Adverse Outcome Pathway Networks and the AOP Knowledgebase Stephen - PowerPoint PPT Presentation

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

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

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

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

AOP Wiki Collaborative development of AOP descriptions & evidence Effectopedia http://aopkb.org/ AOP Xplorer Detailed development of structured & computational Visualize attribute AOPs networks to discover & https://aopwiki.org/ explore AOPs in a broader context https://www.effectopedia.org/ Intermediate Effects DB Put AOP-KB e.AOP.portal chemical-related AOP components in a regulatory context Third party Applications, plugins AOP-XML

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

Carole Yauk – https://aopwiki.org/aops/15 Yauk et al., Environ Mol Mutagen (2015) 56 :724-50. doi: 10.1002/em.21954.

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

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).

Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations Organism Cellular Molecular Heritable Insufficient or DNA, mutations in incorrect DNA Alkylation offspring, repair Increase Mutations, Increase Cataia Ives https://aopwiki.org/aops/15

Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations Organism Molecular Cellular Heritable Insufficient or DNA, mutations in incorrect DNA Alkylation offspring, repair Increase Process: DNA alkyla0on Process: dna repair Object: DNA Object: DNA Process: induced mutation Ac0on: increased Ac0on: func0onal change Object: DNA Context: eukaryo0c cell Context: eukaryotic cell Ac0on: increased Context: Mutations, Increase Process: induced muta0on Object: DNA Ac0on: increased Context: eukaryotic cell Cataia Ives https://aopwiki.org/aops/15

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, 2016. • Currently working on instructions for authors to annotate their own AOPs in the future. Ivana Campia

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

AOP Provides Understanding & Scaffold for Data

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

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

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

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

AOP Network as Stored in the AOP-Wiki

Dan Villeneuve – https://aopwiki.org/aops/25

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

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

Factors Determining Predictivity of Early Key Events Macro- Cellular Organ Organism Population Molecular Toxicants Responses Responses Responses Responses Interactions 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

Too many AOPs, too little time …

Bell et al. (2016) Toxicol. Sci., 150 :510-520 doi:10.1093/toxsci/kfw017 Oki & Edwards (2016) Toxicology , 350–352 :49–61 doi:10.1016/j.tox.2016.04.004 Oki et al. (2016) Current Environmental Health Reports, 3(1): 53-63 doi:10.1007/s40572-016-0079-y Noffisat Oki, Shannon Bell

Accelerating AOP Development

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

OECD AOP-KB (http://aopkb.org/) Supports All Stages of Development AOP-Xplorer – http://apps.cytoscape.org/ apps/aopxplorer AOP-Wiki –https://aopwiki.org/ Effectopedia –http://effectopedia.org/

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

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