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Bioinformatics Advance Access published online on October 25, 2005
Bioinformatics, doi:10.1093/bioinformatics/bti737
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© The Author (2005). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 10, 2005
Revised September 28, 2005
Accepted October 20, 2005

Article

Integrating time-course microarray gene expression profiles with cytotoxicity for identification of biomarkers in primary rat hepatocytes exposed to cadmium#

Yongxi Tan 1, Leming Shi 2, Saber M. Hussain 3, Jun Xu 1, Weida Tong 2, John M. Frazier 3 {sect}, and Charles Wang 4* {sect}

1 Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
2 Center for Toxicoinformatics, National Center for Toxicological Research, FDA, Jefferson, AR 72079
3 Applied Biotechnology, US Air Force Research Laboratory, WPAFB, OH 4543
4 Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; David Geffen School of Medicine, UCLA, Los Angeles, CA 90048

* To whom correspondence should be addressed.
Charles Wang, E-mail: cwang61{at}ucla.edu; oxwang@gmail.com


  Abstract

Motivation: DNA microarrays can provide information about the expression levels of thousands of genes simultaneously at the transcriptomic level, while conventional cell viability and cytotoxicity measurement methods provide information about the biological functions at the cellular level. Integrating these data at different levels provides a promising approach for evaluating or predicting how cells respond to chemical exposure. It is important to investigate the multi-scale biological system in a systematic way to better understand the gene regulation networks and signal transduction pathways involved in the cellular responses to environmental factors.

Results: Primary rat hepatocytes were exposed to cadmium acetate at 0, 1.25, and 2 µM. mRNA expression profiles at 0, 3, 6, 12 and 24 h were measured using the Affymetrix RatTox U34 GeneChip® arrays. Simultaneously, cytotoxicity was assessed by lactase dehydrogenase (LDH) leakage assay. Gene expression profiles at different time points were used to evaluate cytotoxicity at subsequent time points using partial least squares (PLS), and it was found that gene expression profiles at 0 h had the best prediction accuracy for the cytotoxicity observed at 12 h. Some biomarkers whose expression profiles showed strong relationship with cytotoxicity were identified and the underlying pathways were reconstructed to illustrate how hepatocytes respond to cadmium exposure. Permutation studies were also applied to assess the reliability of the predictive models.

Availability: Matlab source code is available upon request and DNA microarray data are available at GEO (http://www.ncbi.nlm.nih.gov/geo).

#This study was supported by the U.S. Air Force Office of Scientific Research (AFOSR) and all laboratory work related to data collection were completed at the Genomics and Proteomics Lab, the US Air Force Research Laboratory, WPAFB, OH.

{sect}Both JMF and CW are equal senior authors of this paper.


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