title: Discriminating the molecular basis of hepatotoxicity using the large-scale characteristic molecular signatures of toxicants by expression profiling analysis.
abstract: 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 C3H/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 (2,4,5-T, 150-60 mg/kg)). Large-scale molecular changes elicited by these four hepatotoxicants 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.
authors.affiliation: Department of Pathology, College of Medicine and Microdissection Genomics Research Center, The Catholic University of Korea, Seocho-Gu, Seoul, Republic of Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Ryu
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Noh
authors.forename: Min-Jae
authors.initials: MJ
authors.lastname: Lee
authors.forename: Ja-Jun
authors.initials: JJ
authors.lastname: Jang
authors.forename: Jae Chun
authors.initials: JC
authors.lastname: Ryu
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Kim
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Bae
authors.forename: Hongjian
authors.initials: H
authors.lastname: Xie
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
mesh_terms: D015085:2,4,5-Trichlorophenoxyacetic Acid / Q000633:toxicity; D000452:Aldrin / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D019327:Copper Sulfate / Q000633:toxicity; D003627:Data Interpretation, Statistical; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D007306:Insecticides / Q000633:toxicity; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D046228:Microarray Analysis; D009929:Organ Size / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D014752:Vinyl Chloride / Q000633:toxicity
chemical_list: D002273:Carcinogens; D007306:Insecticides; D012313:RNA; D015085:2,4,5-Trichlorophenoxyacetic Acid; D019327:Copper Sulfate; D000452:Aldrin; D014752:Vinyl Chloride