Methyl isocyanate: An evaluation of in vivo cytogenetic activity

Abstract

The ability of inhaled methyl isocyanate (MIC) to induce genotoxic and cytotoxic damage in vivo was evaluated by assessing the induction of chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) in bone marrow metaphase cells, the induction of micronuclei in polychromatic erythrocytes (MN-PCEs), and the inhibition of bone marrow cellular proliferation and erythropoiesis. B6C3F1 mice were exposed to MIC by two exposure regiments: in two experiments, male mice only were exposed to 3, 10, and 30 ppm for 2 hr; in four experiments, male and female mice were exposed to 1 and 3 ppm (in one experiment, to 6 ppm, also), 6 hr per day for 4 consecutive days. The various cytogenetic endpoints were analyzed in bone marrow and peripheral blood (4-day exposure regimen only) samples taken from bromodeoxyuridine tablet-implanted animals killed 11 to 22 hr after cessation of the exposure to MIC. Exposure to MIC for 2 hr induced a significant delay in cellular proliferation but did not induce a significant increase in CAs, SCEs (evaluated at 3 and 10 ppm, only) or in bone marrow MN-PCEs. Also, this exposure regimen did not inhibit the rate of erythropoiesis. Following exposure to MIC for 4 days, a weak but significant increase in CAs and SCEs was observed in male (in one experiment) and in female (in two experiments) mice. The induction was especially apparent in the single experiment in which mice were exposed to 6 ppm MIC. At this concentration, a significant increase in MN-PCEs in peripheral blood was observed in male but not female mice. Delay in bone marrow cell proliferation was observed in male mice beginning at 3 ppm and in female mice at 6 ppm. The 4-day exposure regimen resulted also in a depressed rate of erythropoiesis, with male mice appearing to exhibit greater depression than female mice. The results demonstrate that exposure to MIC by inhalation results in bone marrow damage, indicating the systemic genotoxic/cytotoxic activity of MIC and/or reactive metabolites.

Genotoxic and Carcinogenic Effects of Methyl Isocyanate (MIC) Reviewed on Exposed Bhopal Population and Future Perspectives for Assessment of Long-Term MIC-Effect

“…Depression of mitotic (MI) and replicative indices (RI) in Ghosh et al [26] study was not consistent with MIC-exposure in Bhopal population, which was consistent with Conner et al [32] in murine alveolar macrophages. However, delayed cell cycle was reported by Deo et al [28] in peripheral lymphocytes of the MIC-exposed people, and also in experimental animals [33].…”

“…However, a significant increase in micronucleated polychromatic erythrocytes was observed in peripheral blood of male mice in one experiment. Genotoxic/ cytotoxic effect was evidenced through depression in bone marrowcellularity in animals exposed by inhalation [33]. Genotoxic response of MIC-modified DNA described decrease in plaque formation in E. coli.…”

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

“…Besides, the immunotoxic (Karol et al, 1987), genotoxic (Conner et al, 1987;Tice et al, 1987), reproductive and developmental toxic effects (Schwetz et al, 1987) are well-documented in humans and animals. However, the etiology of MIC in carcinogenesis is far from completely understood (Senthilkumar et al, 2012;Senthilkumar, 2012).…”

A retrospective review of cytogenetic studies on methyl isocyanate with special reference to the Bhopal gas tragedy: Is the next generation also at risk?

“…Striking findings of resistance were documented in plants like Artocarpus integrifolia, Casuarina equisetifolia, Ficus bengalensis and Mangifera indica [8] Genotoxic potential of MIC in exposed animal subjects MIC has a significant potential for inducing cancer in rodents [47] Sister chromatid exchanges (SCEs) and cell cycle kinetics in murine tissues [40] Chromosomal aberrations and sister chromatid exchanges in bone marrow metaphase cells, induction of micronuclei in polychromatic erythrocytes and the inhibition of bone marrow cellular proliferation and erythropoiesis in mice [48] In vivo micronucleus test, chromosomal aberrations, sister chromatid exchanges in bone marrow cells of rodent somatic cells [49] In vivo micronucleus test and chromosomal analysis of bone marrow cells in mice [50] Mutagenic and cytotoxic effects in mouse micronucleus test [51] Genotoxic potential of MIC in exposed human subjects…”

“…The non-targeted effects of toxic exposure such as bystander responses, genomic instability, gene induction, adaptive responses and low hypersensitivity may also be mirrored as trans-generational health effects. Sarangi et al [57] report that exposure of pregnant workers have demonstrated that exposure to MIC by inhalation results in bone marrow damage, indicating that MIC or its reactive metabolites possess systemic genotoxic/cytotoxic activity [48][49][50]. MIC exposure was found to lead to inhibition of bone marrow cell proliferation by evaluation of the mutagenic and cytotoxic effects of MIC with a mouse micronucleus test [51].…”