TY - JOUR
T1 - Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish
AU - Margiotta-Casaluci, Luigi
AU - Owen, Stewart F.
AU - Huerta, Belinda
AU - Rodríguez-Mozaz, Sara
AU - Kugathas, Subramanian
AU - Barceló, Damià
AU - Rand-Weaver, Mariann
AU - Sumpter, John P.
N1 - Funding Information:
This work was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) Research Grant (BB/100646X/1), co-funded by the AstraZeneca Global Safety, Health and Environment research programme, to JPS and MR-W supporting LM-C.
PY - 2016/2/26
Y1 - 2016/2/26
N2 - 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-species 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.
AB - 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-species 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.
UR - http://www.scopus.com/inward/record.url?scp=84959378859&partnerID=8YFLogxK
U2 - 10.1038/srep21978
DO - 10.1038/srep21978
M3 - Article
C2 - 26917256
AN - SCOPUS:84959378859
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 21978
ER -