A Quantitative Source-to-Outcome Case Study To Demonstrate the Integration of Human Health and Ecological End Points Using the Aggregate Exposure Pathway and Adverse Outcome Pathway Frameworks

2019 ◽  
Vol 53 (18) ◽  
pp. 11002-11012 ◽  
Author(s):  
David E. Hines ◽  
Rory B. Conolly ◽  
Annie M. Jarabek
Keyword(s):  
Human Health ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
End Points ◽  
Exposure Pathway

scholarly journals Application of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates

2020 ◽  
Vol 66 ◽  
pp. 104855 ◽  
Author(s):  
Rebecca A. Clewell ◽  
Jeremy A. Leonard ◽  
Chantel I. Nicolas ◽  
Jerry L. Campbell ◽  
Miyoung Yoon ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Adverse Outcome ◽  
Cumulative Risk ◽  
Adverse Outcome Pathway ◽  
Exposure Pathway

Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment

2018 ◽  
Vol 29 (1-2) ◽  
pp. 190-204 ◽  
Author(s):  
Holly M. Mortensen ◽  
John Chamberlin ◽  
Bonnie Joubert ◽  
Michelle Angrish ◽  
Nisha Sipes ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Health Risk ◽  
Human Health ◽  
Health Risk Assessment ◽  
Adverse Outcome ◽  
Human Health Risk ◽  
Human Health Risk Assessment ◽  
Adverse Outcome Pathway

scholarly journals Example of Adverse Outcome Pathway Concept Enabling Genome-to-Phenome Discovery in Toxicology

2020 ◽  
Vol 60 (2) ◽  
pp. 375-384 ◽  
Author(s):  
Kurt A Gust ◽  
Qing Ji ◽  
Xiao Luo
Keyword(s):  
Biological Sciences ◽  
Weight Loss ◽  
Body Weight ◽  
Amino Acid ◽  
Adverse Outcome ◽  
Body Weight Loss ◽  
Energy Budgets ◽  
Adverse Outcome Pathway ◽  
Biological Organization

Synopsis The following article represents a mini-review of an intensive 10-year progression of genome-to-phenome (G2P) discovery guided by the adverse outcome pathway (AOP) concept. This example is presented as a means to stimulate crossover of this toxicological concept to enhance G2P discovery within the broader biological sciences community. The case study demonstrates the benefits of the AOP approach for establishing causal linkages across multiple levels of biological organization ultimately linking molecular initiation (often at the genomic scale) to organism-level phenotypes of interest. The case study summarizes a US military effort to identify the mechanism(s) underlying toxicological phenotypes of lethargy and weight loss in response to nitroaromatic munitions exposures, such as 2,4,6-trinitrotoluene. Initial key discoveries are described including the toxicogenomic results that nitrotoluene exposures inhibited expression within the peroxisome proliferator activated receptor α (PPARα) pathway. We channeled the AOP concept to test the hypothesis that inhibition of PPARα signaling in nitrotoluene exposures impacted lipid metabolic processes, thus affecting systemic energy budgets, ultimately resulting in body weight loss. Results from a series of transcriptomic, proteomic, lipidomic, in vitro PPARα nuclear signaling, and PPARα knock-out investigations ultimately supported various facets of this hypothesis. Given these results, we next proceeded to develop a formalized AOP description of PPARα antagonism leading to body weight loss. This AOP was refined through intensive literature review and polished through multiple rounds of peer-review leading to final international acceptance as an Organisation for Economic Cooperation and Development-approved AOP. Briefly, that AOP identifies PPARα antagonist binding as the molecular initiating event (MIE) leading to a series of key events including inhibition of nuclear transactivation for genes controlling lipid metabolism and ketogenesis, inhibition of fatty acid beta-oxidation and ketogenesis dynamics, negative energy budget, and ultimately the adverse outcome (AO) of body-weight loss. Given that the PPARα antagonism MIE represented a reliable indicator of AO progression within the pathway, a phylogenetic analysis was conducted which indicated that PPARα amino acid relatedness generally tracked species relatedness. Additionally, PPARα amino acid relatedness analysis using the Sequence Alignment to Predict Across Species Susceptibility predicted susceptibility to the MIE across vertebrates providing context for AOP extrapolation across species. Overall, we hope this illustrative example of how the AOP concept has benefited toxicology sows a seed within the broader biological sciences community to repurpose the concept to facilitate enhanced G2P discovery in biology.

scholarly journals Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro: A Case Study with Cyproconazole

2018 ◽  
Vol 31 (8) ◽  
pp. 784-798 ◽  
Author(s):  
Claudia Luckert ◽  
Albert Braeuning ◽  
Georges de Sousa ◽  
Sigrid Durinck ◽  
Efrosini S. Katsanou ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway

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.

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