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ToxSci Advance Access published online on April 21, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh099
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 5, 2003
Accepted January 27, 2004

Safety Evaluation

The Value of DNA Methylation Analysis in Basic, Initial Toxicity Assessments

Rebecca E. Watson 1, James M. McKim 2, Gary L. Cockerell 2, Jay I. Goodman 1*

1 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824
2 Pharmacia Corporation, Investigative Toxicology, Kalamazoo, Michigan 49048

* To whom correspondence should be addressed. E-mail: goodman3{at}msu.edu.


  Abstract

DNA methylation is an epigenetic mechanism regulating patterns of gene expression. Here, our goal was to take a first step towards determining if assessment of DNA methylation might be a useful tool when used in conjunction with initial, basic in vitro tests, to provide a more informative preliminary appraisal of the toxic potential of chemicals in order to prioritize them for further evaluation. Our aim is to provide a better picture of a compound's toxic potential and an indication of its possible mechanism of action at an earlier time, thus contributing to a rational approach toward an overall reduction in testing by helping to make improved decisions early in the process. Global and GC-rich patterns of DNA methylation were evaluated along with more traditional cytolethality measurements, e.g., cytolethality and genotoxicity assessments, on rat hepatoma (H4IIE) cells. The relative "toxic" potential of model compounds camptothecin, 5-fluorouracil, rotenone, and staurosporine was estimated by employing DNA methylation assessments combined with our cytolethality data plus genotoxicity information gleaned from the literature. The overall contribution of the methylation assessment was threefold, it: 1) strengthened a ranking based upon genotoxicity, 2) provided an indication that a compound might be more potentially problematic than what cytolethality and genotoxicity assessments alone would indicate, and 3) suggested that compounds, particularly nongenotoxins, that are more potent regarding ability to alter methylation, especially at non-cytolethal concentrations, may be more potentially toxic. Altered methylation per se is not proof of toxicity, this needs to be viewed as a component of an evaluation.


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