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Title: Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study

Abstract

Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as 'carcinogenic', and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as 'non-carcinogenic'; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as 'carcinogenic', and 4-AAF, 2,6-DAT, and 1-NP as 'non-carcinogenic'. After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a 'carcinogenic' branch. 2-NpP wasmore » in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [3];  [4];  [4];  [5]
  1. Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan). E-mail: k-nakayama@ankaken.co.jp
  2. Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan)
  3. Chemical Evaluation and Research Institute, Tokyo (Japan)
  4. Sumitomo Chemical Co., Ltd., Osaka (Japan)
  5. Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan)
Publication Date:
OSTI Identifier:
20850504
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.008; PII: S0041-008X(06)00319-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLAMINOFLUORENES; DOSES; GENES; ISOMERS; LIVER; RATS; SKELETON; TOXICITY

Citation Formats

Nakayama, Koji, Kawano, Yukiko, Kawakami, Yuuki, Moriwaki, Norichika, Sekijima, Masaru, Otsuka, Masanori, Yakabe, Yoshikuni, Miyaura, Hideki, Saito, Koichi, Sumida, Kayo, and Shirai, Tomoyuki. Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.008.
Nakayama, Koji, Kawano, Yukiko, Kawakami, Yuuki, Moriwaki, Norichika, Sekijima, Masaru, Otsuka, Masanori, Yakabe, Yoshikuni, Miyaura, Hideki, Saito, Koichi, Sumida, Kayo, & Shirai, Tomoyuki. Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study. United States. doi:10.1016/j.taap.2006.09.008.
Nakayama, Koji, Kawano, Yukiko, Kawakami, Yuuki, Moriwaki, Norichika, Sekijima, Masaru, Otsuka, Masanori, Yakabe, Yoshikuni, Miyaura, Hideki, Saito, Koichi, Sumida, Kayo, and Shirai, Tomoyuki. Fri . "Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study". United States. doi:10.1016/j.taap.2006.09.008.
@article{osti_20850504,
title = {Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study},
author = {Nakayama, Koji and Kawano, Yukiko and Kawakami, Yuuki and Moriwaki, Norichika and Sekijima, Masaru and Otsuka, Masanori and Yakabe, Yoshikuni and Miyaura, Hideki and Saito, Koichi and Sumida, Kayo and Shirai, Tomoyuki},
abstractNote = {Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as 'carcinogenic', and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as 'non-carcinogenic'; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as 'carcinogenic', and 4-AAF, 2,6-DAT, and 1-NP as 'non-carcinogenic'. After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a 'carcinogenic' branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity.},
doi = {10.1016/j.taap.2006.09.008},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}