Capturing a Comprehensive Picture of Biological Events From Adverse Outcome Pathways in the Drug Exposome

Background: The chemical part of the exposome, including drugs, may explain the increase of health effects with outcomes such as infertility, allergies, metabolic disorders, which cannot be only explained by the genetic changes. To better understand how drug exposure can impact human health, the concepts of adverse outcome pathways (AOPs) and AOP networks (AONs), which are representations of causally linked events at different biological levels leading to adverse health, could be used for drug safety assessment.Methods: To explore the action of drugs across multiple scales of the biological organization, we investigated the use of a network-based approach in the known AOP space. Considering the drugs and their associations to biological events, such as molecular initiating event and key event, a bipartite network was developed. This bipartite network was projected into a monopartite network capturing the event–event linkages. Nevertheless, such transformation of a bipartite network to a monopartite network had a huge risk of information loss. A way to solve this problem is to quantify the network reduction. We calculated two scoring systems, one measuring the uncertainty and a second one describing the loss of coverage on the developed event–event network to better investigate events from AOPs linked to drugs.Results: This AON analysis allowed us to identify biological events that are highly connected to drugs, such as events involving nuclear receptors (ER, AR, and PXR/SXR). Furthermore, we observed that the number of events involved in a linkage pattern with drugs is a key factor that influences information loss during monopartite network projection. Such scores have the potential to quantify the uncertainty of an event involved in an AON, and could be valuable for the weight of evidence assessment of AOPs. A case study related to infertility, more specifically to “decrease, male agenital distance” is presented.Conclusion: This study highlights that computational approaches based on network science may help to understand the complexity of drug health effects, with the aim to support drug safety assessment.

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Weight of Evidence Frameworks in Evaluation of Adverse Outcome Pathways

A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment ◽

10.1007/978-3-319-66084-4_15 ◽

2018 ◽

pp. 303-316 ◽

Cited By ~ 1

Author(s):

Taylor Rycroft ◽

Olivia Massey ◽

Christy M. Foran ◽

Igor Linkov

Keyword(s):

Adverse Outcome ◽

Weight Of Evidence ◽

Adverse Outcome Pathways

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AOP4EUpest: mapping of pesticides in adverse outcome pathways using a text mining tool

Bioinformatics ◽

10.1093/bioinformatics/btaa545 ◽

2020 ◽

Vol 36 (15) ◽

pp. 4379-4381 ◽

Cited By ~ 1

Author(s):

Florence Jornod ◽

Marylène Rugard ◽

Luc Tamisier ◽

Xavier Coumoul ◽

Helle R Andersen ◽

...

Keyword(s):

Adverse Outcome ◽

Experimental Studies ◽

Adverse Outcomes ◽

Vulnerable Groups ◽

Supplementary Information ◽

Human Populations ◽

Biological Organization ◽

Linear Representations ◽

Pubmed Database ◽

Adverse Outcome Pathways

Abstract Motivation Exposure to pesticides may lead to adverse health effects in human populations, in particular vulnerable groups. The main long-term health concerns are neurodevelopmental disorders, carcinogenicity as well as endocrine disruption possibly leading to reproductive and metabolic disorders. Adverse outcome pathways (AOP) consist in linear representations of mechanistic perturbations at different levels of the biological organization. Although AOPs are chemical-agnostic, they can provide a better understanding of the Mode of Action of pesticides and can support a rational identification of effect markers. Results With the increasing amount of scientific literature and the development of biological databases, investigation of putative links between pesticides, from various chemical groups and AOPs using the biological events present in the AOP-Wiki database is now feasible. To identify co-occurrence between a specific pesticide and a biological event in scientific abstracts from the PubMed database, we used an updated version of the artificial intelligence-based AOP-helpFinder tool. This allowed us to decipher multiple links between the studied substances and molecular initiating events, key events and adverse outcomes. These results were collected, structured and presented in a web application named AOP4EUpest that can support regulatory assessment of the prioritized pesticides and trigger new epidemiological and experimental studies. Availability and implementation http://www.biomedicale.parisdescartes.fr/aop4EUpest/home.php. Supplementary information Supplementary data are available at Bioinformatics online.

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Increasing Scientific Confidence in Adverse Outcome Pathways: Application of Tailored Bradford-Hill Considerations for Evaluating Weight of Evidence

Regulatory Toxicology and Pharmacology ◽

10.1016/j.yrtph.2015.04.004 ◽

2015 ◽

Vol 72 (3) ◽

pp. 514-537 ◽

Cited By ~ 106

Author(s):

Richard A. Becker ◽

Gerald T. Ankley ◽

Stephen W. Edwards ◽

Sean W. Kennedy ◽

Igor Linkov ◽

...

Keyword(s):

Adverse Outcome ◽

Weight Of Evidence ◽

Bradford Hill ◽

Adverse Outcome Pathways

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Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

Particle and Fibre Toxicology ◽

10.1186/s12989-020-00344-4 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 10

Author(s):

Sabina Halappanavar ◽

Sybille van den Brule ◽

Penny Nymark ◽

Laurent Gaté ◽

Carole Seidel ◽

...

Keyword(s):

Safety Assessment ◽

Adverse Outcome ◽

Advanced Materials ◽

Testing Strategies ◽

Adverse Outcome Pathways

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Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death

The Science of The Total Environment ◽

10.1016/j.scitotenv.2017.01.113 ◽

2017 ◽

Vol 584-585 ◽

pp. 751-775 ◽

Cited By ~ 20

Author(s):

Carlie A. LaLone ◽

Daniel L. Villeneuve ◽

Judy Wu-Smart ◽

Rebecca Y. Milsk ◽

Keith Sappington ◽

...

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Honey Bees ◽

Adverse Outcome ◽

Weight Of Evidence ◽

Nicotinic Acetylcholine ◽

Evidence Evaluation ◽

Adverse Outcome Pathways

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An Adverse Outcome Pathway Linking Organohalogen Exposure to Mitochondrial Disease

Journal of Toxicology ◽

10.1155/2019/9246495 ◽

2019 ◽

Vol 2019 ◽

pp. 1-24

Author(s):

Brooke McMinn ◽

Alicia L. Duval ◽

Christie M. Sayes

Keyword(s):

Mitochondrial Disease ◽

Mitochondrial Membrane ◽

Adverse Outcome ◽

Health Hazard ◽

Reactive Oxygen Species Generation ◽

Atp Depletion ◽

Weight Of Evidence ◽

Adverse Outcome Pathway ◽

Biological Organization ◽

Adverse Health Effects

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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