An adverse outcome pathway on the disruption of retinoic acid metabolism leading to developmental craniofacial defects
Autor: | Anna Beronius, Francesca Metruccio, Anastasia Spyropoulou, Maria Battistoni, Johanna Zilliacus, Angelo Moretto, Kyriaki Machera, Christina H.J. Veltman, Katerina Kyriakopoulou, Francesca Di Renzo, Elena Menegola, Leo T.M. van der Ven, Mirjam Luijten |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Azoles
Male 0301 basic medicine Retinoic acid Tretinoin Context (language use) Biology Toxicology Bioinformatics Risk Assessment Craniofacial Abnormalities Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Adverse Outcome Pathway Animals Humans Craniofacial Hox gene AOP Cytochrome P450 Family 26 Conazoles Adverse Outcome Pathways Neural crest Robustness (evolution) 030104 developmental biology Cyp 26 inhibition Gene Expression Regulation chemistry Neural Crest Female Biological plausibility Craniofacial defects 030217 neurology & neurosurgery |
Popis: | Adverse outcome pathway (AOP) is a conceptual framework that links a molecular initiating event (MIE) via intermediate key events (KEs) with adverse effects (adverse outcomes, AO) relevant for risk assessment, through defined KE relationships (KERs). The aim of the present work is to describe a linear AOP, supported by experimental data, for skeletal craniofacial defects as the AO. This AO was selected in view of its relative high incidence in humans and the suspected relation to chemical exposure. We focused on inhibition of CYP26, a retinoic acid (RA) metabolizing enzyme, as MIE, based on robust previously published data. Conazoles were selected as representative stressors. Intermediate KEs are RA disbalance, aberrant HOX gene expression, disrupted specification, migration, and differentiation of neural crest cells, and branchial arch dysmorphology. We described the biological basis of the postulated events and conducted weight of evidence (WoE) assessments. The biological plausibility and the overall empirical evidence were assessed as high and moderate, respectively, the latter taking into consideration the moderate evidence for concordance of dose-response and temporal relationships. Finally, the essentiality assessment of the KEs, considered as high, supported the robustness of the presented AOP. This AOP, which appears of relevance to humans, thus contributes to mechanistic underpinning of selected test methods, thereby supporting their application in integrated new approach test methodologies and strategies and application in a regulatory context. |
Databáze: | OpenAIRE |
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