Differential gene expression profiling between genotoxic and non-genotoxic hepatocarcinogens in young rat liver determined by quantitative real-time PCR and principal component analysis

Suenaga, Kazuya; Takasawa, Hironao; Watanabe, Takashi; Wako, Yumi; Suzuki, Takayoshi; Hamada, Shuichi; Furihata, Chie

doi:10.1016/j.mrgentox.2012.11.003

Cited by 22 publications

(23 citation statements)

References 21 publications

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“…Our results conˆrmed this. As in our previous advanced qPCR studies (8-10) we did not examine PAH, and we did not observe remarkable increases in these genes (8)(9)(10). It was reported that Cyp1a1 and Cyp1a2 were regulated by arylhydrocarbon receptor (AhR) (16).…”

Section: Discussionmentioning

confidence: 52%

“…Chrysene exhibited statistically signiˆcant increases of gene expression in 15 genes (Bax, Btg2, Casp1, Ccng1, Ccng2, Cdkn1a, Crp, Ephx1, Gdf15, Hmox1, Igfbp1, Lcn2, Mdm2, Phlda3 and Pmm1) and increase tendencies in 3 genes (Ddit4, Hspb1 and Pml) among these genes. However, the gene expression of Trp53 itself did not show changes from 4 to 48 h. In our previous studies (7)(8)(9)(10), the gene expression of Trp53 scarcely changed in the mouse and rat liver 4 and 48 h and 28 days after the administration of genotoxic and non-genotoxic hepatocarcinogens. The basal gene expression of Trp53 in the control animals may already be su‹cient for DNA damage under the present experimental conditions.…”

Section: Discussionmentioning

confidence: 68%

“…More recently, we succeeded in applying a similar study in rat liver. qPCR with 33 candidate genes and statistical analysis via PCA successfully diŠerentiate the genotoxic hepatocarcinogens (DEN and 2,6-dinitrotoluene) from the non-genotoxic hepatocarcinogen (DEHP) and the non-genotoxic non-hepatocarcinogen (phenacetin) (10). The present study was a preceding study to determine the optimal examination time within 48 h of the administration of the genotoxic hepatocarcinogen chrysene for the clariˆcation of biomarker genes; to this end, we examined the gene expression proˆles at 4,16,20,24, and 48 h after the administration of this chemical.…”

Section: Introductionmentioning

confidence: 99%

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Time-course Comparison of Gene Expression Profiles Induced by the Genotoxic Hepatocarcinogen, Chrysene, in the Mouse Liver

Sakurai

Watanabe

Suzuki

et al. 2014

Genes and Environment

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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Time-course Comparison of Gene Expression Profiles Induced by the Genotoxic Hepatocarcinogen, Chrysene, in the Mouse Liver

Sakurai

Watanabe

Suzuki

et al. 2014

Genes and Environment

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“…DiŠerential gene expression proˆling between genotoxic and non-genotoxic rat hepatocarcinogens as analyzed by qPCR and PCA: More recently, we applied our mouse candidate marker genes (9,17,18) to rat hepatocarcinogens in an established rat liver genotoxicity test system (46). We evaluated the gene expression proˆles in rat liver treated with 4 chemicals [DEN, 2,6-dinitrotoluene (DNT), DEHP, and phenacetin (PNT)] that were previously examined using the liver micronucleus assay by the CSGMT/JEMS･MMS collaborative study group (47,48).…”

Section: Introductionmentioning

confidence: 99%

“…3A-2 and 3B-2). (46) and the non-genotoxic hepatocarcinogen (DEHP) in 19 genes (Aen, Btg2, Ccnf, Ccng1, Ddit4l, Gadd45g, Gdf15, Hspb1, Jun, Lpp, Myc, Net1, Phlda3, Plk2, Pml, Pmm1, Rcan1, Tnf, and Tubb2c) and between genotoxic hepatocarcinogens and the non-genotoxic non-hepatocarcinogen (PNT) in 18 genes (Aen, Bax, Ccnf, Ccng1, Ddit4l, Ephx1, Gdf15, Hspb1, Jun, Myc, Net1, Phlda3, Plk2, Pml, Pmm1, Rcan1, Tnf, and Tubb2c)…”

Section: Introductionmentioning

confidence: 99%

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

Furihata

2013

Genes and Environment

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The primary motivation for conducting short-term tests for environmental mutagens and carcinogens has been to predict mutagens and/or carcinogens and to assess any associated risks. Organ-speciˆc in vivo short-term tests in rodents are valuable because chemical carcinogenesis is generally organ-speciˆc. I have attempted to develop various organ-speciˆc in vivo short-term tests mainly in rodent liver and stomach. Recently, our collaborative study group, Toxicogenomics/Japanese Environmental Mutagen Society･Mammalian Mutagenicity Study Group (JEMS･ MMS), attempted to use gene expression proˆling in in vivo short-term tests, conducted DNA microarrays to extract candidate marker genes, and later shifted to quantitative real-time PCR (qPCR) to proˆle the expression of selected genes. We successfully discriminated 8 genotoxic hepatocarcinogens from 4 non-genotoxic hepatocarcinogens by statistical analysis using principal component analysis (PCA) based on the gene expression proˆles for 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb2c) in mouse liver at 4 and 48 h following a single intraperitoneal administration of chemicals as determined by qPCR. More recently, we successfully performed a similar study in rat liver. Previously, my collaborators and I developed various organspeciˆc in vivo short-term test methods, including UDS (unscheduled DNA synthesis); RDS (replicative DNA synthesis) using a liquid scintillation counter in rat glandular stomach, forestomach, colon, and liver and hairless mouse epidermis; DNA single-strand scission (DSS); and ornithine decarboxylase assay (ODC) in rat glandular stomach on 62 compounds. Developing short-term tests that are helpful for the risk assessment of human mutagens and carcinogens would contribute to the development of ideal prediction methods.

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Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms

Tian

Locker

2013

Advances in Experimental Medicine and Biology

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Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45β. In liver cancer, promoter methylation frequently silences Gadd45β, demonstrating due to a suppressive function that is often proapoptotic. This contrasts with normal hepatocytes, where Gadd45β facilitates cell survival, growth, and proliferation. Gadd45β binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45b-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (i.e., compensatory growth and proliferation). Liver hyperplasia (i.e., de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45b-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45β normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45β protects the liver through two entirely different processes: binding MKK7 to block damaging signal transduction or binding CAR to coactivate anabolic transcription.

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Differential gene expression profiling between genotoxic and non-genotoxic hepatocarcinogens in young rat liver determined by quantitative real-time PCR and principal component analysis

Cited by 22 publications

References 21 publications

Time-course Comparison of Gene Expression Profiles Induced by the Genotoxic Hepatocarcinogen, Chrysene, in the Mouse Liver

Time-course Comparison of Gene Expression Profiles Induced by the Genotoxic Hepatocarcinogen, Chrysene, in the Mouse Liver

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms

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