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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}
}
  • Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. Inmore » the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of cholinergic signaling. • CPZ suppressed immediate–early gene-mediated neuronal plasticity in dentate GCL. • Lack of reelin response may be responsible for severe effects on neurogenesis.« less
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