Cargando…

RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across

Chemical structure-based read-across represents a promising method for chemical toxicity evaluation without the need for animal testing; however, a chemical structure is not necessarily related to toxicity. Therefore, in vitro studies were often used for read-across reliability refinement; however,...

Descripción completa

Detalles Bibliográficos
Autores principales: Amano, Yuto, Yamane, Masayuki, Honda, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354856/
https://www.ncbi.nlm.nih.gov/pubmed/35935858
http://dx.doi.org/10.3389/fphar.2022.879907
_version_ 1784763163834580992
author Amano, Yuto
Yamane, Masayuki
Honda, Hiroshi
author_facet Amano, Yuto
Yamane, Masayuki
Honda, Hiroshi
author_sort Amano, Yuto
collection PubMed
description Chemical structure-based read-across represents a promising method for chemical toxicity evaluation without the need for animal testing; however, a chemical structure is not necessarily related to toxicity. Therefore, in vitro studies were often used for read-across reliability refinement; however, their external validity has been hindered by the gap between in vitro and in vivo conditions. Thus, we developed a virtual DNA microarray, regression analysis–based inductive DNA microarray (RAID), which quantitatively predicts in vivo gene expression profiles based on the chemical structure and/or in vitro transcriptome data. For each gene, elastic-net models were constructed using chemical descriptors and in vitro transcriptome data to predict in vivo data from in vitro data (in vitro to in vivo extrapolation; IVIVE). In feature selection, useful genes for assessing the quantitative structure–activity relationship (QSAR) and IVIVE were identified. Predicted transcriptome data derived from the RAID system reflected the in vivo gene expression profiles of characteristic hepatotoxic substances. Moreover, gene ontology and pathway analysis indicated that nuclear receptor-mediated xenobiotic response and metabolic activation are related to these gene expressions. The identified IVIVE-related genes were associated with fatty acid, xenobiotic, and drug metabolisms, indicating that in vitro studies were effective in evaluating these key events. Furthermore, validation studies revealed that chemical substances associated with these key events could be detected as hepatotoxic biosimilar substances. These results indicated that the RAID system could represent an alternative screening test for a repeated-dose toxicity test and toxicogenomics analyses. Our technology provides a critical solution for IVIVE-based read-across by considering the mode of action and chemical structures.
format Online
Article
Text
id pubmed-9354856
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-93548562022-08-06 RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across Amano, Yuto Yamane, Masayuki Honda, Hiroshi Front Pharmacol Pharmacology Chemical structure-based read-across represents a promising method for chemical toxicity evaluation without the need for animal testing; however, a chemical structure is not necessarily related to toxicity. Therefore, in vitro studies were often used for read-across reliability refinement; however, their external validity has been hindered by the gap between in vitro and in vivo conditions. Thus, we developed a virtual DNA microarray, regression analysis–based inductive DNA microarray (RAID), which quantitatively predicts in vivo gene expression profiles based on the chemical structure and/or in vitro transcriptome data. For each gene, elastic-net models were constructed using chemical descriptors and in vitro transcriptome data to predict in vivo data from in vitro data (in vitro to in vivo extrapolation; IVIVE). In feature selection, useful genes for assessing the quantitative structure–activity relationship (QSAR) and IVIVE were identified. Predicted transcriptome data derived from the RAID system reflected the in vivo gene expression profiles of characteristic hepatotoxic substances. Moreover, gene ontology and pathway analysis indicated that nuclear receptor-mediated xenobiotic response and metabolic activation are related to these gene expressions. The identified IVIVE-related genes were associated with fatty acid, xenobiotic, and drug metabolisms, indicating that in vitro studies were effective in evaluating these key events. Furthermore, validation studies revealed that chemical substances associated with these key events could be detected as hepatotoxic biosimilar substances. These results indicated that the RAID system could represent an alternative screening test for a repeated-dose toxicity test and toxicogenomics analyses. Our technology provides a critical solution for IVIVE-based read-across by considering the mode of action and chemical structures. Frontiers Media S.A. 2022-07-22 /pmc/articles/PMC9354856/ /pubmed/35935858 http://dx.doi.org/10.3389/fphar.2022.879907 Text en Copyright © 2022 Amano, Yamane and Honda. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Amano, Yuto
Yamane, Masayuki
Honda, Hiroshi
RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title_full RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title_fullStr RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title_full_unstemmed RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title_short RAID: Regression Analysis–Based Inductive DNA Microarray for Precise Read-Across
title_sort raid: regression analysis–based inductive dna microarray for precise read-across
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354856/
https://www.ncbi.nlm.nih.gov/pubmed/35935858
http://dx.doi.org/10.3389/fphar.2022.879907
work_keys_str_mv AT amanoyuto raidregressionanalysisbasedinductivednamicroarrayforprecisereadacross
AT yamanemasayuki raidregressionanalysisbasedinductivednamicroarrayforprecisereadacross
AT hondahiroshi raidregressionanalysisbasedinductivednamicroarrayforprecisereadacross