Synthetic progestins disrupt the glial cell specific-brain aromatase expression in the developing brain of fish

Abstract : Few studies have addressed the biological effects of natural and synthetic ligands of the nuclear progesterone receptor (nPR) on fish development and reproduction, resulting in a significant lack of data to assess the hazard and risk posed by these compounds on aquatic organisms. Yet progesterone plays key roles in many vertebrates and recent data showed that some progestins are present in the aquatic environment at concentrations that can impair reproduction. In light of this context, we studied the effects of progesterone and a panel of synthetic nPR ligands on the estrogen-receptor (ER)-signaling pathway by investigating the expression of the zebrafish brain aromatase cyp19a1b gene using zebrafish-specific mechanism-based in vitro and in vivo assays. Twenty-four nPR ligands were screened on transgenic cyp19a1b-GFP zebrafish embryos to assess their potential estrogenic effect. Progesterone and its isomer dydrogesterone as well as drospirenone and all the progesterone-derived progestins had no effect on GFP expression. However, all progestins derived from 19-nortesterone induced the cyp19a1b expression in an ER- and concentration-dependent manner with EC50 ranging from the low nM to the µM range. These results show that progestins are estrogenic to fish and that early-life exposure of fish to 19-nortestosterone disrupts the ER-signaling pathway within the developing brain. The 19-nortestosterone derived progestins levonorgestrel and norethindrone were further tested in U251-MG cells transfected with any of the three zebrafish ER subtypes zfERα, zfERβ1, or zfERβ2. Progesterone had no effect on luciferase activity with either of the zfER subtypes. Norethindrone and levonorgestrel both induced luciferase activity that was blocked by co-exposing the cells with ICI 182,780. An ER competition assay showed that both progestins were unable to bind to and activate ER except at very high concentrations (10-5M), suggesting they require metabolic activation prior to elicit estrogenic activity. This study highlights the relevance of using zebrafish-specific screening assays to characterize endocrine disrupting properties of emerging contaminants and demonstrates that 19-nortestosterone derived progestins are pro-estrogenic compounds targeting radial glial cells inducing cyp19a1b expression in the developing brain of fish. Given that ER signaling is one of the very first to emerge during early-life stage development, the consequences should be further investigated.
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  • HAL Id : ineris-01854202, version 1

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Clémentine Garoche, Joel Cano-Nicolau, Jean-Marc Porcher, Olivier Kah, François Brion. Synthetic progestins disrupt the glial cell specific-brain aromatase expression in the developing brain of fish. 26. SETAC Europe annual meeting, May 2016, Nantes, France. ⟨ineris-01854202⟩

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