Eun, Jung Woo Ryu, So Yeon Noh, Ji Heon Lee, Min-Jae Jang, Ja-Jun Ryu, Jae Chun Jung, Kwang Hwa Kim, Jeong Kyu Bae, Hyun Jin Xie, Hongjian Kim, Su Young Lee, Sug Hyung Park, Won Sang Yoo, Nam Jin Lee, Jung Young Nam, Suk Woo 2024-01-20T23:02:02Z 2024-01-20T23:02:02Z 2021-09-03 2008-07-30 0300-483X https://pubs.kist.re.kr/handle/201004/133310 Predicting the potential human health risk posed by chemical stressors; has long been a major challenge for toxicologists, and the use of microarrays to measure responses to toxicologically relevant genes, and to identify selective, sensitive biomarkers of toxicity is a major application of predictive and discovery toxicology. To investigate this possibility, we investigated whether carcinogens (at doses known to induce liver tumors in chronic exposure bioassays) deregulate characteristic sets of genes in mice. Male OH/He mice were dosed with two hepatocarcinogens (vinyl chloride (VC, 50-25 mg/kg), aldrin (AD, 0.8-0.4 mg/kg)), or two non-hepatocarcinogens (copper sulfate (CS, 150-60 mg/kg), 2,4,5-trichlorophenoxyacetic acid (2,4,5T, 150-60 mg/kg)). Large-scale molecular changes elicited by these four hepatotaxicants in liver tissues were analyzed using DNA microarray. Three days after administration, no significant phenotypic changes were induced by these four different hepatotoxicants in terms of histological examination or blood biochemical assay. However, unsupervised hierarchical analysis of gene expressional changes induced by hepatotoxicants resulted in two major gene subclusters on dendrogram, i.e., a carcinogen (VN, AD) and non-carcinogen group (CS, 2,4,5-T), and also revealed that distinct molecular signatures exist. These signatures were founded on well-defined functional gene categories and may differentiate genotoxic and non-genotoxic carcinogens. Furthermore, Venn diagram analysis allowed us to identify carcinogen and non-carcinogen-associated molecular signatures. Using statistical methods, we analyzed outlier genes for four different classes (genotoxic-, non-genotoxic-carcinogen, genotoxic-, non-genotoxic non-carcinogen) in terms of their potential to predict different modes-of-action. In conclusion, the identification of large-scale molecular changes in different hepatocarcinogen exposure models revealed that different types of hepatotoxicants are associated with different epigenetic changes and molecular pathways and that these large-scale characteristic molecular changes could be used as predictable toxicity markers. (C) 2008 Elsevier Ireland Ltd. All rights reserved. English ELSEVIER IRELAND LTD NONGENOTOXIC CARCINOGENS HEPATOCELLULAR-CARCINOMA TOXICOGENOMICS NODULE STAGE RNA Discriminating the molecular basis of hepatotoxicity using the large-scale characteristic molecular signatures of toxicants by expression profiling analysis Article 10.1016/j.tox.2008.05.001 1 TOXICOLOGY, v.249, no.2-3, pp.176 - 183 TOXICOLOGY 249 2-3 176 183 scie scopus 000258242100013 2-s2.0-46249118580 Pharmacology & Pharmacy Toxicology Pharmacology & Pharmacy Toxicology Article NONGENOTOXIC CARCINOGENS HEPATOCELLULAR-CARCINOMA TOXICOGENOMICS NODULE STAGE RNA DNA microarray hepatotoxicity expression profiling carcinogen non-carcinogen