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Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment

Several approaches have been used in an attempt to simplify and codify the events that lead to adverse effects of chemicals including systems biology, ‘omics, in vitro assays and frameworks such as the Adverse Outcome Pathway (AOP). However, these approaches are generally not integrated despite thei...

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Autores principales: Perkins, Edward J., Woolard, E. Alice, Garcia-Reyero, Natàlia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987526/
https://www.ncbi.nlm.nih.gov/pubmed/35399296
http://dx.doi.org/10.3389/ftox.2022.786057
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author Perkins, Edward J.
Woolard, E. Alice
Garcia-Reyero, Natàlia
author_facet Perkins, Edward J.
Woolard, E. Alice
Garcia-Reyero, Natàlia
author_sort Perkins, Edward J.
collection PubMed
description Several approaches have been used in an attempt to simplify and codify the events that lead to adverse effects of chemicals including systems biology, ‘omics, in vitro assays and frameworks such as the Adverse Outcome Pathway (AOP). However, these approaches are generally not integrated despite their complementary nature. Here we propose to integrate toxicogenomics data, systems biology information and AOPs using causal biological networks to define Key Events in AOPs. We demonstrate this by developing a causal subnetwork of 28 nodes that represents the Key Event of regenerative proliferation – a critical event in AOPs for liver cancer. We then assessed the effects of three chemicals known to cause liver injury and cell proliferation (carbon tetrachloride, aflatoxin B(1), thioacetamide) and two with no known cell proliferation effects (diazepam, simvastatin) on the subnetwork using rat liver gene expression data from the toxicogenomic database Open TG-GATEs. Cyclin D1 (Ccnd1), a gene both causally linked to and sufficient to infer regenerative proliferation activity, was overexpressed after exposures to carbon tetrachloride, aflatoxin B(1) and thioacetamide, but not in exposures to diazepam and simvastatin. These results were consistent with known effects on rat livers and liver pathology of exposed rats. Using these approaches, we demonstrate that transcriptomics, AOPs and systems biology can be applied to examine the presence and progression of AOPs in order to better understand the hazards of chemical exposure.
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spelling pubmed-89875262022-04-08 Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment Perkins, Edward J. Woolard, E. Alice Garcia-Reyero, Natàlia Front Toxicol Toxicology Several approaches have been used in an attempt to simplify and codify the events that lead to adverse effects of chemicals including systems biology, ‘omics, in vitro assays and frameworks such as the Adverse Outcome Pathway (AOP). However, these approaches are generally not integrated despite their complementary nature. Here we propose to integrate toxicogenomics data, systems biology information and AOPs using causal biological networks to define Key Events in AOPs. We demonstrate this by developing a causal subnetwork of 28 nodes that represents the Key Event of regenerative proliferation – a critical event in AOPs for liver cancer. We then assessed the effects of three chemicals known to cause liver injury and cell proliferation (carbon tetrachloride, aflatoxin B(1), thioacetamide) and two with no known cell proliferation effects (diazepam, simvastatin) on the subnetwork using rat liver gene expression data from the toxicogenomic database Open TG-GATEs. Cyclin D1 (Ccnd1), a gene both causally linked to and sufficient to infer regenerative proliferation activity, was overexpressed after exposures to carbon tetrachloride, aflatoxin B(1) and thioacetamide, but not in exposures to diazepam and simvastatin. These results were consistent with known effects on rat livers and liver pathology of exposed rats. Using these approaches, we demonstrate that transcriptomics, AOPs and systems biology can be applied to examine the presence and progression of AOPs in order to better understand the hazards of chemical exposure. Frontiers Media S.A. 2022-03-24 /pmc/articles/PMC8987526/ /pubmed/35399296 http://dx.doi.org/10.3389/ftox.2022.786057 Text en Copyright © 2022 Perkins, Woolard and Garcia-Reyero. 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 Toxicology
Perkins, Edward J.
Woolard, E. Alice
Garcia-Reyero, Natàlia
Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title_full Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title_fullStr Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title_full_unstemmed Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title_short Integration of Adverse Outcome Pathways, Causal Networks and ‘Omics to Support Chemical Hazard Assessment
title_sort integration of adverse outcome pathways, causal networks and ‘omics to support chemical hazard assessment
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987526/
https://www.ncbi.nlm.nih.gov/pubmed/35399296
http://dx.doi.org/10.3389/ftox.2022.786057
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