Azole pharmaceuticals induce germinal vesicle breakdown (GVBD) in preovulatory oocytes of zebrafish ( Danio rerio ): an
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RESEARCH ARTICLE
Azole pharmaceuticals induce germinal vesicle breakdown (GVBD) in preovulatory oocytes of zebrafish (Danio rerio): an in vitro study Pancharatna A. Katti 1 & Basavaraj B. Goundadkar 1 Received: 23 December 2019 / Accepted: 2 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Azoles, the antifungal pharmaceuticals are emerging as a new class of water contaminants with a potential to influence the endocrine physiology of surrounding aquatic fauna. In this study, we made an attempt to assess the relative efficacy of widely used azoles belonging to two subclasses, i.e., (i) triazoles (letrozole, fluconazole, itraconazole) and (ii) imidazoles (ketaconazole, ornidazole, clotrimazole), on the onset of germinal vesicle breakdown (GVBD) (an initial step in the final maturation of oocytes) in fully grown preovulatory oocytes of zebrafish (Danio rerio) using an in vitro model. Oocytes (> 650 μm) isolated manually from gravid ovaries were exposed to (i) 0.01 and/or 0.1, 1.0, 5.0, 10, 15, and 20 ng/ml and (ii) 1.0, 2.0, 3.0, 4.0, and 5.0 μg/ml of drugs. Zebrafish Ringer’s solution (vehicle) and 0.01% ethyl alcohol (solvent) were used as negative controls. 17α, 20 βDihydroxy-4-pregnen-3-one (17α-DHP) and diethylstibestrol (DES), potent inducers of GVBD in fish, were used as positive controls. GVBD was scored hourly from 0–6 h. In negative controls, there were no indications of GVBD even at the 6th hour, while in 17α-DHP- and DES-exposed oocytes, GVBD was initiated from the 1st hour, reaching 80% and 76% respectively at the 6th hour. Among azoles, letrozole induced GVBD in 73–85%, fluconazole (30–33%), itraconazole (23–33%), ketaconazole (46– 53%), ornidazole (36–40%), and clotrimazole (30–33%) of oocytes. These results suggest that azole pharmaceuticals induce GVBD in fish oocytes that may be attributed to their variable degree of cytochrome P450 enzyme inhibitor activity. Keywords Azoles . Anti-aromatase . Cytochrome inhibitor . GVBD . Preovulatory oocytes . Zebrafish
Introduction Azoles belong to a class of five-member nitrogen containing heterocyclic ring compounds with at least one other noncarbon atom, nitrogen, sulfur, or oxygen (Eicher and Hauptmann 2003). Azole compounds (triazoles and imidazoles) are widely used as fungicides in agriculture, as biocides in wood preservation/other products, and as antimycotic pharmaceuticals to treat infections in human and veterinary medical practices and as antiestrogens in cancer therapy (Kokil and Bhatia 2009; Egbuta et al. 2014; Linardi et al. 2017).They are designed to supress/block the synthesis of cytochrome superfamily enzymes including cytochrome Responsible editor: Philippe Garrigues * Pancharatna A. Katti [email protected] 1
Department of Zoology, Karnatak University, Dharwad 580003, India
P450 aromatase which is involved in the conversion of androgens to estrogens (Zarn et al. 2003; Trosken et al. 2004; Rime et al. 2010; Beijer 2015). In recent years, azole fungicides are emerging as a new class of water pollutants
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