Dimopoulou Myrto, Verhoef Aart, Pennings Jeroen L A, van Ravenzwaay Bennard, Rietjens Ivonne M C M, Piersma Aldert H
Wageningen University, Division of Toxicology, Stippeneng 4, 6708WE Wageningen, The Netherlands; National Institute of Public Health and the Environment (RIVM), 3720BA Bilthoven, the Netherlands.
National Institute of Public Health and the Environment (RIVM), 3720BA Bilthoven, the Netherlands.
Toxicology. 2017 Dec 1;392:96-105. doi: 10.1016/j.tox.2017.09.014. Epub 2017 Sep 29.
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 ID 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 ID 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.
