Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis

Abstract

A rapid and sensitive method to determine the characteristics of carcinogens is needed. In this study, we used a microarray-based genomics approach, with a short-term in vivo model, in combination with insights from statistical and mechanistic analyses to determine the characteristics of carcinogens. Carcinogens were evaluated based on the different mechanisms involved in the responses to genotoxic carcinogens and non-genotoxic carcinogens. Gene profiling was performed at two time points after treatment with six training and four test carcinogens. We mapped the DEG (differentially expressed gene)-related pathways to analyze cellular processes, and we discovered significant mechanisms that involve critical cellular components. Classification results were further supported by Comet and Micronucleus assays. Mechanistic studies based on gene expression profiling enhanced our understanding of the characteristics of different carcinogens. Moreover, the efficiency of this study was demonstrated by the short-term nature of the animal experiments that were conducted.C arcinogens can be categorized as either genotoxic (GTX) or non-genotoxic (NGTX), according to their specific pathogenic mechanism. Most GTX carcinogens are electrophiles that interact directly with DNA through the formation of covalent bonds, resulting in DNA-carcinogen complexes (DNA adducts). These complexes lead to various types of DNA damage, including the formation of cross-links between the two helices, chemical bonds between adjacent bases, removal of DNA bases (hydration) and cleavage of the DNA strands, all of which result in modifications to the information stored within the DNA. Such mutations are typically fixed by DNA repair mechanisms; however, if DNA replication occurs prior to the action of a repair mechanism, mutations can become permanent and may eventually cause tumors. Conversely, NGTX carcinogens have no direct interaction with DNA; they are believed to cause tumors by disrupting cellular structures and by changing the rate of either cell proliferation or of processes that increase the risk of genetic error.These types of differences in the sub-mechanisms of carcinogenicity also affect the gene expression patterns of cells exposed to carcinogens, which encourages genomic approaches in toxicological studies [1][2][3] . Previous studies have found that GTX carcinogens activate p53 tumor suppressor gene products in response to DNA damage, which leads to the initiation of sub-mechanisms, including the activation of cell cycle arrest, apoptosis and DNA repair processes, and which results in changes in the expression of specific genes, such as Cdkn1a, Mdm2 and Bcl2 4,5 . NGTX carcinogens display complicated and varying mechanisms that are not completely understood. However, these mechanisms have been associated with an alteration in oxidative stress, modulation of metabolizing enzymes, induction of peroxisome proliferation, alteration of intercellular communication and disruption of the balance between proliferation and apoptosis 5,6 . Theref...

Transcriptomic effect marker patterns of genotoxins – a comparative study with literature data

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A novel chemoprotective effect of tiopronin against diethylnitrosamine‐induced hepatocellular carcinoma in rats: Role of ASK1/P38 MAPK‐P53 signalling cascade

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A new genotoxicity assay based on p53 target gene induction

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