scholarly journals The 2021 update of the EPA’s adverse outcome pathway database

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Holly M. Mortensen ◽  
Jonathan Senn ◽  
Trevor Levey ◽  
Phillip Langley ◽  
Antony J. Williams
Keyword(s):  
Adverse Outcome ◽  
Adverse Outcomes ◽  
Semantic Mapping ◽  
Adverse Outcome Pathway ◽  
Pathway Database ◽  
Protein Targets ◽  
Functional Variants ◽  
Interface Potential ◽  
Gene Data ◽  
Recent Version

AbstractThe EPA developed the Adverse Outcome Pathway Database (AOP-DB) to better characterize adverse outcomes of toxicological interest that are relevant to human health and the environment. Here we present the most recent version of the EPA Adverse Outcome Pathway Database (AOP-DB), version 2. AOP-DB v.2 introduces several substantial updates, which include automated data pulls from the AOP-Wiki 2.0, the integration of tissue-gene network data, and human AOP-gene data by population, semantic mapping and SPARQL endpoint creation, in addition to the presentation of the first publicly available AOP-DB web user interface. Potential users of the data may investigate specific molecular targets of an AOP, the relation of those gene/protein targets to other AOPs, cross-species, pathway, or disease-AOP relationships, or frequencies of AOP-related functional variants in particular populations, for example. Version updates described herein help inform new testable hypotheses about the etiology and mechanisms underlying adverse outcomes of environmental and toxicological concern.

scholarly journals sAOP: linking chemical stressors to adverse outcomes pathway networks

2019 ◽  
Author(s):  
Alejandro Aguayo-Orozco ◽  
Karine Audouze ◽  
Troels Siggaard ◽  
Robert Barouki ◽  
Søren Brunak ◽  
...  
Keyword(s):  
Decision Making ◽  
Human Health ◽  
Adverse Outcome ◽  
Adverse Outcomes ◽  
Supplementary Information ◽  
Adverse Outcome Pathway ◽  
Supplementary Data ◽  
Biological Organization ◽  
Regulatory Decision ◽  
Pathway Networks

Abstract Motivation Adverse outcome pathway (AOP) is a toxicological concept proposed to provide a mechanistic representation of biological perturbation over different layers of biological organization. Although AOPs are by definition chemical-agnostic, many chemical stressors can putatively interfere with one or several AOPs and such information would be relevant for regulatory decision-making. Results With the recent development of AOPs networks aiming to facilitate the identification of interactions among AOPs, we developed a stressor-AOP network (sAOP). Using the ‘cytotoxitiy burst’ (CTB) approach, we mapped bioactive compounds from the ToxCast data to a list of AOPs reported in AOP-Wiki database. With this analysis, a variety of relevant connections between chemicals and AOP components can be identified suggesting multiple effects not observed in the simplified ‘one-biological perturbation to one-adverse outcome’ model. The results may assist in the prioritization of chemicals to assess risk-based evaluations in the context of human health. Availability and implementation sAOP is available at http://saop.cpr.ku.dk Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Deciphering Adverse Outcome Pathway Network Linked to Bisphenol F Using Text Mining and Systems Toxicology Approaches

2019 ◽  
Vol 173 (1) ◽  
pp. 32-40 ◽  
Author(s):  
Marylène Rugard ◽  
Xavier Coumoul ◽  
Jean-Charles Carvaillo ◽  
Robert Barouki ◽  
Karine Audouze
Keyword(s):  
Text Mining ◽  
Manufacturing Industry ◽  
Adverse Outcome ◽  
Protein Complexes ◽  
Experimental Studies ◽  
Adverse Outcomes ◽  
Adverse Outcome Pathway ◽  
Pathway Network ◽  
Toxicological Effects ◽  
Bisphenol F

Abstract Bisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. To support decision making on BPF’s safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to adverse outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Over-representation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as adverse outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF, and trigger new epidemiological and experimental studies.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

scholarly journals Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

2014 ◽  
Vol 15 (5) ◽  
pp. 7651-7666 ◽  
Author(s):  
Ivanka Tsakovska ◽  
Merilin Al Sharif ◽  
Petko Alov ◽  
Antonia Diukendjieva ◽  
Elena Fioravanzo ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Mode Of Action ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway ◽  
Modelling Study

scholarly journals Prolonged Emergency Department Length of Stay as a Predictor of Adverse Outcomes in Patients with Intracranial Hemorrhage

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Erica M. Jones ◽  
Amelia K. Boehme ◽  
Aimee Aysenne ◽  
Tiffany Chang ◽  
Karen C. Albright ◽  
...  
Keyword(s):  
Emergency Department ◽  
Length Of Stay ◽  
Adverse Outcome ◽  
Independent Predictor ◽  
Adverse Outcomes ◽  
Stroke Patients ◽  
Significant Independent Predictor ◽  
Prolonged Length ◽  
Stroke Center ◽  
Shift Change

Objectives. Extended time in the emergency department (ED) has been related to adverse outcomes among stroke patients. We examined the associations of ED nursing shift change (SC) and length of stay in the ED with outcomes in patients with intracerebral hemorrhage (ICH). Methods. Data were collected on all spontaneous ICH patients admitted to our stroke center from 7/1/08–6/30/12. Outcomes (frequency of pneumonia, modified Rankin Scale (mRS) score at discharge, NIHSS score at discharge, and mortality rate) were compared based on shift change experience and length of stay (LOS) dichotomized at 5 hours after arrival. Results. Of the 162 patients included, 60 (37.0%) were present in the ED during a SC. The frequency of pneumonia was similar in the two groups. Exposure to an ED SC was not a significant independent predictor of any outcome. LOS in the ED ≥5 hours was a significant independent predictor of discharge mRS 4–6 (OR 3.638, 95% CI 1.531–8.645, and P = 0.0034) and discharge NIHSS (OR 3.049, 95% CI 1.491–6.236, and P = 0.0023) but not death. Conclusions. Our study found no association between nursing SC and adverse outcome in patients with ICH but confirms the prior finding of worsened outcome after prolonged length of stay in the ED.

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