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Effect of in Vivo Chronic Exposure to Clotrimazole on Zebrafish Testis Function

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Effect of in Vivo Chronic Exposure to Clotrimazole on Zebrafish Testis Function Environ Sci Pollut Res DOI 10.1007/s11356-013-1474-7 ECOTOXICOLOGY AND ENVIRONMENTAL TOXICOLOGY : NEW CONCEPTS, NEW TOOLS Effect of in vivo chronic exposure to clotrimazole on zebrafish testis function Damien Baudiffier & Nathalie Hinfray & Catherine Ravaud & Nicolas Creusot & Edith Chadili & Jean-Marc Porcher & Rüdiger W. Schulz & François Brion Received: 1 October 2012 /Accepted: 7 January 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Clotrimazole is an azole fungicide used as a human of 11-KT had increased. Morphometric analysis of the testes pharmaceutical that is known to inhibit cytochrome P450 did not show an effect of clotrimazole on meiotic (CYP) enzymatic activities, including several steroidogenic (spermatocytes) or postmeiotic (spermatids and spermatozoa) CYP. In a previous report, we showed that a 7-day exposure stages, but we observed an increase in the number of type A to clotrimazole induced the expression of genes related to spermatogonia, in agreement with an increase in mRNA levels steroidogenesis in the testes as a compensatory response, in- of piwil1, a specific molecular marker of type A spermatogo- volving the activation of the Fsh/Fshr pathway. In this context, nia. Our study demonstrated that clotrimazole is able to affect the aim of the present study was to assess the effect of an in testicular physiology and raised further concern about the vivo 21-day chronic exposure to clotrimazole (30–197 μg/L) impact of clotrimazole on reproduction. on zebrafish testis function, i.e., spermatogenesis and androgen release. The experimental design combined (1) gene transcript Keywords Clotrimazole . Endocrine disruption . levels measurements along the brain–pituitary–gonad axis, (2) Spermatogenesis . Steroidogenesis . HPG axis . Zebrafish 11-ketotestosterone (11-KT) quantification in the blood, and (3) histology of the testes, including morphometric analysis. The chronic exposure led to an induction of steroidogenesis- Introduction related genes and fshr in the testes as well as fshβ in the pituitary. Moreover, increases of the gonadosomatic index Spermatogenesis is a cyclic and tightly regulated develop- and of the volume proportion of interstitial Leydig cells were mental process during which a small number of spermato- observed in clotrimazole-exposed fish. In accordance with gonial stem cells proliferate and differentiate to form a large these histological observations, the circulating concentration number of spermatozoa (Nobrega et al. 2009; Schulz et al. 2010). Germ cells can only survive and develop in close and Responsible editor: Markus Hecker continuous relationship with Sertoli cells (Matta et al. 2002). Spermatogenesis is supported by testicular steroidogenesis, Electronic supplementary material The online version of this article a multistep process involving a cascade of enzymatic reac- (doi:10.1007/s11356-013-1474-7) contains supplementary material, which is available to authorized users. tions and producing steroid hormones (Miller 1988; Parker and Schimmer 1995) that control various physiological D. Baudiffier : N. Hinfray : C. Ravaud : N. Creusot : E. Chadili : J.-M. Porcher : F. Brion (*) functions (Miller 1988). Spermatogenesis and steroidogen- Direction des Risques Chroniques, Pôle VIVA, Unité esis are under the control of the hypothalamus–pituitary– d’écotoxicologie in vitro et in vivo, INERIS, gonad (HPG) axis: hypothalamic gonadotropin-releasing Parc Technologique Alata, BP2, hormone stimulates the release of pituitary gonadotropins, 60550 Verneuil-en-Halatte, France e-mail: [email protected] luteinizing hormone (Lh), and follicle-stimulating hormone (Fsh) that interact with their gonadal G protein-coupled R. W. Schulz receptors, Fsh receptor (Fshr) and Lh receptor. Androgenic Science Faculty, Department Biology, Division sex steroids synthesized in Leydig cells in response to Developmental Biology, Reproductive Biology Group, University of Utrecht, Padualaan 8, gonadotropic stimulation interact with the androgen receptor 3584 CH Utrecht, Netherlands expressed by Sertoli or interstitial somatic cells in the testis Environ Sci Pollut Res (Burns and Matzuk 2002; Kumar 2005; Petersen and Soder 2001;Schulzetal.2010), would be affected by 2006; Pierce and Parsons 1981). In fish, testicular expres- clotrimazole. sion sites of gonadotropin receptors overlap in Sertoli and Therefore, the present study aimed at assessing the Leydig cells (Garcia-Lopez et al. 2009; Ohta et al. 2007), effect of a prolonged in vivo exposure of fish to clo- and Fsh is a potent steroidogenic hormone (Kazeto et al. trimazole on steroidogenesis and spermatogenesis, 2008;Planasetal.1993). Follicle stimulating hormone addressing the following questions: (1) Does biological activates the Fshr on Leydig and Sertoli cells to control compensation in response to inhibiting enzymatic activ- steroidogenesis and spermatogenesis, respectively (Garcia- ities still occur after a prolonged 21-day exposure of Lopez et al. 2009, 2010; Ohta et al. 2007; Schulz et al. male fish to clotrimazole at similar concentrations as 2010). In male fish, Leydig cells produce 11-oxygenated those previously used for the 7-day exposure experi- androgens, such as 11-ketotestosterone (11-KT), which ment? (2) Does a prolonged exposure have a significant stimulates spermatogenesis (Miura et al. 1991). Sertoli cells effect on spermatogenesis? but not germ cells expressed functional receptors for both androgens and Fsh, so these cells act as a regulatory inter- face between the endocrine system and the germ cells Methods (Petersen and Soder 2006). Azole fungicides inhibit cytochrome P450 (CYP) 51, 14α- The experimental design and most of the biological analyses lanosterol demethylase, disrupting ergosterol synthesis, and have been described in a previous study (Baudiffier et al. 2012). increasing cell permeability in fungi (Georgopapadakou 1998; Henry and Sisler 1984). Several azole fungicides such as Animals and treatments ketoconazole or prochloraz also inhibit other CYP enzyme activities and have the capacity to alter gonadal steroidogen- All experiments were approved by the ethical committee of the esis and reproductive function in fish (Ankley et al. 2007; National Institute of Industrial Environment and Risks Villeneuve et al. 2007a; Zhang et al. 2008a). For example, (INERIS). Wild-type adult male zebrafish (Danio rerio,AB several azole compounds inhibit steroidogenic cytochrome strain) were obtained from our breeding units (INERIS, P450 17α-hydroxylase/17,20-lyase (Cyp17) and aromatase Verneuil-en-Halatte, France). Fish were raised on a 14:10 light/- (Cyp19) in mammals and fish (Ayub and Levell 1987; dark cycle in a recirculated water system (Tecniplast, France) at Heneweer et al. 2004; Hinfray et al. 2006b; Monod et al. 25.1±1 °C. Clotrimazole (purity≥98 %) was purchased from 1993; Vinggaard et al. 2000). Data on the occurrence and fate Sigma-Aldrich (France), and all the stock solutions were pre- of azole fungicides in the aquatic environment are scarce pared in dimethylsulfoxide (DMSO; Sigma-Aldrich). although the concentrations of several azoles such as clotri- Zebrafish were exposed to three concentrations of clotri- mazole, propiconazole, fluconazole, and tebuconazole have mazole (30, 67, and 197 μg/L) or solvent alone (DMSO, been reported at concentrations ranging from the low nano- 0.004 %v/v) for 21 days under semi-static conditions with a grams per liter to the low micrograms per liter range total renewal of the contaminated water every day (temper- (Berenzen et al. 2005; Kahle et al. 2008;Kreuger1998; ature, 25±0.7 °C; pH, 8.01±0.37; conductivity, 374.5± Peschka et al. 2007; Roberts and Thomas 2006;Thomasand 27.6 μS/cm; dissolved oxygen, 5.8±0.8 mg/L). Each con- Hilton 2004). Despite their occurrence in aquatic habitat, there dition contained 21 fish equally distributed in three replicate exist very few studies on their in vivo endocrine-disrupting 4-L glass tanks. Water samples were collected from each potencies in fish (Brown et al. 2011; Hinfray et al. 2011). condition at day 11 and day 18 at the time of water renewal In a previous short-term experiment of 7 days, we inves- (t=0 h) and 24 h later (t=24 h). tigated the effect of clotrimazole on the pituitary–gonad axis at the molecular level in adult male zebrafish. Our data Fish sampling showed that clotrimazole induced a biological compensation as revealed by increased expression of steroidogenesis- At the end of the exposure, fish were sacrificed in ice-cold related genes and protein de novo synthesis in Leydig cells water and blood (2.5 or 5 μL) was collected. The liver, while the 11-KT plasma concentration was not affected. pituitary, and brain were removed and preserved in RNA Clotrimazole exposure also induced overexpression of pitu- later™ (Sigma-Aldrich, France) until quantification of gene itary fshβ and its testicular receptor fshr. These results expression. The testes were removed, weighted, and pre- suggested that Fsh/Fshr signalling is involved in the served in RNA later™ (Sigma-Aldrich, France) or fixed in clotrimazole-induced steroidogenesis (Baudiffier et al. Bouin’s fluid for histological and immunohistochemistry 2012; Hinfray et al. 2011). Moreover, this raised the ques- experiments. Testis mass was determined to calculate the tion if also spermatogenesis, a process regulated by andro- Gonadosomatic Index (GSI, gonad wet mass/total body wet gens and Fsh (McLachlan et al. 2002; Plant and Marshall mass × 100). Environ Sci Pollut Res Measurement of actual
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