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

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

Nature Publishing Group

Autor: Margiotta-Casaluci, Luigi
Owen, Stewart F.
Huerta Buitrago, Belinda
Rodríguez Mozaz, Sara
Kugathas, Subramanian
Barceló i Cullerés, Damià
Rand-Weaver, Mariann
Sumpter, John P.
Resum: 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
Accés al document: http://hdl.handle.net/2072/285697
Llenguatge: eng
Editor: Nature Publishing Group
Drets: Attribution 4.0 Spain
URI Drets: http://creativecommons.org/licenses/by/4.0/es/
Matèria: Ecofisiologia
Ecophysiology
Fisiologia
Physiology
Peixos -- Ecofisiologia
Fishes -- Ecophysiology
Peixos -- Efecte dels productes químics
Fishes -- Effect of chemicals on
Títol: Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish
Tipus: info:eu-repo/semantics/article
Repositori: Recercat

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