Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion
Integrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the ad...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Current Research in Toxicology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X23000221 |
| _version_ | 1797397522105237504 |
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| author | Alun Myden Susanne A. Stalford Adrian Fowkes Emma White Akihiko Hirose Takashi Yamada |
| author_facet | Alun Myden Susanne A. Stalford Adrian Fowkes Emma White Akihiko Hirose Takashi Yamada |
| author_sort | Alun Myden |
| collection | DOAJ |
| description | Integrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the adverse outcome pathway (AOP) concept. To utilise AOPs fully in this context, a sufficient number of pathways need to be present to develop fit for purpose IATAs. In silico approaches can support IATA through the provision of predictive models and also through data integration to derive conclusions using a weight-of-evidence approach. To examine the maturity of a developmental and reproductive toxicity (DART) AOP network derived from the literature, an assessment of its coverage was performed against a novel toxicity dataset. A dataset of diverse compounds, with data from studies performed according to OECD test guidelines TG-421 and TG-422, was curated to test the performance of an in silico model based on the AOP network – allowing for the identification of knowledge gaps within the network. One such gap in the knowledge was filled through the development of an AOP stemming from the molecular initiating event ‘glutathione reaction with an electrophile’ leading to male fertility toxicity. The creation of the AOP provided the mechanistic rationale for the curation of pre-existing structural alerts to relevant key events. Integrating this new knowledge and associated alerts into the DART AOP network will improve its coverage of DART-relevant chemical space. In addition, broadening the coverage of AOPs for a particular regulatory endpoint may facilitate the development of, and confidence in, robust IATAs. |
| first_indexed | 2024-03-09T01:11:13Z |
| format | Article |
| id | doaj.art-09e1b1b6506a456faa670334abe7c064 |
| institution | Directory Open Access Journal |
| issn | 2666-027X |
| language | English |
| last_indexed | 2024-03-09T01:11:13Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Toxicology |
| spelling | doaj.art-09e1b1b6506a456faa670334abe7c0642023-12-11T04:17:13ZengElsevierCurrent Research in Toxicology2666-027X2023-01-015100124Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletionAlun Myden0Susanne A. Stalford1Adrian Fowkes2Emma White3Akihiko Hirose4Takashi Yamada5Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United Kingdom; Corresponding author.Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United KingdomLhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United KingdomLhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United KingdomDivision of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki 210-9501, JapanDivision of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki 210-9501, JapanIntegrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the adverse outcome pathway (AOP) concept. To utilise AOPs fully in this context, a sufficient number of pathways need to be present to develop fit for purpose IATAs. In silico approaches can support IATA through the provision of predictive models and also through data integration to derive conclusions using a weight-of-evidence approach. To examine the maturity of a developmental and reproductive toxicity (DART) AOP network derived from the literature, an assessment of its coverage was performed against a novel toxicity dataset. A dataset of diverse compounds, with data from studies performed according to OECD test guidelines TG-421 and TG-422, was curated to test the performance of an in silico model based on the AOP network – allowing for the identification of knowledge gaps within the network. One such gap in the knowledge was filled through the development of an AOP stemming from the molecular initiating event ‘glutathione reaction with an electrophile’ leading to male fertility toxicity. The creation of the AOP provided the mechanistic rationale for the curation of pre-existing structural alerts to relevant key events. Integrating this new knowledge and associated alerts into the DART AOP network will improve its coverage of DART-relevant chemical space. In addition, broadening the coverage of AOPs for a particular regulatory endpoint may facilitate the development of, and confidence in, robust IATAs.http://www.sciencedirect.com/science/article/pii/S2666027X23000221Adverse outcome pathwayGlutathioneMale fertility toxicityStructure activity relationship |
| spellingShingle | Alun Myden Susanne A. Stalford Adrian Fowkes Emma White Akihiko Hirose Takashi Yamada Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion Current Research in Toxicology Adverse outcome pathway Glutathione Male fertility toxicity Structure activity relationship |
| title | Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion |
| title_full | Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion |
| title_fullStr | Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion |
| title_full_unstemmed | Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion |
| title_short | Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion |
| title_sort | enhancing developmental and reproductive toxicity knowledge a new aop stemming from glutathione depletion |
| topic | Adverse outcome pathway Glutathione Male fertility toxicity Structure activity relationship |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X23000221 |
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