigenetic regulation through promoter methylation and miRNA expression alters gene expression profiling leading to genome more vulnerable and unstable towards cancer risk. Moreover, mutations or silencing of pro-apoptotic genes can lead to genomic instability by allowing survival of damaged cells that would otherwise die. Although a large body of information is now generated regarding arsenic-induced carcinogenesis; further studies exploring genome-wide association, role of environment and diet are needed for a better understanding of the arsenic-induced genomic instability.
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http://dx.doi.org/10.1016/j.envint.2012.12.004DOI Listing
March 2013