Adverse Outcome Pathway Networks and the AOP Knowledgebase

Transcription

1 Adverse Outcome Pathway Networks and the AOP Knowledgebase Stephen Edwards U.S. Environmental Protection Agency Integrated Systems Toxicology Division

2 Knowledge management Evidence assembly Data organization Computational modeling AOP Networks Automatic assembly by design Basis for decision support tools Challenges and opportunities Outline

3 AOPs Connect Toxicity Pathways to Regulatory Endpoints Predictivity of measurement for AO decreases Time between exposure and effect increases

4 Factors Determining Predictivity of Early Key Events Evidence supporting the KERs between that KE and the AO Quantitative understanding of the downstream KERs Modifying factors that influence downstream KEs & KERs

5 AOP Wiki Collaborative development of AOP descriptions & evidence Effectopedia Detailed development of structured & computational AOPs AOP Xplorer Visualize attribute networks to discover & explore AOPs in a broader context Intermediate Effects DB Put chemical-related AOP components in a regulatory context e.aop.portal AOP-KB AOP-XML Third party Applications, plugins

6 Factors Determining Predictivity of Early Key Events Evidence supporting the KERs between that KE and the AO Quantitative understanding of the downstream KERs Modifying factors that influence downstream KEs & KERs

7 Carole Yauk Yauk et al., Environ Mol Mutagen (2015) 56: doi: /em

8 Ontologies that describe key events in existing AOPs AOP Stressor (MIE) (AO) AOP Components Level of Organization Molecular Cellular Tissue Organ Individual Population Context Cellular (CL) Organ (Uberon) Species (NCBI) Key Event KER Key Event KER Key Event Event Title Level of Org Event(s) Tissue Event Component Process Object Action Process GO, etc Action PATO Object GO, etc. Lyle Burgoon Cataia Ives

9 Event components-definitions Process Biological process, dynamics of the underlying biological system (e.g. receptor signaling). Ideally this represents the normal biology that is perturbed as part of the AOP not the perturbation itself. Object Biological object (e.g. specific biological receptor that is activated or inhibited). This term again represents the object only and is associated with the normal biology of the system. Action This represents the perturbation of this system described by the other two terms that results in this key event (e.g. decreased in the case the a receptor is inhibited to indicate a decrease in the signaling by that receptor).

10 Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations Molecular Cellular Organism DNA, Alkylation Insufficient or incorrect DNA repair Heritable mutations in offspring, Increase Mutations, Increase Cataia Ives

11 Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations Molecular Cellular Organism DNA, Alkylation Process: DNA alkyla0on Object: DNA Ac0on: increased Context: eukaryo0c cell Insufficient or incorrect DNA repair Process: dna repair Object: DNA Ac0on: func0onal change Context: eukaryotic cell Heritable mutations in offspring, Increase Process: induced mutation Object: DNA Ac0on: increased Context: Mutations, Increase Cataia Ives Process: induced muta0on Object: DNA Ac0on: increased Context: eukaryotic cell

12 What's new in the AOP Wiki The AOP Wiki now provides authors the ability to tag AOPs with terms from controlled vocabularies and ontologies. In order to harmonize the tagging of existing AOPs in the Wiki, we worked with authors to annotate all AOPs in the AOP-Wiki as of December 4, Currently working on instructions for authors to annotate their own AOPs in the future. Ivana Campia

13 Factors Determining Predictivity of Early Key Events Evidence supporting the KERs between that KE and the AO Quantitative understanding of the downstream KERs Modifying factors that influence downstream KEs & KERs

14 AOP Provides Understanding & Scaffold for Data

15 In-Vitro Tox21 Aromatase Inhibition Fadrozole f(x) In-Silico Petko Petkov s model Applicability domain Executable source code f(x) In-vivo Radio Immuno Assay Fathead minnow Fadrozole f(x) Pathway Elements and quantitative information Sex mixed Fadrozole Aromatase Inhibition amphioxus vertebrates Reduced E2 synthesis amphioxus vertebrates f(x) f(x) f(x) f(x) In-Vitro H295R human cells Fadrozole In-Vivo Aromatase inhibition in primary tissue Fathead minnow Fadrozole Ex-Vivo Aromatase inhibition Fathead minnow Fadrozole In-Silico Model Applicability domain Executable source code Effectopedia Hristo Aladjov molecular organelle cellular Level of Biological Organisation

16 Transformation of Dose-Response to Response- Response Key Event 1 Key Event 2 Key Event 2 Key Event 1 Concentration, [log M]

17 Factors Determining Predictivity of Early Key Events Evidence supporting the KERs between that KE and the AO Quantitative understanding of the downstream KERs Modifying factors that influence downstream KEs & KERs

18 AOP networks emerge as AOPs are entered into the AOP-Wiki Key Events Shared by Multiple AOPs AOP:30 AOP:25 AOP:23 Linkages Shared by Multiple AOPs Courtesy of Dan Villeneuve

19 AOP Network as Stored in the AOP-Wiki

20 Dan Villeneuve

21 Chemical Interactions Emerge from AOP Networks Nelms, M.D., et al. (2017) in Chemical Mixtures and Combined Chemical and Nonchemical Stressors: Exposure, Toxicity, Analysis and Risk

22 AOP Networks Incorporate Effect Modifiers Gallagher, et al., (2010) in Biomarkers in Medicine, Drug Discovery and Environmental Health

23 Factors Determining Predictivity of Early Key Events Toxicants Macro- Molecular Interactions Cellular Responses Organ Responses Organism Responses Population Responses Time & Modifying Factors (Genetics, Disease, Prior Exposures, Subsequent Exposures, Sex, Life Stage, ) Evidence supporting the KERs between that KE and the AO Quantitative understanding of the downstream KERs Modifying factors that influence downstream KEs & KERs

24 Too many AOPs, too little time

25 Bell et al. (2016) Toxicol. Sci., 150: doi: /toxsci/kfw017 Oki & Edwards (2016) Toxicology, :49 61 doi: /j.tox Oki et al. (2016) Current Environmental Health Reports, 3(1):53-63 doi: /s y Noffisat Oki, Shannon Bell

26 Accelerating AOP Development

27 AOP Wiki Collaborative development of AOP descriptions & evidence Effectopedia Detailed development of structured & computational AOPs AOP Xplorer Visualize attribute networks to discover & explore AOPs in a broader context github.com/ DataSciBurgoon/ aop_networks Intermediate Effects DB Put chemical-related AOP components in a regulatory context e.aop.portal AOP-KB AOP-XML Third party Applications, plugins

28 OECD AOP-KB ( Supports All Stages of Development AOP-Xplorer apps/aopxplorer AOP-Wiki Effectopedia

29

30

31 Environmental/Personal Exposure Monitoring Biomarkers of Exposure Bioindicators of Key Events Toxicity Pathway, NRC 2007 Apical Endpoints/ Adverse Outcomes Aggregate Exposure Pathway, Teeguarden 2016 Adverse Outcome Pathway, Ankley 2010, Villeneuve 2014 Measurement Understanding

32 Stephen Edwards Dan Villeneuve Kevin Crofton Gary Ankley Robert Kavlock Evgeniia Kazymova Cataia Ives Rose Combs Landon Grindheim Max Felsher Brendan Ferreri-Hanberry David Lyons OECD AOP-KB Working Group Clemens Wittwehr Brigitte Landesmann Ivana Campia Sharon Munn Ahmed Sayed Maurice Whelan Hristo Aladjov Magda Sachana Joop DeKnecht Acknowledgements Ed Perkins Lyle Burgoon Natalia Garcia Reyero Collaborative Partners OECD External Advisory Group on Molecular Screening & Toxicogenomics IPCS/WHO Mode of Action Steering Committee Cataia Ives Ivana Campia Clemens Wittwehr Rong-Lin Wang Lyle Burgoon Kyle Painter CSS AOP Discovery & Development Project Team OECD AOP Ontology Efforts AOP-KB Ontology Effort Stephen Edwards Cataia Ives Clemens Wittwehr Ivana Campia Brigitte Landesmann Hristo Aladjov Magda Sachana Lyle Burgoon OECD Ontology WG Richard Currie (chair) Ahmed Abdelaziz Annamaria Colacci George Fotakis Ignacio Tripodi Nikolai Georgiev Nikolov Nina Jeliazkova Olga Tcheremenskaia AOP-KB Representatives

33 Additional Information Available Online Reference Training