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EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) ON ARSENITE INDUCED GENOTOXICITY
Citation:
Barnes, J A., B W. Collins, D J. Dix, AND J W. Allen. EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) ON ARSENITE INDUCED GENOTOXICITY. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 40(4):236-242, (2002).
Description:
Arsenic (As), a human carcinogen, is known to be genotoxic although its mechanism(s) of action for tumorigenesis is not well understood. Among the toxicity-related properties of this chemical are its clastogenic and aneugenic activities, as well as its capacity for inducing stress-response in the form of elevated heat shock protein (HSP) expression. In the present study, we have evaluated the effects of Hsp70 expression on arsenite production of structural and numerical types of chromosome anomalies in human cells. Human MCF-7 Tet-off cells stably transfected with a pTRE/Hsp70-1 transgene construct were used to regulate Hsp70 levels prior to in vitro arsenite exposures. A cytokinesis block micronucleus assay with kinetochore immunostaining was used to detect micronuclei (MN) derived from chromosome breakage (K-MN) or loss (K+MN). These studies demonstrated significant increases in micronucleus frequencies in response to arsenite following either a long exposure (5 or 10 mM for 46 hrs), or short exposure (10 or 40 mM for 8 hrs) protocol. Overall, the long protocol was more efficient in producing K+ MN and cells with multiple MN. Cells expressing elevated Hsp70 revealed significant reductions in the percent of cells positive for MN for both the long and short arsenite exposure protocols. Both K+ and K- types of arsenite-induced MN were observed to be lower in cells with elevated Hsp70 as compared to cells without overexpression of Hsp70. We conclude that the dose and duration of arsenite exposure influence the type as well as amount of chromosomal alteration produced, and that inducible Hsp70 protects against both clastogenic and aneugenic effects from this chemical.