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A transcriptomic approach for evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture

Author:
Dimopoulou, Myrto, Verhoef, Aart, Pennings, Jeroen L.A., van Ravenzwaay, Bennard, Rietjens, Ivonne M.C.M., Piersma, Aldert H.
Source:
Toxicology 2017
ISSN:
0300-483X
Subject:
azoles, biochemical pathways, biomarkers, biosynthesis, developmental toxicity, drugs, embryo culture, embryogenesis, genes, mechanism of action, rats, retinoic acid, screening, sterols, transcriptomics
Abstract:
We 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 ID10 concentration (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 ID10 for 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.
Agid:
5838576