Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish
Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of...
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doaj-2dfc80e36e00424f99ea24accbf45c1d2021-06-15T08:39:32ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-06-011210.3389/fgene.2021.652632652632Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval ZebrafishRoman A. Li0Roman A. Li1Marja Talikka2Sylvain Gubian3Colette vom Berg4Florian Martin5Manuel C. Peitsch6Julia Hoeng7Anze Zupanic8Anze Zupanic9Eawag, Dübendorf, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandEawag, Dübendorf, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandEawag, Dübendorf, SwitzerlandNational Institute of Biology, Ljubljana, SloveniaAdverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.https://www.frontiersin.org/articles/10.3389/fgene.2021.652632/fullsystems toxicologyzebrafishdevelopmental neurotoxicityklf8rb1tp53 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roman A. Li Roman A. Li Marja Talikka Sylvain Gubian Colette vom Berg Florian Martin Manuel C. Peitsch Julia Hoeng Anze Zupanic Anze Zupanic |
spellingShingle |
Roman A. Li Roman A. Li Marja Talikka Sylvain Gubian Colette vom Berg Florian Martin Manuel C. Peitsch Julia Hoeng Anze Zupanic Anze Zupanic Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish Frontiers in Genetics systems toxicology zebrafish developmental neurotoxicity klf8 rb1 tp53 |
author_facet |
Roman A. Li Roman A. Li Marja Talikka Sylvain Gubian Colette vom Berg Florian Martin Manuel C. Peitsch Julia Hoeng Anze Zupanic Anze Zupanic |
author_sort |
Roman A. Li |
title |
Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish |
title_short |
Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish |
title_full |
Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish |
title_fullStr |
Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish |
title_full_unstemmed |
Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish |
title_sort |
systems toxicology approach for assessing developmental neurotoxicity in larval zebrafish |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2021-06-01 |
description |
Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context. |
topic |
systems toxicology zebrafish developmental neurotoxicity klf8 rb1 tp53 |
url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.652632/full |
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