Abstract
Purpose: Inadvertent exposure to environmental and industrial contaminants on human health is now a serious concern. However, liver work as a first line of defence against environmental as well as occupational toxins. Isocyanates, an important chemical entity with diverse industrial usage have drawn significant attention in the recent past as they react with DNA to produce toxicogenomic insults due to high degree of reactivity and low molecular weight having functional group -N=C=O. Moreover, health complications resulting from occupational and accidental exposures of these compounds are yet too elusive.This study was to explicate the role of different cellular proteins in cultured mouse liver epithelial cells after environmental stress using isocyanates. Methods: The present study was carried in NCTC clone 1469 (liver epithelial cell line) to assess cellular response of methyl isocyanate (MIC) using 0.005 μM of N-succinimidyl N-methylcarbamate, a surrogate chemical substitute to MIC. Studies were conducted in different time intervals to evaluate different cellular responses through addressing the role of different DNA damage responsive proteins; ATM, ATR & γH2AX; cell cycle regulatory proteins: cyclin A and E & cdk2; tumor suppressor proteins: p53, p21& Gadd45 and repair proteins: Mre11, Nbs1 & Rad50 through immuno-blotting and immunofluorescence. Results: Analysis of different cellular modulators through Western blot and immunofluorescence reveals interesting results. With initial activation of DNA damage sensors, different tumor suppressor proteins viz. p53, p21 and Gadd45 and repair proteins- Mre11, Rad50 & Nbs1 showed distress expression in N-succinimidyl N-methylcarbamate treated cells during different time intervals denoting their incompetence to regulate cell cycle due to profuse genetic alteration in comparison to controls cells. On the other hand, over-expression cyclins (cyclin A & cyclin E) and Cdk2 proteins were observed in different progressive time intervals in contrast to controls implicating their role in tumorigenesis due to inactivation of cell cycle checkpoints that, in turn, resulting abnormal cell proliferation. Conclusion: In conclusion, our investigation enlightens the tumorigenic proficiency of MIC with increased phosphorylation of DNA damage responsive proteins, impaired DNA repair process, deregulation of cyclins and decreased expression of different tumor suppressor proteins. The toxicant may affect the cascade of signaling mechanism of p53 and p21 proteins expression involved in cell cycle arrest with perturbation of GADD45 expression. Over-expression of cyclins and cdk2 expression further substantiated the progression of liver carcinogenesis.
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