Toxicogenomics discrimination of potential hepatocarcinogenicity of non‐genotoxic compounds in rat liver

Yamada, Fumihiko; Sumida, Kayo; Uehara, Takeki; Morikawa, Yuji; Yamada, Hiroshi; Urushidani, Tetsuro; Ohno, Yasuo

doi:10.1002/jat.2790

Cited by 33 publications

(30 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, although this is a well-known mechanism in carcinogenesis, few reports have been published regarding tumor immunity in terms of early epigenetic events of chemicalinduced carcinogenesis or relevant reactions (Franco et al, 2008;Friedman, 2008;Komatsu et al, 2012). In contrast to previous toxicogenomics-based prediction mod-els based on comprehensive gene expression profiling (Ellinger-Ziegelbauer et al, 2008;Uehara et al, 2011;Yamada et al, 2013), we applied a different approach in the present study, using DNA methylation profiling to select signature genes in carcinogenic responses. This combined approach allowed us to focus on a specifi c gene and might therefore have the advantage of placing attention on the specifi c reaction instead of on other conspicuous effects, even though the main mechanisms are already known.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

et al. 2014

Self Cite

View full text Add to dashboard Cite

-Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

“…A number of effective prediction models using hepatic gene expression profiling have been developed (Ellinger-Ziegelbauer et al, 2008;Uehara et al, 2011;Yamada et al, 2013). In contrast, the MARCAR project aimed to identify early biological indicators to predict non-genotoxic carcinogens.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The application of transcriptomics approaches to detect carcinogenic features of chemicals has been extensively investigated in vivo as well as in vitro (EllingerZiegelbauer et al 2009a;Fielden et al 2011;Thomas et al 2009;Tsujimura et al 2006;Yamada et al 2012). Overall, these studies have yielded biologically relevant gene signatures, which can be employed to distinguish different chemical classes, e.g, (non-) genotoxic carcinogens versus noncarcinogens (Ellinger-Ziegelbauer et al 2008;Melis et al 2014; Thomas et al 2009;Watanabe et al 2012;Yamada et al 2012). Besides classification, gene expression profiling has also been demonstrated to be a useful tool to gain insight into the possible mode of action of a (carcinogenic) substance (Fielden et al 2011;Guyton et al 2009;Waters et al 2010).…”

Section: Introductionmentioning

confidence: 99%

A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens

et al. 2014

View full text Add to dashboard Cite

Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

show abstract

“…In the last decade, a number of carcinogenic prediction models have been constructed using gene expression data obtained from short-term bioassays in rat organs (Nie et al, 2006;Fielden et al, 2007;Ellinger-Ziegelbauer et al, 2008;Uehara et al, 2008, Yamada et al, 2013. Many of these models evaluate hepatocarcinogenicity and can discriminate GTX, NGTX carcinogens, and non-carcinogens with an accuracy of 80% to 90% (Waters et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The Open TG-GATEs [http://toxico.nibio.go.jp/ english/index.html] provides comprehensive gene expression data, and a detailed description of experimental conditions and procedures has been provided by Igarashi et al (2015). Two research groups have generated prediction models for detecting NGTX hepatocarcinogens using gene expression data derived from Open TG-GATEs (Uehara et al, 2008(Uehara et al, , 2011Yamada et al, 2013). Although the prediction models used by these groups detected hepatocarcinogenicity in rats, issues such as low sensitivity for enzyme inducers and PPARα agonists remain to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

Kanki

Fujioka

et al. 2016

J. Toxicol. Sci.

View full text Add to dashboard Cite

-Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator-activated receptor α (PPARα) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets. Principal component analysis (PCA) was applied to discriminate different MOAs, and a support vector machine algorithm was applied to construct the prediction model. This approach identified 106 probe sets as gene marker sets for PCA and enabled the prediction model to be constructed. In PCA, NGTX hepatocarcinogens were classified as follows based on their MOAs: cytotoxicants, PPARα agonists, or enzyme inducers. The prediction model detected hepatocarcinogenicity with an accuracy of more than 90% in 14-and 28-day repeated-dose studies. In addition, the doses capable of predicting NGTX hepatocarcinogenicity were close to those required in rat carcinogenicity assays. In conclusion, our PCA and prediction model using gene marker sets will help assess the risk of hepatocarcinogenicity in humans based on MOAs and reduce the number of two-year rodent bioassays.

show abstract

Toxicogenomics discrimination of potential hepatocarcinogenicity of non‐genotoxic compounds in rat liver

Cited by 33 publications

References 37 publications

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

Contact Info

Product

Resources

About