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An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease

Adverse outcome pathways (AOPs) are pragmatic tools in human health hazard characterization and risk assessment. As such, one of the main goals of AOP development is to provide a clear, progressive, and linear mechanistic representation of pertinent toxicological key events (KEs) occurring along the...

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Autores principales: McMinn, Brooke, Duval, Alicia L., Sayes, Christie M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463576/
https://www.ncbi.nlm.nih.gov/pubmed/31057609
http://dx.doi.org/10.1155/2019/9246495
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author McMinn, Brooke
Duval, Alicia L.
Sayes, Christie M.
author_facet McMinn, Brooke
Duval, Alicia L.
Sayes, Christie M.
author_sort McMinn, Brooke
collection PubMed
description Adverse outcome pathways (AOPs) are pragmatic tools in human health hazard characterization and risk assessment. As such, one of the main goals of AOP development is to provide a clear, progressive, and linear mechanistic representation of pertinent toxicological key events (KEs) occurring along the different levels of biological organization. Here, we present an AOP framework that depicts how exposure to organohalogens can lead to mitochondrial disease. Organohalogens are disinfectant by-products (DBPs) found in our drinking water. Chloroform, trichloroacetic acid, and trichlorophenol were selected to represent specific types of organohalogens for the development of this AOP. Although each of these compounds contains chlorine atoms, they differ in aromaticity and solubility, which have a significant impact on their potency. This AOP consists of two main pathways, both of which are triggered by the molecular initiating event (MIE) of excessive reactive oxygen species generation. Pathway 1 details the downstream consequences of oxidative stress, which include mitochondrial DNA damage, protein aggregation, and depolarization of the mitochondrial membrane. Pathway 2 shows the KEs that result from inadequate supply of glutathione, including calcium dysregulation and ATP depletion. Pathways 1 and 2 converge at a common KE: opening of the mitochondrial membrane transition pore (mPTP). This leads to the release of cytochrome c, caspase activation, apoptosis, and mitochondrial disease. This AOP was developed according to the Organisation for Economic Co-operation and Development guidance, including critical consideration of the Bradford Hill criteria for Weight of Evidence assessment and key questions for evaluating confidence. The presented AOP is expected to serve as the basis for designing new toxicological tests as well as the characterization of novel biomarkers for disinfectant by-product exposure and adverse health effects.
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spelling pubmed-64635762019-05-05 An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease McMinn, Brooke Duval, Alicia L. Sayes, Christie M. J Toxicol Research Article Adverse outcome pathways (AOPs) are pragmatic tools in human health hazard characterization and risk assessment. As such, one of the main goals of AOP development is to provide a clear, progressive, and linear mechanistic representation of pertinent toxicological key events (KEs) occurring along the different levels of biological organization. Here, we present an AOP framework that depicts how exposure to organohalogens can lead to mitochondrial disease. Organohalogens are disinfectant by-products (DBPs) found in our drinking water. Chloroform, trichloroacetic acid, and trichlorophenol were selected to represent specific types of organohalogens for the development of this AOP. Although each of these compounds contains chlorine atoms, they differ in aromaticity and solubility, which have a significant impact on their potency. This AOP consists of two main pathways, both of which are triggered by the molecular initiating event (MIE) of excessive reactive oxygen species generation. Pathway 1 details the downstream consequences of oxidative stress, which include mitochondrial DNA damage, protein aggregation, and depolarization of the mitochondrial membrane. Pathway 2 shows the KEs that result from inadequate supply of glutathione, including calcium dysregulation and ATP depletion. Pathways 1 and 2 converge at a common KE: opening of the mitochondrial membrane transition pore (mPTP). This leads to the release of cytochrome c, caspase activation, apoptosis, and mitochondrial disease. This AOP was developed according to the Organisation for Economic Co-operation and Development guidance, including critical consideration of the Bradford Hill criteria for Weight of Evidence assessment and key questions for evaluating confidence. The presented AOP is expected to serve as the basis for designing new toxicological tests as well as the characterization of novel biomarkers for disinfectant by-product exposure and adverse health effects. Hindawi 2019-04-01 /pmc/articles/PMC6463576/ /pubmed/31057609 http://dx.doi.org/10.1155/2019/9246495 Text en Copyright © 2019 Brooke McMinn et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
McMinn, Brooke
Duval, Alicia L.
Sayes, Christie M.
An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title_full An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title_fullStr An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title_full_unstemmed An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title_short An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease
title_sort adverse outcome pathway linking organohalogen exposure to mitochondrial disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463576/
https://www.ncbi.nlm.nih.gov/pubmed/31057609
http://dx.doi.org/10.1155/2019/9246495
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