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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| Format: | Article |
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Wiley
2019-01-01
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| Series: | Journal of Toxicology |
| Online Access: | http://dx.doi.org/10.1155/2019/9246495 |
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| author | Brooke McMinn Alicia L. Duval Christie M. Sayes |
| author_facet | Brooke McMinn Alicia L. Duval Christie M. Sayes |
| author_sort | Brooke McMinn |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-e9f1418b4cd24b1483b1a83af8f37a6d |
| institution | Kabale University |
| issn | 1687-8191 1687-8205 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
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| series | Journal of Toxicology |
| spelling | doaj-art-e9f1418b4cd24b1483b1a83af8f37a6d2025-02-03T05:50:59ZengWileyJournal of Toxicology1687-81911687-82052019-01-01201910.1155/2019/92464959246495An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial DiseaseBrooke McMinn0Alicia L. Duval1Christie M. Sayes2Department of Environmental Science, Baylor University, One Bear Place # 97266, Waco, TX 76798-7266, USADepartment of Environmental Science, Baylor University, One Bear Place # 97266, Waco, TX 76798-7266, USADepartment of Environmental Science, Baylor University, One Bear Place # 97266, Waco, TX 76798-7266, USAAdverse 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.http://dx.doi.org/10.1155/2019/9246495 |
| spellingShingle | Brooke McMinn Alicia L. Duval Christie M. Sayes An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease Journal of Toxicology |
| 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 |
| url | http://dx.doi.org/10.1155/2019/9246495 |
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