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Differentiation of the mechanism of micronuclei induced by cysteine and glutathione conjugates of methylenedi-p-phenyl diisocyanate from that of 4,4'-methylenedianiline.

Authors
Zhong-BZ; Depree-GJ; Siegel-PD
Source
Mutat Res 2001 Oct; 497(1-2):29-37
NIOSHTIC No.
20021942
Abstract
Methylenedi-p-phenyl diisocyanate (MDI) is widely used in the production of polyurethane products. Diisocyanates are reactive compounds, MDI can react under physiological conditions with various functional groups found on biological molecules resulting in conjugate formation or undergo non-enzymatic hydrolysis to form 4,4'-methylenedianiline (MDA). We have previously reported that addition of MDI directly to Chinese hamster lung fibroblasts (V79) cultures did not induce micronuclei (MN), but MDA, and the glutathione and cysteine conjugates of MDI (BisGS-MDI and BisCYS-MDI), induced a concentration-dependent increase in the frequency of MN. The conventional MN assay does not discriminate between MN produced by acentric chromosome fragments from those arising due to whole lagging chromosomes that were not incorporated into daughter nuclei at the time of cell division. The mechanism of MN induction from these potential MDI metabolites/reaction products was explored in the present study using immunofluorescent staining of kinetochore in MN of cytokinesis-blocked V79 cells. This assay discerns the presence of centromere within the MN to distinguish the MN containing centric chromosomes from those containing acentric fragments. Eighty five percent of MDA-induced MN were negative with respect to anti-kinetochore antibody binding (KC(-)). This is consistent with an interaction between MDA and DNA resulting in chromosome breakage. However, BisGS-MDI and BisCYS-MDI induced a higher percentage of MN that were positively stained by the anti-kinetochore antibody (KC(+)). These results suggest that the mechanism of MN formation induced by BisGS-MDI and BisCYS-MDI is mediated through disruption and/or by affecting the function of the mitotic spindle. This mechanism is distinctly different from the mechanism of MN induction by MDA.
Keywords
Physiological-factors; Physiological-effects; Molecular-biology; Laboratory-animals; Animals; Animal-studies; DNA-damage; Cell-morphology; Cellular-reactions; Cell-division
Contact
Analytical Services Branch, M/S L4218, Health Effect Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA
CODEN
MUREAV
CAS No.
101-77-9; 101-68-8
Publication Date
20011018
Document Type
Journal Article
Email Address
pds3@cdc.gov
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Issue of Publication
1-2
ISSN
0027-5107
NIOSH Division
HELD
Source Name
Mutation Research
State
WV
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