S20: Predictive toxicogenomics to assess chemical carcinogenic potential in rat liver

详细信息    查看全文

• 作者：Tomoyuki Shirai
• 刊名：Experimental and Toxicologic Pathology
• 出版年：2009
• 出版时间：May 2009
• 年：2009
• 卷：61
• 期：3
• 页码：265-266
• 全文大小：60 K

文摘

Toxicogenomics is a new scientific field that is expected to overcome many difficulties encountered with conventional toxicological examinations. The standardized long-term rodent carcinogenicity assay for predicting carcinogenic hazard of chemical substances to human beings is very expensive in terms of financial and human resources and exceedingly time-consuming. As a possible measure to avoid these issues, the Ministry of Economy, Trade and Industry in Japan has undertaken a toxicogenomics project that aims at developing a novel bioassay based on combinations of animal toxicology studies and gene expression profiles.

Male F344 rats aged 5-week old were treated by daily oral gavage with one of 85 hepatocarcinogenic, non-hepatocarcinogenic or non-carcinogenic compounds at two dose levels for 28 days. The livers were sampled at the following 6 time points: Days 1, 3, 7, 14, 21 and 28. For monitoring gene expression levels, an in-house oligomicroarray (NEDO-ToxArray III) covering approximately 6700 genes was prepared. Genes for prediction of carcinogenicity were selected by data cleaning and the Welch's t-test based on classification of the training set of chemical carcinogens. Then, two prediction models were established by supportive vector machine analysis, one based on the expression pattern and the other on analysis of chemical compound classification according to Ames’ mutagenicity profiles.

The data demonstrated very good predictivity; the prediction rates were 100 % for rat hepatocarcinogens (23 chemicals), 78 % for mouse hepatocarcinogens (7/9) and 96 % for other carcinogens (23/24). Negative predictivity was 96 % (24/26). Blind testing (17 chemicals), inter-laboratory validation (4) and external validation (3) all provided good results.

Thus, the toxicogenomics approach was proven to be very valuable tool for prediction of carcinogenic potentials of chemicals.

The data obtained were from collaboration by the Chemicals Evaluation and Research Institute, Sumitomo Chemical Co. Ltd., and Mitsubishi Chemical Safety Institute Ltd.