Craniofacial morphogenesis is affected in rodents by a number of clinical or agrochemical azole fungicides. The hypothesized mode of action of azoles includes abnormal neural crest cell specification and migration from hindbrain to the embryonic branchial region due to retinoic acid (RA) excess. Moreover, the additive effects after the multiple exposure to triazole fungicides account for a common mode of action. In analogy to their antifungal mode of action and hepatic side effects (inhibition of CYP isozymes), the proposed molecular initiating event for azole teratogenicity is the inhibition of embryonic CYP26 isozymes which are key proteins in RA catabolism. Experiments performed on postimplantation rat whole embryo cultures show that all tested azoles are teratogenic at micromolar concentrations, but characterized by different potencies (flusilazole=imazalil=ketoconazole>triadimefon=triadimenol>cyproconazole>tebuconazole>fluconazole). Molecular docking of eight azoles has been performed on CYP26a1, CYP26b1 and CYP26c1 isozymes, which play different roles in their teratogenic outcomes. Different affinities, consistent with the different azole teratogenic profiles and potencies, have been computed, confirming this hypothesis.

Comparison of teratogenic potency of azoles using in silico and in vitro methods / E. Menegola, L. Palazzolo, A. Moretto, M. Battistoni, F. Metruccio, U. Guerrini, F. Di Renzo, I. Eberini. - In: TOXICOLOGY LETTERS. - ISSN 0378-4274. - 258:Supplement(2016 Sep 16), pp. P20-002.S294-P20-002.S294. ((Intervento presentato al 52. convegno Annual congress of the European Society of Toxicology (EUROTOX) : 04th-07th September tenutosi a Seville (Spain) nel 2016 [10.1016/j.toxlet.2016.06.2021].

Comparison of teratogenic potency of azoles using in silico and in vitro methods

E. Menegola
Primo
;
L. Palazzolo
Secondo
;
A. Moretto;M. Battistoni;U. Guerrini;F. Di Renzo
Penultimo
;
I. Eberini
Ultimo
2016-09-16

Abstract

Craniofacial morphogenesis is affected in rodents by a number of clinical or agrochemical azole fungicides. The hypothesized mode of action of azoles includes abnormal neural crest cell specification and migration from hindbrain to the embryonic branchial region due to retinoic acid (RA) excess. Moreover, the additive effects after the multiple exposure to triazole fungicides account for a common mode of action. In analogy to their antifungal mode of action and hepatic side effects (inhibition of CYP isozymes), the proposed molecular initiating event for azole teratogenicity is the inhibition of embryonic CYP26 isozymes which are key proteins in RA catabolism. Experiments performed on postimplantation rat whole embryo cultures show that all tested azoles are teratogenic at micromolar concentrations, but characterized by different potencies (flusilazole=imazalil=ketoconazole>triadimefon=triadimenol>cyproconazole>tebuconazole>fluconazole). Molecular docking of eight azoles has been performed on CYP26a1, CYP26b1 and CYP26c1 isozymes, which play different roles in their teratogenic outcomes. Different affinities, consistent with the different azole teratogenic profiles and potencies, have been computed, confirming this hypothesis.
Settore BIO/06 - Anatomia Comparata e Citologia
European Society of Toxicology (EUROTOX)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/464987
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