Synthetic progestins activate human and zebrafish nuclear progesterone receptor in vitro

Abstract : As compared to (xeno-)estrogens, natural and synthetic ligands of the progesterone receptor (PR) have been scarcely studied on aquatic organisms while the potential risk posed by environmental progestins has been recently pointed out. However, there is still a lack of data to accurately characterize the hazards posed by these compounds. In that respect, the capacity of synthetic progestins to interact with fish nuclear progesterone receptor was poorly investigated. In the present work we aimed at assessing potential endocrine disruption of these compounds towards zebrafish nPR and to compare their effects with that of human nPR to identify possible interspecies differences. Two human cell lines co-expressing either human PR (hPR) or the zebrafish PR (ZfPR) and luciferase gene, namely HELN-hPRB and U2OS-zfPR cells, were developed and characterized using promegestone (R5020) as a reference agonist ligand. R5020 induced luciferase activity in both cell lines in a concentration-dependent manner. These effects were completely blocked by co-exposing the cells with mifepristone (RU486), a potent PR antagonist. A large set of natural and synthetic progestins (25) was screened in the two cell lines. All of the compounds except the natural zebrafish progestin 17α,20β-dihydroxy-4-pregnen-3-one (DHP) activated the hPR. About half of the progestins induced a maximum effect of 100% when compared to R5020 while the other half partially induced luciferase activity. In contrast to cells expressing hPR, progestins behaved very differently with the zfPR since only five of them were active on zfPR. Interestingly, we found that DHP strongly activated zfPR but not hPR. To assess whether some progestins were partial agonists, they were coexposed with R5020. Half of them antagonized the activity induced by R5020 on hPR and are thus partial hPR agonists. All the active progestins on zfPR antagonized R5020 and are therefore partial zfPR agonists. Two new luciferase reporter cell lines were developed and characterized, providing novel information regarding the activity of a large set of progestins on the zfPR. These models allowed us to highlight major interspecies differences. These results support the need to further determine the effects of zfPR agonist progestins on PR-dependent physiological processes in order to characterize the hazards posed by progestins in fish.
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Clémentine Garoche, Selim Ait-Aissa, Nicolas Creusot, Abdelhay Boulahtouf, Patrick Balaguer, et al.. Synthetic progestins activate human and zebrafish nuclear progesterone receptor in vitro. 1st International conference on risk assessment of pharmaceuticals in the environment (ICRAPHE), Sep 2016, Paris, France. ⟨ineris-01854266⟩

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