Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays

Non-genotoxic carcinogens are substances that induce tumorigenesis by non-mutagenic mechanisms and long term rodent bioassays are required to identify them. Recent studies have shown that transcription profiling can be applied to develop early identifiers for long term phenotypes. In this study, we...

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Autores principales: Pérez, Luis Orlando, González José, Rolando, Peral García, Pilar
Formato: Articulo
Lenguaje:Inglés
Publicado: 2016
Materias:
Ciencias Veterinarias
toxicogenomics
non-genotoxic carcinogen
random forest
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/104442
http://hdl.handle.net/11336/39786
http://www.toxicolres.org/journal/view.html?doi=10.5487/TR.2016.32.4.289
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-104442
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Veterinarias
toxicogenomics
non-genotoxic carcinogen
random forest
spellingShingle Ciencias Veterinarias
toxicogenomics
non-genotoxic carcinogen
random forest
Pérez, Luis Orlando
González José, Rolando
Peral García, Pilar
Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
topic_facet Ciencias Veterinarias
toxicogenomics
non-genotoxic carcinogen
random forest
description Non-genotoxic carcinogens are substances that induce tumorigenesis by non-mutagenic mechanisms and long term rodent bioassays are required to identify them. Recent studies have shown that transcription profiling can be applied to develop early identifiers for long term phenotypes. In this study, we used rat liver expression profiles from the NTP (National Toxicology Program, Research Triangle Park, USA) DrugMatrix Database to construct a gene classifier that can distinguish between non-genotoxic carcinogens and other chemicals. The model was based on short term exposure assays (3 days) and the training was limited to oxidative stressors, peroxisome proliferators and hormone modulators. Validation of the predictor was performed on independent toxicogenomic data (TG-GATEs, Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System, Osaka, Japan). To build our model we performed Random Forests together with a recursive elimination algorithm (VarSelRF). Gene set enrichment analysis was employed for functional interpretation. A total of 770 microarrays comprising 96 different compounds were analyzed and a predictor of 54 genes was built. Prediction accuracy was 0.85 in the training set, 0.87 in the test set and increased with increasing concentration in the validation set: 0.6 at low dose, 0.7 at medium doses and 0.81 at high doses. Pathway analysis revealed gene prominence of cellular respiration, energy production and lipoprotein metabolism. The biggest target of toxicogenomics is accurately predict the toxicity of unknown drugs. In this analysis, we presented a classifier that can predict non-genotoxic carcinogenicity by using short term exposure assays. In this approach, dose level is critical when evaluating chemicals at early time points.
format Articulo
Articulo
author Pérez, Luis Orlando
González José, Rolando
Peral García, Pilar
author_facet Pérez, Luis Orlando
González José, Rolando
Peral García, Pilar
author_sort Pérez, Luis Orlando
title Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
title_short Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
title_full Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
title_fullStr Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
title_full_unstemmed Prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
title_sort prediction of non-genotoxic carcinogenicity based on genetic profiles of short term exposure assays
publishDate 2016
url http://sedici.unlp.edu.ar/handle/10915/104442
http://hdl.handle.net/11336/39786
http://www.toxicolres.org/journal/view.html?doi=10.5487/TR.2016.32.4.289
work_keys_str_mv AT perezluisorlando predictionofnongenotoxiccarcinogenicitybasedongeneticprofilesofshorttermexposureassays
AT gonzalezjoserolando predictionofnongenotoxiccarcinogenicitybasedongeneticprofilesofshorttermexposureassays
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bdutipo_str Repositorios
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