Document Detail

Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure.
MedLine Citation:
PMID:  19695278     Owner:  NLM     Status:  MEDLINE    
Titanium dioxide (TiO2) nano-particles (<100 nm in diameter) have been of interest in a wide range of applications, such as in cosmetics and pharmaceuticals because of their low toxicity. However, recent studies have shown that TiO2 nano-particles (nano-TiO2) induce cytotoxicity and genotoxicity in various lines of cultured cells as well as tumorigenesis in animal models. The biological roles of nano-TiO2 are shown to be controversial and no comprehensive study paradigm has been developed to investigate their molecular mechanisms. In this study, we showed that short-term exposure to nano-TiO2 enhanced cell proliferation, survival, ERK signaling activation and ROS production in cultured fibroblast cells. Moreover, long-term exposure to nano-TiO2 not only increased cell survival and growth on soft agar but also the numbers of multinucleated cells and micronucleus (MN) as suggested in confocal microscopy analysis. Cell cycle phase analysis showed G2/M delay and slower cell division in long-term exposed cells. Most importantly, long-term TiO2 exposure remarkably affected mitotic progression at anaphase and telophase leading to aberrant multipolar spindles and chromatin alignment/segregation. Moreover, PLK1 was demonstrated as the target for nano-TiO2 in the regulation of mitotic progression and exit. Notably, a higher fraction of sub-G1 phase population appeared in TiO2-exposed cells after releasing from G2/M synchronization. Our results demonstrate that long-term exposure to nano-TiO2 disturbs cell cycle progression and duplicated genome segregation, leading to chromosomal instability and cell transformation.
Shing Huang; Pin Ju Chueh; Yun-Wei Lin; Tung-Sheng Shih; Show-Mei Chuang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-18
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  241     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-10-30     Completed Date:  2009-11-17     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  182-94     Citation Subset:  IM    
Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 402, Taiwan.
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MeSH Terms
Cell Cycle Proteins / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Cell Transformation, Neoplastic / chemically induced*,  pathology
Chromosome Segregation*
Cytotoxins / administration & dosage,  chemistry,  toxicity*
DNA Damage / drug effects*
Dose-Response Relationship, Drug
Drug Administration Schedule
Extracellular Signal-Regulated MAP Kinases / physiology
Mitosis / drug effects*
NIH 3T3 Cells
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / metabolism
Reactive Oxygen Species / metabolism
Titanium / administration & dosage,  chemistry,  toxicity*
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Cytotoxins; 0/Proto-Oncogene Proteins; 0/Reactive Oxygen Species; 13463-67-7/titanium dioxide; 7440-32-6/Titanium; EC Kinases; EC kinase 1; EC Signal-Regulated MAP Kinases

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