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Jeanclaude Guillemin - One of the best experts on this subject based on the ideXlab platform.
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Quasi-symmetry effects in the threshold photoelectron spectrum of Methyl Isocyanate
Journal of Chemical Physics, 2020Co-Authors: Oliver Harper, Laurent Coudert, Bérenger Gans, Stephane Douin, Séverine Boyé-péronne, Jean-christophe Loison, Gustavo Garcia, Jeanclaude GuilleminAbstract:The vacuum-ultraviolet threshold photoelectron spectrum of Methyl Isocyanate CH3NCO has been recorded from 10.4 eV to 12 eV using synchrotron radiation and a coincidence technique allowing for a mass-discrimination of the photoelectron signal. A significant improvement is achieved over previous investigations as this experimental setup leads to a much more resolved spectrum. Ten sharp peaks and a broad feature spanning 1.2 eV were recorded. This spectrum consists of X̃+ 2A″←X̃ 1A' and Ã+ 2A'←X̃ 1A' ionizing transitions. For the former, the adiabatic ionization energy was determined experimentally to be 10.596(6) eV; for the latter, its value was estimated to be 10.759(50) eV. Seven sharp peaks could be assigned to vibrational modes of the cation X̃+ 2A″ and neutral X̃ 1A' ground electronic states involving only the NCO group atoms. Theoretical modeling of the threshold photoelectron spectrum has proven difficult as Methyl Isocyanate is a non-rigid molecule displaying large amplitude internal rotation of the Methyl group and ∠CNC bending mode, leading to the quasi-symmetry. With the help of ab initio calculations, a theoretical model in which these two large amplitude motions are included in addition to the five small amplitude vibrational modes involving NCO group atoms is proposed. Comparison with the experimental spectrum shows that the broad feature and the strongest peak line positions are well accounted for; their intensities are also fairly well reproduced after adjusting a few parameters.
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laboratory study of Methyl Isocyanate ices under astrophysical conditions
Monthly Notices of the Royal Astronomical Society, 2017Co-Authors: Belen Mate, German Molpeceres, Vicente Timon, Isabel Tanarro, Rafael Escribano, Jeanclaude Guillemin, J Cernicharo, Victor J HerreroAbstract:Methyl Isocyanate has been recently detected in comet 67P/ Churyumov-Gerasimenko (67P/CG) and in the interstellar medium. New physicochemical studies on this species are now necessary as tools for subsequent studies in astrophysics. In this work, infrared spectra of solid CH3NCO have been obtained at temperatures of relevance for astronomical environments. The spectra are dominated by a strong, characteristic multiplet feature at 2350-2250 cm-1, which can be attributed to the antisymmetric stretching of the NCO group. A phase transition from amorphous to crystalline Methyl Isocyanate is observed at ~ 90 K. The band strengths for the absorptions of CH3NCO in ice at 20 K have been measured. Deuterated Methyl Isocyanate is used to help with the spectral assignment. No X-ray structure has been reported for crystalline CH3NCO. Here we advance a tentative theoretical structure, based on Density Functional Theory (DFT) calculations, derived taking as a starting point the crystal of isocyanic acid. A harmonic theoretical spectrum is calculated then for the proposed structure, and compared with the experimental data. A mixed ice of H2O and CH3NCO was formed by simultaneous deposition of water and Methyl Isocyanate at 20 K. The absence of new spectral features indicates that Methyl Isocyanate and water do not react appreciably at 20 K, but form a stable mixture. The high CH3NCO/H2O ratio reported for comet 67P/CG, and the characteristic structure of the 2350-2250 cm-1 band, make of it a very good candidate for future astronomical searches.
Kewal K. Maudar - One of the best experts on this subject based on the ideXlab platform.
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A retrospective review of cytogenetic studies on Methyl Isocyanate with special reference to the Bhopal gas tragedy: Is the next generation also at risk?
International Journal of Occupational Medicine and Environmental Health, 2013Co-Authors: Ravindra M. Samarth, Puneet Gandhi, Kewal K. MaudarAbstract:The world’s worst industrial disaster, at Union Carbide, Bhopal, India, took place on 2–3 December 1984, leading to the leakage of poisonous Methyl-Isocyanate into the environment, causing thousands of deaths, pregnancy loss and for some, incapacitation for life. More than a quarter of a century later, the Indian Council of Medical Research undertook to redefine the abysmal consequences of the toxic gas exposure on the exposed population. This invigorated the interest of scientific community in the evaluation of the long-term effects, with reference to cytogenetic parameters. The thrust area was identified in terms of genetic disorders, low birth weight, developmental/growth disorders and congenital malformations. Also the impact on epigenetic factors, which may have contributed to variations in the functional expression of genes, was not negated, stimulating intense scientific research on in utero exposure and the progeny of the exposed population. To accomplish this mammoth task, molecular cytogenetic investigations must be undertaken in conjunction with conventional cytogenetics, using techniques such as FISH, Immuno-FISH, SKY and SNP analysis, to build up a cytogenetic database of the surviving population.
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Cell cycle deregulation by Methyl Isocyanate: Implications in liver carcinogenesis
Environmental Toxicology, 2012Co-Authors: Hariom Panwar, Gorantla V. Raghuram, Alok K. Ahirwar, Subodh Kumar Jain, Saba Khan, Smita Banerjee, Kewal K. Maudar, Deepika Jain, Neelam Pathak, Pradyumna Kumar MishraAbstract:Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to Methyl Isocyanate (MIC), one of the most toxic Isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 284–297, 2014.
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molecular surveillance of hepatitis and tuberculosis infections in a cohort exposed to Methyl Isocyanate
International Journal of Occupational Medicine and Environmental Health, 2011Co-Authors: Pradyumna Kumar Mishra, Kewal K. Maudar, Neelam Pathak, Arpit Bhargava, Prabha Desikan, Subodh Varshney, Rahul Shrivastava, Aruna JainAbstract:Objective The potential toxic effects on the immune system exerted by occupational and accidental environmental exposures and underlying molecular regulatory mechanisms involved in the etiology and progression of infectious diseases are now being characterized. The Bhopal gas tragedy is undoubtedly one of the worst industrial disasters in the history of mankind. After 25 years of accidental exposure to Methyl Isocyanate (MIC), severe systemic ailments still continue to preoccupy the lives of the affected population that survived this tragedy. We have performed a molecular surveillance study to characterize hepatitis and tuberculosis infections amongst the first and the second generation of survivors exposed to MIC.
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in utero exposure to Methyl Isocyanate in the bhopal gas disaster evidence of persisting hyperactivation of immune system two decades later
Occupational and Environmental Medicine, 2008Co-Authors: Pradyumna Kumar Mishra, Prabha Desikan, Aruna Jain, Sunil Dabadghao, G K Modi, I Mittra, Deepesh Gupta, C Chauhan, S K Jain, Kewal K. MaudarAbstract:The Methyl Isocyanate (MIC) gas leak from the Union Carbide Plant at Bhopal, India, in 1984 represents the worst chemical disaster in modern industrial history. The leak resulted in release of 30–40 tons of MIC spreading over approximately 30 square miles. The estimated mortality of this accident is believed to have been between 2500 and 6000 people, with up to 200 000 injured.1 Given the nature and intensity of the accident, many facets of the event have been studied through at least 24 cohort studies among survivors but exposure to MIC and its possible immunological implications never received much attention. Two early studies conducted on exposed adult victims by Deo et al 2 and Saxena et al 3 reported significant delay of the cell cycle and a decreased response to mitogen-activated stimulation of proliferative lymphocytes studied. The study was approved by the institutional review board of Bhopal Memorial …
Pradyumna Kumar Mishra - One of the best experts on this subject based on the ideXlab platform.
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Cell cycle deregulation by Methyl Isocyanate: Implications in liver carcinogenesis
Environmental Toxicology, 2012Co-Authors: Hariom Panwar, Gorantla V. Raghuram, Alok K. Ahirwar, Subodh Kumar Jain, Saba Khan, Smita Banerjee, Kewal K. Maudar, Deepika Jain, Neelam Pathak, Pradyumna Kumar MishraAbstract:Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to Methyl Isocyanate (MIC), one of the most toxic Isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 284–297, 2014.
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molecular surveillance of hepatitis and tuberculosis infections in a cohort exposed to Methyl Isocyanate
International Journal of Occupational Medicine and Environmental Health, 2011Co-Authors: Pradyumna Kumar Mishra, Kewal K. Maudar, Neelam Pathak, Arpit Bhargava, Prabha Desikan, Subodh Varshney, Rahul Shrivastava, Aruna JainAbstract:Objective The potential toxic effects on the immune system exerted by occupational and accidental environmental exposures and underlying molecular regulatory mechanisms involved in the etiology and progression of infectious diseases are now being characterized. The Bhopal gas tragedy is undoubtedly one of the worst industrial disasters in the history of mankind. After 25 years of accidental exposure to Methyl Isocyanate (MIC), severe systemic ailments still continue to preoccupy the lives of the affected population that survived this tragedy. We have performed a molecular surveillance study to characterize hepatitis and tuberculosis infections amongst the first and the second generation of survivors exposed to MIC.
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in utero exposure to Methyl Isocyanate in the bhopal gas disaster evidence of persisting hyperactivation of immune system two decades later
Occupational and Environmental Medicine, 2008Co-Authors: Pradyumna Kumar Mishra, Prabha Desikan, Aruna Jain, Sunil Dabadghao, G K Modi, I Mittra, Deepesh Gupta, C Chauhan, S K Jain, Kewal K. MaudarAbstract:The Methyl Isocyanate (MIC) gas leak from the Union Carbide Plant at Bhopal, India, in 1984 represents the worst chemical disaster in modern industrial history. The leak resulted in release of 30–40 tons of MIC spreading over approximately 30 square miles. The estimated mortality of this accident is believed to have been between 2500 and 6000 people, with up to 200 000 injured.1 Given the nature and intensity of the accident, many facets of the event have been studied through at least 24 cohort studies among survivors but exposure to MIC and its possible immunological implications never received much attention. Two early studies conducted on exposed adult victims by Deo et al 2 and Saxena et al 3 reported significant delay of the cell cycle and a decreased response to mitogen-activated stimulation of proliferative lymphocytes studied. The study was approved by the institutional review board of Bhopal Memorial …
Thomas A Baillie - One of the best experts on this subject based on the ideXlab platform.
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selective and irreversible inhibition of glutathione reductase in vitro by carbamate thioester conjugates of Methyl Isocyanate
Biochemical Pharmacology, 1994Co-Authors: Claudia M Jochheim, Thomas A BaillieAbstract:Abstract Exposure of yeast glutathione reductase (GR) in vitro to S-(N-Methylcarbamoyl)glutathione (SMG) and S-(N-Methylcarbamoyl)cysteine (SMC), two carbamoylating metabolites of Methyl Isocyanate (MIC), led to a time-dependent, irreversible loss of enzyme activity (50–90%) over a period of 3 hr. The extent of inhibition was dependent upon the concentration of these carbamate thioester conjugates (0.1 to 1.0 mM) and on the presence of NADPH (100 μM). Omission of NADPH markedly attenuated the inhibitory effects of both SMG and SMC, while oxidized glutathione (GSSG), the natural substrate of the enzyme, protected against the inhibition. Parallel experiments with the antineoplastic drug N,N′-bis-(2-chloroethyl)-N-nitrosourea (BCNU), a carbamoylating agent which is known to inhibit GR selectively, gave results that were similar to those obtained with the above conjugates. When analogs of SMG and SMC labeled with 14C in the carbamoyl group were incubated with GR, radioactivity became bound covalently to the enzyme. These findings, together with the results of kinetic experiments on the release of GSH from SMG and cysteine from SMC, suggested that while both conjugates inhibit GR by carbamoylation of an active-site thiol(s), sMG exhibits a greater affinity for the active site than SMC. In contrast to the studies with GR, SMG and SMC failed to inhibit either glutathione-S-transferase (GST) or glutathione peroxidase (GPO) enzymes in vitro. It is concluded, therefore, that these conjugates most likely inhibit GR by carbamoylating free thiol groups in the active site of this enzyme, which are absent (or inaccessible) at the active-site of GST and GPO.
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studies on the metabolic fate of caracemide an experimental antitumor agent in the rat evidence for the release of Methyl Isocyanate in vivo
Chemical Research in Toxicology, 1993Co-Authors: J G Slatter, Deog Hwa Han, Margaret R Davis, P G Pearson, Thomas A BaillieAbstract:Following administration to rats of a single ip dose (6.6 mg kg-1) of the investigational antitumor agent caracemide (N-acetyl-N,O-bis[Methylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S-(N-Methylcarbamoyl)cysteine (AMCC) was identified in urine by thermospray LC-MS. Quantification of this conjugate was carried out by stable isotope dilution thermospray LC-MS, which indicated that the fraction of the caracemide dose recovered as AMCC in 24-h urine collections was 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urinary metabolite of Methyl Isocyanate (MIC) in the rat, the results of this study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deuterium-labeled analog of caracemide ([carbamoyloxy-C2H3]caracemide), it was shown that the Methylcarbamoyl group of AMCC derived from both the O-Methylcarbamoyl (72%) and N-Methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemide acts as a latent form of MIC in vivo and that this reactive Isocyanate (or labile S-linked conjugates thereof) may contribute to the antitumor properties and/or adverse side-effects of caracemide.
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toxicity of the Methyl Isocyanate metabolite s n Methylcarbamoyl gsh on mouse embryos in culture
Teratology, 1992Co-Authors: Ian Guest, Thomas A Baillie, Daya R VarmaAbstract:Methyl Isocyanate, the chemical involved in the 1984 accident at Bhopal, India, forms a labile conjugate, S-(N-Methylcarbamoyl)GSH (SMG), by way of a reversible reaction with GSH. We studied the toxicity of SMG on mouse embryos explanted on day 8 of gestation and cultured in rat serum for 42 hr. SMG caused concentration-dependent decreases in growth and development over the range 0.1–2 mM, without causing significant mortality. At a concentration of 2 mM, SMG completely arrested embryo development, but heartbeat was absent in only one of nine embryos at 42 hr. At a concentration of 0.25 mM, SMG reduced embryo size to 75% and protein content to 63% of the control; 18% of embryos failed to rotate. At this concentration (0.25 mM), which was selected for all other studies, spinal kinks and somite pair distortion in the region of the forelimb were evident in 38% of embryos; no other abnormalities were noted. DNA content of and thymidine incorporation by embryos and yolk sacs was reduced by SMG, although this was more pronounced in the yolk sac than in embryos. At subtoxic concentrations, the L-cysteine precursor (−)-2-oxo-4-thiazolidine-carboxylic acid did not, but GSH did, inhibit embryotoxicity of SMG. It is concluded that SMG exerts embryotoxic and dysmorphogenic effects and may contribute to systemic toxicity of Methyl Isocyanate. © 1992 Wiley-Liss, Inc.
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carbamoylation of peptides and proteins in vitro by s n Methylcarbamoyl glutathione and s n Methylcarbamoyl cysteine two electrophilic s linked conjugates of Methyl Isocyanate
Chemical Research in Toxicology, 1991Co-Authors: Paul G Pearson, Mohamed S Rashed, J. Greg Slatter, Thomas A BaillieAbstract:: The reactivity toward peptides and proteins of S-(N-Methylcarbamoyl)glutathione (SMG), the glutathione conjugate of Methyl Isocyanate, and the corresponding cysteine adduct, S-(N-Methylcarbamoyl)cysteine (SMC), was investigated with the aid of in vitro model systems. Incubation of SMC or a trideuterioMethyl analogue of SMC with either the reduced or oxidized forms of oxytocin afforded similar mixtures of mono-, bis- and tris-N-Methylcarbamoylated peptides. Structure elucidation of the mono and bis adducts by fast atom bombardment tandem mass spectrometry indicated that carbamoylation of oxytocin occurred preferentially at Cys-6 and that Cys-1 and/or Tyr-2 were secondary sites of modification. Upon incubation of S-[N-([14C]Methyl)carbamoyl]glutathione (14C-SMG) with native bovine serum albumin (BSA), radioactivity became bound covalently to the protein in a time- and concentration-dependent fashion. "Blocking" of the lone Cys-34 thiol group of BSA in the form of a disulfide prior to exposure of the protein to 14C-SMG failed to decrease significantly the extent or time course of this covalent binding. It is concluded that carbamate thioester conjugates of MIC are reactive, carbamoylating entities which can donate the elements of MIC to nucleophilic functionalities on peptides and proteins. Free thiols appear to be preferred sites for such carbamoylation processes, a phenomenon that may have important toxicological consequences in the pathology of tissue lesions induced by MIC and related Isocyanates.
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biotransformation of Methyl Isocyanate in the rat evidence for glutathione conjugation as a major pathway of metabolism and implications for Isocyanate mediated toxicities
Chemical Research in Toxicology, 1991Co-Authors: J G Slatter, Paul G Pearson, Mohamed S Rashed, Deog Hwa Han, Thomas A BaillieAbstract:S-(N-Methylcarbamoyl)-N-acetylcysteine (AMCC), a chemically labile mercapturic acid conjugate, was identified by liquid chromatography-mass spectrometry (LC-MS) in the urine of rats dosed intraperitoneally with Methyl Isocyanate (MIC; 45.2 mumol). The corresponding cysteine conjugate, however, was not detected in urine. Following Methylation, urine extracts were analyzed by thermospray LC-MS and the AMCC Methyl ester was quantified by means of a stable isotope dilution assay procedure which utilized S-(N-Methylcarbamoyl)-N-[2H3]-acetylcysteine [( 2H3]AMCC) as internal standard. The results showed that the fraction of the injected dose of MIC which appeared in 24-h urine collections as AMCC was 24.8 +/- 1.9% (mean +/- SD, N = 4). Thus, conjugation of MIC with glutathione (GSH), followed by metabolism of the resulting adduct to AMCC, appears to represent a quantitatively important pathway of biotransformation of MIC in the rat. However, in view of the known carbamoylating properties and in vitro cytotoxicity of S-linked conjugates of MIC, it seems unlikely that the GSH pathway of metabolism fulfills a conventional detoxification role in the case of MIC. In contrast, it is proposed that carbamate thioester conjugates of MIC, which can revert spontaneously to free MIC under physiological conditions, may actually contribute to the multisystem adverse effects of this highly toxic Isocyanate in vivo.
Jean-christophe Loison - One of the best experts on this subject based on the ideXlab platform.
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Quasi-symmetry effects in the threshold photoelectron spectrum of Methyl Isocyanate
Journal of Chemical Physics, 2020Co-Authors: Oliver Harper, Laurent Coudert, Bérenger Gans, Stephane Douin, Séverine Boyé-péronne, Jean-christophe Loison, Gustavo Garcia, Jeanclaude GuilleminAbstract:The vacuum-ultraviolet threshold photoelectron spectrum of Methyl Isocyanate CH3NCO has been recorded from 10.4 eV to 12 eV using synchrotron radiation and a coincidence technique allowing for a mass-discrimination of the photoelectron signal. A significant improvement is achieved over previous investigations as this experimental setup leads to a much more resolved spectrum. Ten sharp peaks and a broad feature spanning 1.2 eV were recorded. This spectrum consists of X̃+ 2A″←X̃ 1A' and Ã+ 2A'←X̃ 1A' ionizing transitions. For the former, the adiabatic ionization energy was determined experimentally to be 10.596(6) eV; for the latter, its value was estimated to be 10.759(50) eV. Seven sharp peaks could be assigned to vibrational modes of the cation X̃+ 2A″ and neutral X̃ 1A' ground electronic states involving only the NCO group atoms. Theoretical modeling of the threshold photoelectron spectrum has proven difficult as Methyl Isocyanate is a non-rigid molecule displaying large amplitude internal rotation of the Methyl group and ∠CNC bending mode, leading to the quasi-symmetry. With the help of ab initio calculations, a theoretical model in which these two large amplitude motions are included in addition to the five small amplitude vibrational modes involving NCO group atoms is proposed. Comparison with the experimental spectrum shows that the broad feature and the strongest peak line positions are well accounted for; their intensities are also fairly well reproduced after adjusting a few parameters.
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Methyl Isocyanate ch3nco an important missing organic in current astrochemical networks
Monthly Notices of the Royal Astronomical Society: Letters, 2018Co-Authors: Jean-christophe Loison, Liton Majumdar, M Ruaud, P Gratier, Valentine Wakelam, A CoutensAbstract:Methyl Isocyanate (CH3NCO) is one of the important complex organic molecules detected on the comet 67P/Churyumov-Gerasimenko by Rosetta's Philae lander. It was also detected in hot cores around high-mass protostars along with a recent detection in the solar-type protostar IRAS 16293-2422. We propose here a gas-grain chemical model to form CH3NCO after reviewing various formation pathways with quantum chemical computations. We have used NAUTILUS 3-phase gas-grain chemical model to compare observed abundances in the IRAS 16293-2422. Our chemical model clearly indicates the ice phase origin of CH3NCO.