Discriminating the molecular basis of hepatotoxicity using the large-scale characteristic molecular signatures of toxicants by expression profiling analysis.
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.
Eun
Jung Woo
JW
Department of Pathology, College of Medicine and Microdissection Genomics Research Center, The Catholic University of Korea, Seocho-Gu, Seoul, Republic of Korea.
Ryu
So Yeon
SY
Noh
Ji Heon
JH
Lee
Min-Jae
MJ
Jang
Ja-Jun
JJ
Ryu
Jae Chun
JC
Jung
Kwang Hwa
KH
Kim
Jeong Kyu
JK
Bae
Hyun Jin
HJ
Xie
Hongjian
H
Kim
Su Young
SY
Lee
Sug Hyung
SH
Park
Won Sang
WS
Yoo
Nam Jin
NJ
Lee
Jung Young
JY
Nam
Suk Woo
SW
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
D002273:Carcinogens; D007306:Insecticides; D012313:RNA; D015085:2,4,5-Trichlorophenoxyacetic Acid; D019327:Copper Sulfate; D000452:Aldrin; D014752:Vinyl Chloride