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

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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sAOP: linking chemical stressors to adverse outcomes pathway networks

Bioinformatics ◽

10.1093/bioinformatics/btz570 ◽

2019 ◽

Cited By ~ 3

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.

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

Frontiers in Public Health ◽

10.3389/fpubh.2021.763962 ◽

2021 ◽

Vol 9 ◽

Author(s):

Qier Wu ◽

Youcef Bagdad ◽

Olivier Taboureau ◽

Karine Audouze

Keyword(s):

Health Effects ◽

Drug Safety ◽

Safety Assessment ◽

Drug Exposure ◽

Adverse Outcome ◽

Information Loss ◽

Weight Of Evidence ◽

Bipartite Network ◽

Biological Organization ◽

Adverse Outcome Pathways

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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Novel Methods and Approaches for Safety Evaluation of Nanoparticle Formulations: A Focus Towards In Vitro Models and Adverse Outcome Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.612659 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mounika Gayathri Tirumala ◽

Pratibha Anchi ◽

Susmitha Raja ◽

Mahesh Rachamalla ◽

Chandraiah Godugu

Keyword(s):

Risk Assessment ◽

Adverse Outcome ◽

Safety Concern ◽

Single Cells ◽

High Surface ◽

Adverse Outcomes ◽

Novel Methods ◽

Adverse Outcome Pathways

Nanotoxicology is an emerging field employed in the assessment of unintentional hazardous effects produced by nanoparticles (NPs) impacting human health and the environment. The nanotoxicity affects the range between induction of cellular stress and cytotoxicity. The reasons so far reported for these toxicological effects are due to their variable sizes with high surface areas, shape, charge, and physicochemical properties, which upon interaction with the biological components may influence their functioning and result in adverse outcomes (AO). Thus, understanding the risk produced by these materials now is an important safety concern for the development of nanotechnology and nanomedicine. Since the time nanotoxicology has evolved, the methods employed have been majorly relied on in vitro cell-based evaluations, while these simple methods may not predict the complexity involved in preclinical and clinical conditions concerning pharmacokinetics, organ toxicity, and toxicities evidenced through multiple cellular levels. The safety profiles of nanoscale nanomaterials and nanoformulations in the delivery of drugs and therapeutic applications are of considerable concern. In addition, the safety assessment for new nanomedicine formulas lacks regulatory standards. Though the in vivo studies are greatly needed, the end parameters used for risk assessment are not predicting the possible toxic effects produced by various nanoformulations. On the other side, due to increased restrictions on animal usage and demand for the need for high-throughput assays, there is a need for developing and exploring novel methods to evaluate NPs safety concerns. The progress made in molecular biology and the availability of several modern techniques may offer novel and innovative methods to evaluate the toxicological behavior of different NPs by using single cells, cell population, and whole organisms. This review highlights the recent novel methods developed for the evaluation of the safety impacts of NPs and attempts to solve the problems that come with risk assessment. The relevance of investigating adverse outcome pathways (AOPs) in nanotoxicology has been stressed in particular.

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Adverse outcome pathways – development and potential regulatory application

10.22239/2317-269x.01835 ◽

2021 ◽

Vol 9 (3) ◽

pp. 2-13

Author(s):

Thania Rios Rossi Lima ◽

◽

Nathália Pereira de Souza ◽

Lílian Cristina Pereira ◽

João Lauro Viana de Camargo ◽

...

Keyword(s):

Decision Making ◽

Scientific Community ◽

Adverse Outcome ◽

Adverse Outcomes ◽

Empirical Science ◽

Chemical Safety ◽

Mechanisms Of Toxicity ◽

Testing Procedures ◽

Regulatory Decision ◽

Adverse Outcome Pathways

Introduction: Over the last two decades, chemical safety assessment and regulatory toxicology have progressed from empirical science based on direct observation of apical adverse outcomes in whole organisms to a predictive practice that infers outcomes and risks on the basis of accumulated understanding of toxicological mechanisms and modes of action. Objective: To provide general concepts on how Adverse Outcome Pathways (AOPs) are developed and examples related to skin sensitization, endocrine, disruption, and mitochondrial dysfunction. Method: Narrative review based on data of the scientific literature relevant to the theme addressed and on the experience of the authors. Results: An AOP framework provides a systematic approach to organize knowledge about mechanisms of toxicity that may inform analytical domains in regulatory decision-making. AOPs are open structures that may indicate not only data gaps in the understanding of a toxicity process, but also testing procedures that will generate the necessary knowledge to fill those gaps. Every AOP should be continuously refined through the collaborative efforts of the scientific community. Depending on the amount and detail of information that is successively inserted, AOP may progress from the stage of a putative AOP to the stages of qualitative and quantitative AOPs, which are more fit-for-purpose to support regulatory decision-making. Conclusions: Continuous collaboration between AOP developers within the scientific community and the regulatory corps toward the development of this mechanistic structure will support the advancement of toxicological sciences, regardless of its immediate application for regulatory purposes.

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

Toxicological Sciences ◽

10.1093/toxsci/kfz214 ◽

2019 ◽

Vol 173 (1) ◽

pp. 32-40 ◽

Cited By ~ 7

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.

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Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Environmental Toxicology and Chemistry ◽

10.1002/etc.60 ◽

2011 ◽

pp. n/a-n/a ◽

Cited By ~ 1

Author(s):

Gerald T. Ankley ◽

Richard S. Bennett ◽

Russell J. Erickson ◽

Dale J. Hoff ◽

Michael W. Hornung ◽

...

Keyword(s):

Risk Assessment ◽

Conceptual Framework ◽

Adverse Outcome ◽

Adverse Outcome Pathways

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

Journal of Critical Care Medicine ◽

10.1155/2015/526319 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 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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