title: Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish.
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.
authors.affiliation: Brunel University London, Institute of Environment, Health and Societies, London, UB8 3PH, United Kingdom.|AstraZeneca, Global Environment, Alderley Park, Macclesfield, SK10 4TF, United Kingdom.
authors.forename: Luigi
authors.initials: L
authors.lastname: Margiotta-Casaluci
authors.affiliation: AstraZeneca, Global Environment, Alderley Park, Macclesfield, SK10 4TF, United Kingdom.
authors.forename: Stewart F
authors.initials: SF
authors.lastname: Owen
authors.affiliation: Catalan Institute for Water Research (ICRA), Scientific and Technological Park of the University of Girona, Girona, 17003, Spain.
authors.forename: Belinda
authors.initials: B
authors.lastname: Huerta
authors.affiliation: Catalan Institute for Water Research (ICRA), Scientific and Technological Park of the University of Girona, Girona, 17003, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Mozaz
authors.affiliation: Brunel University London, Institute of Environment, Health and Societies, London, UB8 3PH, United Kingdom.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Kugathas
authors.affiliation: Catalan Institute for Water Research (ICRA), Scientific and Technological Park of the University of Girona, Girona, 17003, Spain.|Water and Soil Quality Research Group, Department of Environmental Chemistry, IDAEA-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Damià
authors.initials: D
authors.lastname: Barceló
authors.affiliation: Brunel University London, College of Health and Life Sciences, London, UB8 3PH, United Kingdom.
authors.forename: Mariann
authors.initials: M
authors.lastname: Rand-Weaver
authors.affiliation: Brunel University London, Institute of Environment, Health and Societies, London, UB8 3PH, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Sumpter
mesh_terms: D000818:Animals; D001507:Beclomethasone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005399:Fishes / Q000378:metabolism*; D005938:Glucocorticoids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D012098:Reproduction / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D001507:Beclomethasone