TESTING CHEMICAL CARCINOGENICITY BY USING A TRANSCRIPTOMICS HEPARG-BASED MODEL?

Fecha de publicación: 01/01/2014

Autores de IIS La Fe

Bernardo Roque Bort Martí

Autor
José Vicente Castell Ripoll

Autor

Participantes ajenos a IIS La Fe

Doktorova TY
Yildirimman R
Ceelen L
Vilardell M
Vanhaecke T
Vinken M
Ates G
Heymans A
Gmuender H
Corvi R
Phrakonkham P
Li R
Mouchet N
Chesne C
van Delft J
Kleinjans J
Herwig R
Rogiers V

Grupos

Hepatología experimental y Trasplante hepático

Investigador Principal

Laia Tolosa Pardo
Unidad Mixta de Investigación en Hepatología Experimental

Investigador Principal

Ramiro Jover Atienza

Abstract

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances.

Datos de la publicación

ISSN/ISSNe:: 1611-2156,
Tipo:: Article
Páginas:: 623-637
DOI:
PubMed:: 26417288
Factor de Impacto:: 0,242 SCImago ℠
Cuartil:: Q3 SCImago ℠

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Métricas

Filiaciones

Doktorova TY:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
Yildirimman R:: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
Ceelen L:: Pathlicon, 9940, Evergem, Belgium
Vilardell M:: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
Vanhaecke T:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
Vinken M:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
Ates G:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
Heymans A:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
Gmuender H:: Genedata AG, 4053, Basel, Switzerland
Bort R:: Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain

University of Valencia, Faculty of Medicine, Department of Biochemistry and Molecular Biology, E-46009, Valencia, Spain
Corvi R:: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy
Phrakonkham P:: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy
Li R:: Biopredic International, 35000, Rennes, France
Mouchet N:: Institut Génétique et Développement de Rennes, 6290, Rennes, France
Chesne C:: Biopredic International, 35000, Rennes, France
Castell J:: Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain

University of Valencia, Faculty of Medicine, Department of Biochemistry and Molecular Biology, E-46009, Valencia, Spain
Herwig R:: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
Rogiers V:: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium

Keywords

genotoxic carcinogens; non-genotoxic carcinogens; gene expression profiling; pathways-based analysis; HepaRG cell line; liver-based in vitro models

Proyectos y Estudios Clínicos

DESARROLLO DE UN MODELO HEPATOCELULAR HUMANO DIFERENCIADO PARA ESTUDIOS DE METABOLISMO Y POTENCIAL INDUCTOR DE NUEVOS FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

SAF2003-09353 . 2003

A-CUTE-TOX

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2004-512051-ACUTE TOX . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

DESARROLLO DE NUEVAS ESTRATEGIAS DIAGNOSTICAS BASADAS EN EL ESTUDIO DE LA CAPACIDAD METABOLIZANTE DE LA PIEL Y DEL PAPEL DE LAS CELULAS DENDITRICAS EN LA INDUCCION DE LAS REACCIONES ALERGICAS FRENTE A FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

PARTIC PI05/2290 - FUND IMABIS . INSTITUTO DE SALUD CARLOS III; FUNDACION FIMABIS . 2007

DEVELOPMENT OF A HIGH THROUGHPUT GENOMICS-BASED TEST FOR ASSESSING GENOTOXIC AND CARCINOGENIC PROPERTIES OF CHEMICAL COMPOUNDS IN VITRO

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CARCINOGENOMICS . COMISION EUROPEA . 2006

LINTOP

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2006-037499 - LINTOP . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

MECANISMOS TRNACRIPCIONALES IMPLICADOS EN LA ETIOLOGIA DEL HIGADO GRASO NO ALCOHOLICO. ESTUDIOS EN UN MODELO CELULAR HUMANO DE ESTEATOSIS Y APLICACION AL TRANSPLANTE DE HEPATOCITOS EN TERAPIA CELULAR.

Investigador Principal: RAMIRO JOVER ATIENZA

PI07/0550 . INSTITUTO DE SALUD CARLOS III . 2007

TU HOSPITAL INVESTIGA PARA TI

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CCT005-07-00936 . 2007

PROYECTO CAIBER

CAI08/01/0061 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

FORINVITOX

Investigador Principal: MARÍA JOSÉ GÓMEZ-LECHÓN MOLINER

FORINVITOX 1, START UP 2 . REMA; UNIVERSIDAD AUTONOMA BARCELONA; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2008

RED DE INNOVACION EN TECNOLOGIAS MEDICAS Y SANITARIAS - RED ITEMAS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

RD09/0077/00156 . INSTITUTO DE SALUD CARLOS III . 2010

CREACION Y MEJORA DE INFRAESTRUCTURAS EN MEDICINA REGENERATIVA

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PLE2009-0141 ACI-PLAN E . MINISTERIO DE CIENCIA E INNOVACION; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009