A comparison of the embryonic stem cell test and whole embryo culture assay combined with the BeWo placental passage model for predicting the embryotoxicity of azoles
| Autor: | Dimopoulou, Myrto, Verhoef, Aart, Gomes, Caroline A, van Dongen, Catharina W, Rietjens, Ivonne M C M, Piersma, Aldert H, van Ravenzwaay, Bennard, Sub RIVM, dIRAS RA-1 |
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| Přispěvatelé: | Sub RIVM, dIRAS RA-1 |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Azoles Placenta Mammalian/drug effects Retinoic acid Developmental toxicity Developmental/drug effects 010501 environmental sciences Toxicology 01 natural sciences Toxicology Postdoc Mixed Function Oxygenases Embryo Culture Techniques chemistry.chemical_compound Sterol 14-Demethylase Alcohol Oxidoreductases/genetics Mice Pregnancy Myocytes Cardiac Sterol 14-Demethylase/genetics Placenta/drug effects Gene Expression Regulation Developmental Cell Differentiation Mouse Embryonic Stem Cells General Medicine Retinoic Acid 4-Hydroxylase Cell biology Teratogens Embryo Mouse Embryonic Stem Cells/drug effects Whole embryo culture Embryotoxicity Biological Assay Female Mixed Function Oxygenases/genetics Drug Myocytes Cardiac/drug effects Toxicity Tests/methods Azoles/toxicity Embryo Mammalian/drug effects Placental transfer Risk Assessment Cell Line Dose-Response Relationship 03 medical and health sciences Stem cell test In vivo Toxicity Tests Animals Humans Mode of action Toxicologie 0105 earth and related environmental sciences VLAG Myocytes Dose-Response Relationship Drug Gene Expression Regulation Developmental/drug effects Retinoic Acid 4-Hydroxylase/genetics Reproducibility of Results Embryo culture Biological Transport Toxicologie Postdoc Embryo Mammalian Embryonic stem cell In vitro Teratogens/toxicity Alcohol Oxidoreductases Kinetics 030104 developmental biology Cardiac/drug effects chemistry Gene Expression Regulation Cell culture Cell Differentiation/drug effects Biomarkers |
| Zdroj: | Toxicology Letters, 286, 10-21 Toxicology Letters, 286, 10. Elsevier Ireland Ltd. Toxicology Letters 286 (2018) |
| ISSN: | 0378-4274 |
| Popis: | In the present study, we show the value of combining toxico-dynamic and -kinetic in vitro approaches for embryotoxicity testing of azoles. Both the whole embryo culture (WEC) and the embryonic stem cells test (EST) predicted the in vivo potency ranking of twelve tested azoles with moderate accuracy. Combining these results with relative placental transfer rates (Papp values) as determined in the BeWo cell culture model, increased the predictability of both WEC and EST, with R2 values increasing from 0.51 to 0.87 and from 0.35 to 0.60, respectively. The comparison of these in vitro systems correlated well (R2 = 0.67), correctly identifying the in vivo strong and weak embryotoxicants. Evaluating also specific gene responses related with the retinoic acid and sterol biosynthesis pathways, which represent the toxicological and fungicidal mode of action of azoles respectively in the WEC and EST, we observed that the differential regulation of Dhrs3 and Msmo1 reached higher magnitudes in both systems compared to Cyp26a1 and Cyp51. Establishing sensitive biomarkers across the in vitro systems for studying the underlying mechanism of action of chemicals, such as azoles, is valuable for comparing alternative in vitro models and for improving insight in the mechanism of developmental toxicity of chemicals. |
| Databáze: | OpenAIRE |
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