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Toxicology and Industrial Health Apr 2017Methyl isocyanate (MIC) is a toxic industrial chemical that is documented as a potent respiratory toxicant. We investigated cell-mediated immunity (CMI) in the...
Methyl isocyanate (MIC) is a toxic industrial chemical that is documented as a potent respiratory toxicant. We investigated cell-mediated immunity (CMI) in the MIC-exposed long-term survivors and their offspring born after the Bhopal gas-leak tragedy in 1984. Several earlier reports show inconsistency in the assessment of immunological effects of MIC on the human population. In these studies, important factors including lifestyle attributes were overlooked. We incorporated these factors also in our study of the basic cell-mediated immune function in the Bhopal MIC-affected population. Twenty-seven years after exposure, we assessed the circulating T-lymphocyte frequency using E-Rosette assay. A total of 46 MIC-exposed healthy long-term survivors and their offspring were studied vis-a-vis parallel gender-age group-matched unexposed controls from Bhopal and various other regions of India. The influence of several lifestyle variabilities (smoking, alcohol intake, and tobacco chewing) on T-lymphocyte frequency was also taken into consideration. Our observations suggest that Erythrocyte-Rosette-forming cell (E-RFC) distribution frequency is largely insignificant in the MIC-affected population as compared to controls ( p > 0.05). In the MIC-affected tobacco chewers, there was a trend of suppression in CMI (relative decrease = 10.3%) as compared to nonchewers. Overall, our results show negligible long-term effect of MIC on CMI measured in terms of E-RFC frequency. These observations are not in agreement with earlier findings that immunosuppressive effects of MIC exposure persist in the T-cells of the affected population. However, atypical lymphocytes were frequently observed as E-RFC in the exposed females when compared to all other subgroups. Hematopoietic disorders (atypical lymphocytosis) in the MIC-affected population along with previous reports on the cytogenetic and humoral immune system linking cancer risk and chronic obstructive pulmonary disease (COPD) are important.
Topics: Adolescent; Adult; Bhopal Accidental Release; Biomarkers; Child; Female; Gas Poisoning; Humans; Immunity, Cellular; Immunosuppressive Agents; India; Inhalation Exposure; Isocyanates; Lymphocytosis; Male; Maternal Exposure; Middle Aged; Neoplasms; Paternal Exposure; Pesticides; Pulmonary Disease, Chronic Obstructive; Risk; Sex Factors; Survivors; Young Adult
PubMed: 27226017
DOI: 10.1177/0748233716645480 -
Asian Pacific Journal of Cancer... 2015DNA methyltransferase 1 (DNMT1) is a relatively large protein family responsible for maintenance of normal methylation, cell growth and survival in mammals. Toxic...
In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas- Tragedy survivors.
DNA methyltransferase 1 (DNMT1) is a relatively large protein family responsible for maintenance of normal methylation, cell growth and survival in mammals. Toxic industrial chemical exposure associated methylation misregulation has been shown to have epigenetic influence. Such misregulation could effectively contribute to cancer development and progression. Methyl isocyanate (MIC) is a noxious industrial chemical used extensively in the production of carbamate pesticides. We here applied an in silico molecular docking approach to study the interaction of MIC with diverse domains of DNMT1, to predict cancer risk in the Bhopal population exposed to MIC during 1984. For the first time, we investigated the interaction of MIC and its hydrolytic product (1,3-dimethylurea) with DNMT1 interacting (such as DMAP1, RFTS, and CXXC) and catalytic (SAM, SAH, and Sinefungin) domains using computer simulations. The results of the present study showed a potential interaction of MIC and 1,3-dimethylurea with these domains. Obviously, strong binding of MIC with DNMT1 interrupting normal methylation will lead to epigenetic alterations in the exposed humans. We suggest therefore that the MIC- exposed individuals surviving after 1984 disaster have excess risk of cancer, which can be attributed to alterations in their epigenome. Our findings will help in better understanding the underlying epigenetic mechanisms in humans exposed to MIC.
Topics: Binding Sites; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Environmental Exposure; Humans; India; Isocyanates; Methylurea Compounds; Molecular Docking Simulation; Neoplasms; Protein Binding; Protein Structure, Tertiary
PubMed: 26625778
DOI: 10.7314/apjcp.2015.16.17.7663 -
Interdisciplinary Sciences,... Sep 2015This study is an attempt to find the reason for immunological suppression in victims of Bhopal gas tragedy during 1984 against Mycobacterium tuberculosis (Mtb)...
This study is an attempt to find the reason for immunological suppression in victims of Bhopal gas tragedy during 1984 against Mycobacterium tuberculosis (Mtb) infection. Here, we tried to understand this problem by studying interactions between immune proteins associated with susceptibility to tuberculosis and hydrolytic products of methyl isocyanate (MIC) released during the tragedy. The hydrolytic products of MIC i.e. dimethyl urea, trimethyl urea and trimethyl isocyanurate were docked to different human immune proteins against Mtb using AutoDock 4.0. Results shows that all hydrolytic products (dimethyl urea, trimethyl urea and trimethylisocyanurate) strongly inhibit to CD40 ligand, and their binding energies were found to be [Formula: see text] G [Formula: see text]3.51, [Formula: see text]3.79, [Formula: see text]4.55 (Kcal/mole), respectively. Further, to check the stability of docked complex, we performed the molecular dynamics simulation study which also shows that CD40 Ligand was maximally inhibited by trimethylisocyanurate and has a role in the macrophage activation for the destruction of M. tuberculosis. The present study may lead to better understanding of human immune protein inhibition by hydrolytic product of MIC.
Topics: Amino Acids; Catalytic Domain; Humans; Hydrolysis; Immune System; Isocyanates; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Proteins
PubMed: 26297312
DOI: 10.1007/s12539-015-0012-3 -
International Journal of Occupational... 2015December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated... (Review)
Review
December 2014 marked the 30th year anniversary of Bhopal gas tragedy. This sudden and accidental leakage of deadly poisonous methyl isocyanate (MIC) gas instigated research efforts to understand the nature, severity of health damage and sufferings of 570 000 ailing survivors of this tragedy. In a decade-long period, our systematic laboratory investigations coupled with long-term molecular surveillance studies have comprehensively demonstrated that the risk of developing an environmental associated aberrant disease phenotype, including cancer, involves complex interplay of genomic and epigenetic reprogramming. These findings poised us to translate this knowledge into an investigative framework of "molecular biodosimetry" in a strictly selected cohort of MIC exposed individuals. A pragmatic cancer risk-assessment strategy pursued in concert with a large-scale epidemiological study might unfold molecular underpinnings of host-susceptibility and exposureresponse relationship. The challenges are enormous, but we postulate that the study will be necessary to establish a direct initiation-promotion paradigm of environmental carcinogenesis. Given that mitochondrial retrograde signaling-induced epigenetic reprogramming is apparently linked to neoplasticity, a cutting-edge tailored approach by an expert pool of biomedical researchers will be fundamental to drive these strategies from planning to execution. Validating the epigenomic signatures will hopefully result in the development of biomarkers to better protect human lives in an overburdened ecosystem, such as India, which is continuously challenged to meet population demands. Besides, delineating the mechanistic links between MIC exposure and cancer morbidity, our investigative strategy might help to formulate suitable regulatory policies and measures to reduce the overall burden of occupational and environmental carcinogenesis.
Topics: Antisickling Agents; Bhopal Accidental Release; Carcinogens; Disasters; Humans; Incidence; India; Isocyanates; Neoplasms; Radiometry; Risk Assessment; Survival Rate; Survivors
PubMed: 26294196
DOI: 10.13075/ijomeh.1896.00313 -
Science (New York, N.Y.) Jul 2015Comets harbor the most pristine material in our solar system in the form of ice, dust, silicates, and refractory organic material with some interstellar heritage. The...
Comets harbor the most pristine material in our solar system in the form of ice, dust, silicates, and refractory organic material with some interstellar heritage. The evolved gas analyzer Cometary Sampling and Composition (COSAC) experiment aboard Rosetta's Philae lander was designed for in situ analysis of organic molecules on comet 67P/Churyumov-Gerasimenko. Twenty-five minutes after Philae's initial comet touchdown, the COSAC mass spectrometer took a spectrum in sniffing mode, which displayed a suite of 16 organic compounds, including many nitrogen-bearing species but no sulfur-bearing species, and four compounds—methyl isocyanate, acetone, propionaldehyde, and acetamide—that had not previously been reported in comets.
PubMed: 26228156
DOI: 10.1126/science.aab0689 -
Forensic Science Review Jul 2014Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban... (Review)
Review
Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban their use. Nevertheless, since ancient times, toxic agents have been consistently employed to kill and terrorize target populations. The evolution of these weapons is examined here in ways that may allow military, law enforcement, and scientific professionals to gain a perspective on conditions that, in the past, have motivated their use - both criminally and as a matter of national policy during military campaigns. Special emphasis is placed on the genocidal use of chemical weapons by the regime of Saddam Hussein, both against Iranians and on Kurdish citizens of his own country, during the Iran-Iraq War of 1980-88. The historical development of chemical weapons use is summarized to show how progressively better insight into biochemistry and physiology was adapted to this form of warfare. Major attributes of the most frequently used chemical agents and a description of how they affected military campaigns are explained. Portions of this review describing chemical-casualty care devote particular focus to Iranian management of neurotoxic (nerve) agent casualties due to the unique nature of this experience. Both nerve and blistering "mustard" agents were used extensively against Iranian forces. However, Iran is the only nation in history to have sustained large-scale attacks with neurotoxic weapons. For this reason, an understanding of the successes and failures of countermeasures to nerve-agent use developed by the Iranian military are particularly valuable for future civil defense and military planning. A detailed consideration of these strategies is therefore considered. Finally, the outcomes of clinical research into severe chronic disease triggered by mustard-agent exposure are examined in the context of the potential of these outcomes to determine the etiology of illness among US and Allied veterans of the 1991 Persian Gulf War.
PubMed: 26227026
DOI: No ID Found -
International Journal of Yoga 2015
PubMed: 26170601
DOI: 10.4103/0973-6131.154072 -
Asian Pacific Journal of Cancer... 2015The Bhopal gas tragedy involving methyl isocyanate (MIC) is one of the most horrific industrial accidents in recent decades. We investigated the genotoxic effects of MIC...
The Bhopal gas tragedy involving methyl isocyanate (MIC) is one of the most horrific industrial accidents in recent decades. We investigated the genotoxic effects of MIC in long-term survivors and their offspring born after the 1984 occurrence. There are a few cytogenetic reports showing genetic damage in the MIC-exposed survivors, but there is no information about the associated cancer risk. The same is true about offspring. For the first time, we here assessed the micronucleus (MN) frequency using cytokinesis-blocked micronucleus (CBMN) assay to predict cancer risk in the MIC-affected population of Bhopal. A total of 92 healthy volunteers (46 MIC- affected and 46 controls) from Bhopal and various regions of India were studied taking gender and age into consideration. Binucleated lymphocytes with micronuclei (BNMN), total number of micronuclei in lymphocytes (MNL), and nuclear division index (NDI) frequencies and their relationship to age, gender and several lifestyle variabilities (smoking, alcohol consumption and tobacco-chewing) were investigated. Our observations showed relatively higher BNMN and MNL (P<0.05) in the MIC-affected than in the controls. Exposed females (EF) exhibited significantly higher BNMN and MNL (P<0.01) than their unexposed counterparts. Similarly, female offspring of the exposed (FOE) also suffered higher BNMN and MNL (P<0.05) than in controls. A significant reduction in NDI (P<0.05) was found only in EF. The affected group of non-smokers and non-alcoholics featured a higher frequency of BNMN and MNL than the control group of non-smokers and non-alcoholics (P<0.01). Similarly, the affected group of tobacco chewers showed significantly higher BNMN and MNL (P<0.001) than the non-chewers. Amongst the affected, smoking and alcohol consumption were not associated with statistically significant differences in BNMN, MNL and NDI. Nevertheless, tobacco-chewing had a preponderant effect with respect to MNL. A reasonable correlation between MNL and lifestyle habits (smoking, alcohol consumption and tobacco-chewing) was observed only in the controls. Our results suggest that EF and FOE are more susceptible to cancer development, as compared to EM and MOE. The genotoxic outcome detected in FOE reflects their parental exposure to MIC. Briefly, the observed cytogenetic damage to the MIC-affected could contribute to cancer risk, especially in the EF and FOE.
Topics: Adolescent; Adult; Alcohol Drinking; Bhopal Accidental Release; Case-Control Studies; Cell Nucleus Division; Child; Environmental Exposure; Female; Humans; India; Isocyanates; Life Style; Lymphocytes; Male; Maternal Exposure; Micronuclei, Chromosome-Defective; Micronucleus Tests; Middle Aged; Neoplasms; Paternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Sex Factors; Smoking; Survivors; Tobacco, Smokeless; Young Adult
PubMed: 26028107
DOI: 10.7314/apjcp.2015.16.10.4409 -
The Indian Journal of Medical Research Nov 2014Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and... (Review)
Review
Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and increased β-galactosidase activity, biological significance of telomeric attrition in conjunction with senescence associated secretory phenotype (SASP) has been highlighted in SIPS. To gain insight on the potential role of this unique phenomenon invoked upon environmental stress, we sequentially validated the molecular repercussions of this event in ovarian epithelial cells after exposure to methyl isocyanate, an elegant regulator of cellular biotransformation. Persistent accumulation of DNA damage response factors phospho-ATM/γ-H2AX, morphological changes with increased cell size and early yet incremental β-gal staining, imply the inception of premature senescence. Advent of SASP is attributed by prolonged secretion of pro-inflammatory cytokines along with untimely but significant G1/S cell cycle arrest. Telomeric dysfunction associated with premature senescence is indicative of early loss of TRF2 (telomeric repeat binding factor 2) protein and resultant multiple translocations. Induction of senescence-associated heterochromatic foci formation showcases the chromatin alterations in form of trimethylated H3K9me3 in conjunction with H4 hypoacetylation and altered miRNA expression. Anchorage-independent neoplastic growth observed in treated cells reaffirms the oncogenic transformation following the exposure. Collectively, we infer the possible role of SIPS, as a central phenomenon, to perturbed genomic integrity in ovarian surface epithelium, orchestrated through SASP and chromatin level alterations, a hitherto unknown molecular paradigm. Although translational utility of SIPS as a biomarker for estimating ovarian cancer risk seems evident, further investigations will be imperative to provide a tangible way for its precise validation in clinical settings.
Topics: Biomarkers; Carcinogenesis; Cell Transformation, Neoplastic; Cellular Senescence; Epithelial Cells; Female; Histones; Humans; Isocyanates; Ovarian Neoplasms; Ovary; Stress, Physiological; Telomere Shortening; Telomeric Repeat Binding Protein 2
PubMed: 25673532
DOI: No ID Found -
Interdisciplinary Sciences,... Jan 2015This study is an attempt to find the reason for immunological suppression in victims of Bhopal gas tragedy during 1984 against Mycobacterium Tuberculosis (Mtb)...
This study is an attempt to find the reason for immunological suppression in victims of Bhopal gas tragedy during 1984 against Mycobacterium Tuberculosis (Mtb) infection. Here we tried to understand this problem by studying interactions between immune proteins associated with susceptibility to Tuberculosis and hydrolytic products of methyl isocyanate (MIC) released during the tragedy.The hydrolytic products of methyl isocyanate (MIC) i.e. dimethyl urea, trimethyl urea and trimethyl isocyanurate was docked to different human immune proteins against Mtb using autodock 4.0. Results shows that all hydrolytic product (dimethyl urea, trimethyl urea and trimethylisocyanurate) strongly inhibits to CD40 ligand and their binding energies were found to be ΔG -3.51, -3.79, -4.55 (Kcal/Mole) respectively. Further to check the stability of docked complex we performed the molecular dynamics simulation study which also shows that CD40 Ligand was maximum inhibited by trimethylisocyanurate, has a role in the macrophage activation for the destruction of Mycobacterium tuberculosis. The present study may lead to better understanding of human immune protein inhibition by hydrolytic product of methyl isocyanate (MIC).
PubMed: 25595583
DOI: 10.1007/s12539-013-0217-2