Skip Navigation


ToxSci Advance Access originally published online on July 20, 2006
Toxicological Sciences 2006 93(2):341-347; doi:10.1093/toxsci/kfl068
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
93/2/341    most recent
kfl068v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Olaharski, A. J.
Right arrow Articles by Smith, M. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Olaharski, A. J.
Right arrow Articles by Smith, M. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Histone Deacetylase Inhibitor Trichostatin A Has Genotoxic Effects in Human Lymphoblasts In Vitro

Andrew J. Olaharski2, Zhiying Ji, Ji-Young Woo, Sophia Lim, Alan E. Hubbard, Luoping Zhang and Martyn T. Smith1

Molecular Epidemiology and Toxicology Laboratory, School of Public Health, University of California, Berkeley, California 94720-7360

Received May 4, 2006; accepted July 6, 2006

Histone deacetylase inhibitors (HDACi) are a class of putative chemotherapeutic agents for which the mechanism of toxicity has not been fully identified. To explore the possibility that HDACi are genotoxic, human TK6 lymphoblastoid cells were exposed to trichostatin A (TSA) and genetic damage was measured. TSA caused a dose-dependent increase of G1-arrested cells at 24 h that correlated with increasing levels of p21 and apoptosis. Significantly elevated frequencies of structural chromosomal aberrations in cells exposed to TSA were observed using both the kinetochore-antibody micronucleus assay and nonbanding metaphase chromosome analysis. Increased tail intensities, indicative of elevated levels of DNA damage, were observed using the alkaline comet assay. Elevated levels of phosphorylated histone {gamma}H2AX protein were observed as early as 3 h following TSA exposure and peaked at 12 h for 200nM TSA. Significant levels of aneuploidy at the 200nM TSA dose were observed using metaphase analysis, but interestingly, kinetochore-positive micronuclei were not detected at any dose using the kinetochore micronucleus assay, suggesting that TSA induces aneuploidy via a nondisjunction event rather than chromosome lagging. Increases in chromosomal loss and breakage were observed using simultaneous FISH metaphase analysis of chromosomes 5, 7, 8, and 21, consistent with data obtained from the micronucleus and metaphase chromosome analyses. We conclude that TSA is both a clastogen and aneugen in the TK6 cell line and propose that the observed cytostatic and apoptotic properties of TSA may partially be due to this genotoxicity.

Key Words: histone deacetylase inhibitor (HDACi); trichostatin A (TSA); genotoxicity; aneugen; clastogen.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.