A transcriptomic approach for evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture.
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Pennings, Jeroen L A
van Ravenzwaay, Bennard
Rietjens, Ivonne M C M
Piersma, Aldert H
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TitleA transcriptomic approach for evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture.
Published inToxicology 2017; 392:96-105
PubliekssamenvattingWe evaluated the effect of six azoles on embryonic development in the rat whole embryo culture (WEC). Using the total morphological scoring system (TMS), we calculated the ID10concentration (effective dose for 10% decrease in TMS). For evaluating gene specific responses, we combined previously and newly collected transcriptomics data of rat WEC exposed to a total of twelve azoles at their ID10for 4h. Results revealed shared expressions responses in genes involved in the retinoic acid (RA) and sterol biosynthesis pathways, which are respectively representatives of developmental toxicity and targeted fungicidal action of the azoles. Azoles with more pronounced effects on the regulation of RA-associated genes were generally characterized as more potent embryotoxicants. Overall, compounds with strong sterol biosynthesis related responses and low RA related responses were considered as more favourable candidates, as they specifically regulated genes related to a desired target response. Among the identified sterol associated genes, we detected that methylsterol monooxygenase 1 (Msmo1) was more sensitively induced compared to Cyp51, a classical biomarker of this pathway. Therefore, we suggest that Msmo1 could be a better biomarker for screening the fungicidal value of azoles. In summary, we conclude that the embryonic regulation of RA and sterol metabolic pathways could be indicators for ranking azoles as embryotoxicants and determining their drug efficacy.
- Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis.
- Authors: Dimopoulou M, Verhoef A, Pennings JLA, van Ravenzwaay B, Rietjens IMCM, Piersma AH
- Issue date: 2017 May 1
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- Issue date: 2018 Apr
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- Transcriptomics analysis of retinoic acid embryotoxicity in rat postimplantation whole embryo culture.
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