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Ex vivo assessment of testicular toxicity induced by carbendazim and iprodione, alone or in a mixture

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Cédric Pisani 1, Sébastien Voisin 2, Karim Arafah 2, Philippe Durand 3,4, Marie-Hélène Perrard 5, Marie-Roberte Guichaoua 6, Philippe Bulet 2,7 and Odette Prat 1
1 CEA, Direction de la Recherche Fondamentale, BIAM-Marcoule, Bagnols-sur-Cèze, France
2 Plateforme BioPark d’Archamps, Archamps Technopole, Saint Julien en Genevois, France
3 IGFL, UMR 5242 CNRS INRA Ecole Normale Supérieure de Lyon, Lyon, France
4 Current address: Kallistem, SAS, ENS, Lyon, France
5 INSERM U1208, Stem Cell and Brain Research Institute, Université Lyon 1, Bron, France
6 IMBE, UMR CNRS 7263 / IRD 237, Aix-Marseille Université (AMU), Marseille, France
7 Université Grenoble Alpes, Institut Albert Bonniot, Inserm 1209, CNRS UMR5309, Equipe Immunologie Analytique des Pathologies Chroniques, Grenoble, France

Summary

To measure the testicular toxicity of two fungicides (carbendazim and iprodione), alone or in a mixture, we used a rat ex vivo model of seminiferous tubules, greatly reducing the number of rodents used, in accordance with the 3R rule (Replacement, Reduction, and Refinement). This model allows the representation of puberty, a critical life period with regard to endocrine disruptors. The cellular modifications were followed for three weeks through transcriptomic and proteomic profiling analysis. A quantitative and comparative method was developed to estimate how known pathways were disturbed by each substance. This pathway-driven analysis revealed a strong alteration of steroidogenesis and an impairment of meiosis in all cases, albeit the initial molecular events were different for both substances. The ex vivo cytogenetic analysis confirmed that both fungicides alter the course of the first meiotic prophase. In addition, the mixture of both substances triggered effects greater than the sum of their cumulative effects and compromised future sperm motility after a shorter time of exposure compared with the fungicides tested separately. The alliance of an ex vivo culture with omics strategies complemented with a physiological examination is a powerful combination of tools for testing substances, separately or in a mixture, for their testicular toxicity. In particular, proteomics allowed the iden­tification of systematically differentially expressed proteins in the secretomes of exposed cultures, such as FUCO and PEBP1, two proteins linked with the motility and fertilizing ability of spermatozoa, respectively. These proteins may be potential biomarkers of testicular dysfunction and infertility.

 

Keywords: pesticides, toxicogenomics, spermatogenesis, endocrine disruption, biomarker

 

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ALTEX 33(4), 2016: 393-413

doi: 10.14573/altex.1601253


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